ArticlePDF AvailableLiterature Review

The molecular athlete: Exercise physiology from mechanisms to medals

January 2023
Physiological Reviews 103(3)

January 2023
103(3)

DOI:10.1152/physrev.00017.2022

License
CC BY 4.0

Authors:

Christoph Handschin

University of Basel

Human skeletal muscle demonstrates remarkable plasticity, adapting to numerous external stimuli including the habitual level of contractile loading. Accordingly, muscle function and exercise capacity encompass a broad spectrum, from inactive individuals with low levels of endurance and strength, to elite athletes who produce prodigious performances underpinned by pleiotropic training-induced muscular adaptations. Our current understanding of the signal integration, interpretation and output coordination of the cellular and molecular mechanisms that govern muscle plasticity across this continuum is incomplete. As such, training methods and their application to elite athletes largely rely on a "trial and error" approach with the experience and practices of successful coaches and athletes often providing the bases for "post hoc" scientific enquiry and research. This review provides a synopsis of the morphological and functional changes along with the molecular mechanisms underlying exercise adaptation to endurance- and resistance-based training. These traits are placed in the context of innate genetic and inter-individual differences in exercise capacity and performance, with special considerations given to the ageing athletes. Collectively, we provide a comprehensive overview of skeletal muscle plasticity in response to different modes of exercise, and how such adaptations translate from "molecules to medals".

From evolution to modern-day athleticism. Evolutionary selection of 5 main traits has facilitated the prolonged upright, bounding, bipedal locomotion in humans. Energetic barriers are lowered by long, spring-like tendons (in particular the Achilles tendon), the longitudinal plantar foot arch, ankle ligaments, long legs, in particular femur length, and short toes (to increase stride length and reduce vertical trajectories for better locomotor economy), thinner heart ventricles and larger cavity, increased hind limb muscle mass, and other adaptations. Skeletal strength is conferred, e.g., by larger joint areas in lower but not upper limbs to dissipate impact forces. Stabilization for bipedal movement is mediated by large erector spinae and gluteus muscles opposed to reduced forearm mass and an elongated, narrow waist and broad shoulders to facilitate counterrotation of thorax and arms, while decreased facial length helps head stabilization or an integrated system of bio-tensegrity for embedded perturbation repelling. Eccrine sweat glands, with a particular high density in the head for brain cooling, reduced body hair, dense skin vascularization, mouth breathing, and a large nasal epithelial area all contribute to thermoregulation. Finally, coevolution of locomotion and the brain resulted in expanded cerebello-cerebralcortical circuitry (for anticipation, pre-preparation, sensory integration, pre-planned multilevel compensation to deal with perturbations and destabilizations), cognitive capabilities (to recognize landmarks, long-range orientation, recognizing prey and predators, tracking and speculative tracking/anticipation), perception, fine motor control, and balance. See Refs. 1-8 for more information. Modern-day athletic peak performances most likely exceed these general evolutionary traits because of efficient training strategies and paradigms, nutrition and supplements, technological innovations, i.e., pertaining to equipment and facilities, and genetic and epigenetic predispositions. Figure created with BioRender.com, with permission.

…

Innovations that contributed to the progress in the development of world records over time (light blue for women, dark blue for men). Speed skating is one of many cases in which the progression of world records is driven by innovations (63). For example, the invention to improve ice quality (natural vs artificial ice) by refrigerated ovals (first 1958), spraying tiny droplets of water to smoothen the surface (first 1960), followed by the ice resurfacer "Zamboni" (Olympics 1960) and eventually indoor rinks all contributed to new records. Additionally, the development of gear such as tight-fit suits to improve aerodynamics and the invention of the clap skate that enabled a longer contact with the ice as well as further enhanced aerodynamics due to the crouched posture pushed the progress in world record development (http://www.speedskatingstats.com/index.php?file=records). Image on left was taken at the 1932 Winter Olympics and is from Henriksen & Steen (public domain, via Wikimedia Commons); image on right was originally posted to Flickr by adrian8_8.

…

Periodization of training for an elite athlete. Schematic representation of periodization of training along with physiological data collected during preparation for the 2016 Rio Olympic Games for a gold medal-winning female rower. BLa, blood lactate; BM, body mass. See GLOSSARY for other abbreviations. Figure created with BioRender.com, with permission.

…

Whole body adaptations that contribute specifically to higher peak power or endurance performance. Although mainly neural and muscular adaptations improve peak power, for endurance performance various organs and tissues show major changes. To maximize _ VO 2max and thereby endurance performance, changes in respiratory and cardiovascular function as well as adaptations in skeletal muscle are required. In skeletal muscle, the high mitochondrial density, elevated substrate (i.e., fatty acids and glucose) uptake and storage, myoglobin content, and increased vascularization all contribute to the elevated performance of endurance athletes. Strength training-induced adaptations include increased muscle protein synthesis (MPS) resulting in fiber hypertrophy and optimally myonuclear accretion. CD36, platelet glycoprotein 4; GLUT4, glucose transporter type 4; IMCL, intramyocellular lipids. See GLOSSARY for other abbreviations. Sport icon vectors were created by ibrandify/Freepik. Image created with BioRender.com, with permission.

…

Neuromuscular adaptation to training. The number of activated motor units, their firing frequency, as well as size and contractile properties of the muscle fibers determine total force-generating capacity. In trained individuals, neural adaptations include an increased excitatory drive that can lead to an elevated firing frequency and higher number of activated motor units. In addition, the enhanced activation of agonists, synergists, and stabilizers together with the reduced coactivation of antagonists contribute to the increased force production after training. For many of these adaptations only data in rodent models exist, and/or controversial findings in humans have been reported. NMJ, neuromuscular junction. Illustration of person was created by kjpargeter/Freepik. Image created with BioRender.com, with permission.

…

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REVIEW ARTICLE

THE MOLECULAR ATHLETE: EXERCISE

PHYSIOLOGY FROM MECHANISMS TO MEDALS

AUTHORS

Regula Furrer, John A. Hawley,

Christoph Handschin

CORRESPONDENCE

christoph.handschin@unibas.ch;

regula.furrer@unibas.ch;

john.hawley@acu.edu.au

KEY WORDS

athlete; endurance training; exercise; resistance

training; skeletal muscle

CLINICAL HIGHLIGHTS

1) During human evolution, Homo sapiens emerged as mobile hunters and gatherers, dependent on the natural avail-

ability of food. However, today’s sedentary lifestyle and overabundant food availability place a major burden on our

metabolic health and are strong drivers underpinning the dramatic rise in noncommunicable diseases.

2) A sedentary lifestyle, characterized by low maximal oxygen uptake (V

2max

), unfavorable body composition, and low

muscle strength, is an independent risk factor for many chronic diseases and a strong predictor of morbidity and mor-

tality.

3) Despite marked interindividual differences in the response to standardized exercise training, regular physical activity

lowers the risk of and confers therapeutic beneﬁts for many noncommunicable diseases.

4) Endurance- and resistance-based exercise training protocols confer distinct clinical and health-related beneﬁts and

can prevent or reverse many lifestyle-induced metabolic diseases.

5) Clinical exercise tests based on established, validated physiological outcomes are essential for the diagnosis and

subsequent monitoring of clinical conditions.

6) Investigations of elite human performance provide valuable insights into the molecular, cellular, tissue, and whole

body adaptations to extreme metabolic loading. Identiﬁcation of the mechanisms and pathways that limit exercise

capacity may ultimately aid in the identiﬁcation of novel therapeutic targets to be prescribed to patient populations.

FURRER ET AL., 2023, Physiol Rev 103: 1693–1787

Published by the American Physiological Society.

https://doi.org/10.1152/physrev.00017.2022

Downloaded from journals.physiology.org/journal/physrev at University of Basel (131.152.009.037) on May 26, 2023.

THE MOLECULAR ATHLETE: EXERCISE

PHYSIOLOGY FROM MECHANISMS TO MEDALS

Regula Furrer,

John A. Hawley,

and Christoph Handschin

Biozentrum, University of Basel, Basel, Switzerland and

Exercise and Nutrition Research Program, Mary MacKillop Institute for

Health Research, Australian Catholic University, Melbourne, Victoria, Australia

Abstract

Human skeletal muscle demonstrates remarkable plasticity, adapting to numerous external stimuli including the

habitual level of contractile loading. Accordingly, muscle function and exercise capacity encompass a broad spec-

trum, from inactive individuals with low levels of endurance and strength to elite athletes who produce prodigious

performances underpinned by pleiotropic training-induced muscular adaptations. Our current understanding of the

signal integration, interpretation, and output coordination of the cellular and molecular mechanisms that govern

muscle plasticity across this continuum is incomplete. As such, training methods and their application to elite ath-

letes largely rely on a “trial-and-error”approach, with the experience and practices of successful coaches and ath-

letes often providing the bases for “post hoc”scientiﬁc enquiry and research. This review provides a synopsis of

the morphological and functional changes along with the molecular mechanisms underlying exercise adaptation to

endurance- and resistance-based training. These traits are placed in the context of innate genetic and interindivid-

ual differences in exercise capacity and performance, with special consideration given to aging athletes.

Collectively, we provide a comprehensive overview of skeletal muscle plasticity in response to different modes of

exercise and how such adaptations translate from “molecules to medals.”

athlete; endurance training; exercise; resistance training; skeletal muscle

1. INTRODUCTION AND BACKGROUND 1693

2. OPTIMIZING TRAINING ADAPTATIONS TO... 1699

3. PHYSIOLOGICAL AND CELLULAR... 1709

4. ACUTE MOLECULAR MECHANISMS... 1722

5. CAN WE ALL BECOME GOLD MEDALISTS? 1746

6. SUMMARY, CONCLUSIONS, AND... 1754

1. INTRODUCTION AND BACKGROUND

1.1. Historical Context: The Evolution of Human

Movement

The evolution of humankind is inextricably linked to the

attainment of an upright, bipedal gait, which conferred

an advantage for locomotion, foraging, and recognition

of prey and predators (FIGURE 1). Indeed, a superior en-

durance capacity, coupled with an outstanding ability to

thermoregulate, was essential for human survival (1).

Evolutionary theory describes the mechanism of natural

selection as “survival of the ﬁttest,”the underlying sup-

position being that the “ﬁt,”as opposed to the “unﬁt,”

had a greater likelihood of survival (9). In this regard,

human skeletal muscles, limbs, and the supporting venti-

latory, cardiovascular, and metabolic systems were well

suited for upright locomotion, with economy of move-

ment for bipedal walking and running far exceeding that

of other primates (2–5). Modiﬁcations in bone and carti-

lage structure, larger limbs and joints, and spring-like

plantar arches (2,3), combined with a robust system of

perception, ﬁne motor control, and balance, were linked

to a larger brain size and associated cognitive sophisti-

cation (6–8). The evolution of the larger brain in humans

was likely facilitated by the running behavior of our

ancestors that enabled the procurement of high-pro-

tein sources of food essential for brain development

(10). Bipedal, long-distance running not only necessi-

tates complex computation to control gait, balance,

and stride but also requires large-scale cognitive

processes to recall landmarks associated with abun-

dant sources of food, recognize prey and predators,

and enable long-range orientation (10). Such adapta-

tions were supported by adequate energy availability

andoxygensupply,coupledwithahighdegreeof

metabolic regulation and ﬂexibility (6–8). The superior

human proﬁciencies as hunters, gatherers, and ulti-

mately farmers provided dietary subsistence that

enabled the evolution of our energy-costly brain. The

coevolution of skeletal muscle and associated organ

systems was characterized by progressive and itera-

tive mutual interactions (10). The behavioral lifestyle

and energy availability were determined by the

Published by the American Physiological Society.

1693

Physiol Rev 103: 1693–1787, 2023

First published January 5, 2023; doi:10.1152/physrev.00017.2022

REVIEW ARTICLE

Downloaded from journals.physiology.org/journal/physrev at University of Basel (131.152.009.037) on May 26, 2023.

periodic cycles of feasts and famines, with certain

genes evolving to regulate efﬁcient storage and utili-

zation of endogenous fuel stores, the so-called “thrifty

genes”(11,12).

In contrast to the strong evolutionary pressure to opti-

mize endurance capacity (1), the control of skeletal mus-

cle mass and strength evolved in a more restrained

manner.Althoughadequatemusclestrengthwasclosely

aligned to the prevailing environmental demands of the

day and was indispensable for survival, genes encoding

proteins that act on muscle cells to inhibit muscle cell

growth, such as myostatin, escaped negative evolu-

tionary selection. This would appear to be somewhat

of a paradox, as naturally occurring mutations in the

myostatin gene confer several beneﬁts including a

substantial increase in muscle mass in mice, dogs, cat-

tle, and even humans (13). In evolutionary terms, how-

ever, a lower muscle mass would be associated with a

reductioninbothrestingandlocomotiveenergyex-

penditure in times of food scarcity, along with the con-

servation of carbohydrate-based fuels obligatory for

preservation of brain function. Excessive muscle mass

can also lead to parturition issues (i.e., higher birth

weight and larger offspring), predisposing to evolu-

tionary disadvantages (14–16). Non-muscle-related

functions of myostatin such as tendon maintenance

and repair and injury risk could have contributed to

the positive selection of this factor (17). Finally, poten-

tial trade-offs between the promotion of fatigue resist-

ance, stamina, and endurance versus muscle mass,

strength, and power could have affected the evolutionary

process (1). Accordingly, although there exists a certain

degree of synergy, distinct control and adaptation to en-

durance- and strength-based activities have evolved in

humans.

1.2. Major Themes of This Review

The importance of physical activity for health and well-

being was recognized early in human history, dating

back to records from 3000 BCE (18). The concept of

“exercise is medicine”and the appreciation of athletic

prowess were prominent in ancient Greek and Roman

civilizations (18). Notably, the evolutionary adaption of

humans to a phenotype eminently suitable to the pursuit

of long-distance running confers important implications

for human health and athletic performance in the pres-

ent day. Unfortunately, the fundamental link between

endurance-based activities and the evolution of numer-

ous human traits has been severely diminished in mod-

ern societies in which voluntary physical activity is at an

all-time low and has recently been exacerbated by a

global pandemic (19,20). Our twenty-ﬁrst century life-

style that in many societies encompasses round-the-

clock access to energy-dense, nutrient-poor food in the

face of prolonged periods of inactivity has resulted in

the proliferation in the rates of diagnosis of several met-

abolic disease states, a rise in morbidity and mortality,

and a high ﬁnancial burden on health care systems (21).

Paradoxically, at the same time, the standard of athletic

performance at both the amateur and professional levels

continues to advance, indicating a historically unprece-

dented divergence between the physical capabilities

of the great majority of the world’s population of inactive

individuals and a small cohort of elite athletes. Indeed,

Olympic and/or world championship medalists, world re-

cord holders, and athletes achieving within 2% of world-re-

cord performance and/or world-leading performance

comprise <0.00006% (5,000 individuals) of the entire

global population of 8 billion (22). In physiological terms,

the measure of an individual’smaximaloxygenuptake

VO2max), a marker of aerobic ﬁtness, can be two- to three-

fold higher in champion endurance athletes than untrained

individuals (23). The most striking training-induced adapta-

tions contributing to such differing values are an increased

stroke volume of the heart, elevated capillary and mito-

chondrial density, and a predominance of oxidative “slow-

twitch”ﬁbers in the muscles of endurance-trained athletes

(24,25). While a high _

VO2max is a prerequisite for success-

ful endurance performance, this measure is also a better

predictor of morbidity and mortality than any other estab-

lished risk factor or biomarker (26–30). Likewise, relative

muscle mass (31–33) and strength (34–36) are parameters

with high predictive power for overall morbidity and

CLINICAL HIGHLIGHTS

1) During human evolution, Homo sapiens emerged as mobile

hunters and gatherers, dependent on the natural availability of

food. However, today’s sedentary lifestyle and overabundant

food availability place a major burden on our metabolic health

and are strong drivers underpinning the dramatic rise in non-

communicable diseases.

2) A sedentary lifestyle, characterized by low maximal oxygen

uptake ( _

VO2max ), unfavorable body composition, and low mus-

cle strength, is an independent risk factor for many chronic dis-

eases and a strong predictor of morbidity and mortality.

3) Despite marked interindividual differences in the response to

standardized exercise training, regular physical activity lowers

the risk of and confers therapeutic beneﬁts for many noncom-

municable diseases.

4) Endurance- and resistance-based exercise training protocols

confer distinct clinical and health-related beneﬁts and can pre-

vent or reverse many lifestyle-induced metabolic diseases.

5) Clinical exercise tests based on established, validated physio-

logical outcomes are essential for the diagnosis and subse-

quent monitoring of clinical conditions.

6) Investigations of elite human performance provide valuable

insights into the molecular, cellular, tissue, and whole body

adaptations to extreme metabolic loading. Identiﬁcation of the

mechanisms and pathways that limit exercise capacity may ulti-

mately aid in the identiﬁcation of novel therapeutic targets to be

prescribed to patient populations.

FURRER ET AL.

1694 Physiol Rev VOL 103 JULY 2023 www.prv.org

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mortality. Clearly, the biology underlying maximal en-

durance and resistance exercise performance confers

advantages beyond the athletic arena (9,37), and

while differences in physiological capacity between

elite athletes and sedentary individuals highlight the

huge disparity in performance capacity, they also pro-

vide insights into the roles of various organ systems

and the potential limits to human performance.

The last decade has seen major advances in unravel-

ing many of the putative mechanisms by which cellular,

molecular, and biochemical pathways are altered by

exercise (9,18,38–41). However, many of the adapta-

tions that underpin elite athletic performance remain

poorly understood. In particular, the training programs of

world-class athletes owe more to tradition and the “trial-

and-error”methods of pioneering coaches than exer-

cise biologists or sport scientists. Determining the pre-

cise role of exercise intensity, duration, and frequency in

acutely modifying various signaling cascades and coor-

dinating speciﬁc training-induced physiological adapta-

tions in athletes may offer valuable insights into some of

the critical pathways to target in order to ﬁght the battle

against inactivity-related diseases in the general popula-

tion. Not only may sedentary or “at-risk”populations

beneﬁtfrom“personalized”physical activity-based inter-

ventions to prevent and treat chronic lifestyle-induced

Stabilization:

-large erector spinae / gluteus maximus

-narrow waist, broad shoulders

-reduced forearm mass

-decreased facial length

-improved bio-tensegrity

Energetics:

-long, spring-like tendons

-plantar foot arch

-ankle ligaments

-long femur, short toes

-thinner heart ventricles, larger cavity

-increased hind limb muscle mass

Training

paradigms

and strategies

Nutrition

Supplements

Technological

innovations,

equipment,

facilities

Genetics

Epigenetics

Skeletal strength:

-large joint areas in lower,

but not upper limbs

Brain:

-expanded cerebello-

cerebralcortical circuitry

-cognitive abilities

-perception

-fine motor control and balance

Thermoregulation:

-eccrine sweat glands

-reduced body hair / fur

-mouth breathing

-dense skin vascularization

-large nasal epithelial area

FIGURE 1. From evolution to modern-day athleticism. Evolutionary selection of 5 main traits has facilitated the prolonged upright, bounding, bipedal

locomotion in humans. Energetic barriers are lowered by long, spring-like tendons (in particular the Achilles tendon), the longitudinal plantar foot arch,

ankle ligaments, long legs, in particular femur length, and short toes (to increase stride length and reduce vertical trajectories for better locomotor

economy), thinner heart ventricles and larger cavity, increased hind limb muscle mass, and other adaptations. Skeletal strength is conferred, e.g.,by

larger joint areas in lower but not upper limbs to dissipate impact forces. Stabilization for bipedal movement is mediated by large erector spinae and

gluteus muscles opposed to reduced forearm mass and an elongated, narrow waist and broad shoulders to facilitate counterrotation of thorax and

arms, while decreased facial length helps head stabilization or an integrated system of bio-tensegrity for embedded perturbation repelling. Eccrine

sweat glands, with a particular high density in the head for brain cooling, reduced body hair, dense skin vascularization, mouth breathing, and a large

nasal epithelial area all contribute to thermoregulation. Finally, coevolution of locomotion and the brain resulted in expanded cerebello-cerebralcortical

circuitry (for anticipation, pre-preparation, sensory integration, pre-planned multilevel compensation to deal with perturbations and destabilizations),

cognitive capabilities (to recognize landmarks, long-range orientation, recognizing prey and predators, tracking and speculative tracking/anticipation),

perception, ﬁne motor control, and balance. See Refs. 1–8for more information. Modern-day athletic peak performances most likely exceed these gen-

eral evolutionary traits because of efﬁcient training strategies and paradigms, nutrition and supplements, technological innovations, i.e., pertaining to

equipment and facilities, and genetic and epigeneticpredispositions. Figure created with BioRender.com, with permission.

THE MOLECULAR ATHLETE: FROM MOLECULES TO MEDALS

Physiol Rev VOL 103 JULY 2023 www.prv.org 1695

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pathologies (42–44), but mechanistic insights could

reveal targets for novel pharmacological interventions

(45–47). A better understanding of the molecular mecha-

nisms that control skeletal muscle cell plasticity may also

provide a stimulus for further improvements in elite ath-

letic performance (48,49). The fastest 100 m sprint by a

male athlete under 18 (10.31 s, Brume Okeoghene, June

17, 2021) would have won the gold medal at the 1980

Olympics, whereas Usain Bolt’s 100 m world record of

9.58 s in 2009 far exceeded predictive statistical models

at that time (50). In recent years, much scientiﬁcdebate

has been focused on the limits to the men’s marathon

(42.195 km) (51–54).Changesinboththecultureofsport

and the recognition of modern sports science research

have supported emerging activities in which “barriers”to

performance have been tackled as science-driven endeav-

ors (55). The “sub-2 hour marathon project”is an example:

the course design, ambient temperature, humidity, wind,

elevation above sea level, and comprehensive use of

pacemakers in highly choreographed formations helped

Kenyan runner Eliud Kipchoge run 1:59:40.2 in a specially

paced time trial in October 2019 (53,56). Likewise, there

have also been substantial advances in world-best per-

formances by female and masters-level athletes during

this time (57–59).

Technological innovations in sport now drive perform-

ance enhancements at the elite/professional level, as

witnessed in track and ﬁeld (60), swimming (61), cycling

(62), and speed skating (FIGURE 2)(63), with such advan-

ces ﬁltering down to amateur athletes, epitomized by the

widespread access to new footwear that improves running

economy (64,65). The use of novel technologies, such as

ﬁtness trackers, step counters in cell phones, or other wear-

ables, reveals behavioral aspects of physical activity linked

to performance outcomes at both a recreational and an

elite level. Such technologies can inform training design as

well as the impact of speciﬁc interventions on health and

performance outcomes (66). In the ﬁnal analysis, however,

progress in athletic performance is multifactorial, encom-

passing gene-environment interactions (67–70), advances

in infrastructure, training paradigms, and design (71), nutri-

tion and ergogenic aids (72,73), as well as techniques facili-

tating recovery and regeneration, social and economic

factors, prior athletic experience and physical activity back-

ground (74), and, in an unknown number of athletes,

the use of sophisticated doping strategies (FIGURE 3)(58,

75). The range in performance capabilities, the ongoing

improvements in athletic records, and the accomplishments

of older individuals at the masters level (57)inoctogenar-

ians (76)orevencentenarians(77)alludetothevastcontin-

uum of the adaptive response of muscle tissue and other

organs to a sedentary lifestyle or exercise training. In this

review, we provide a synopsis of the training strategies of

elite athletes, the bidirectional dialogue between science,

1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 2030

Year

Time (min)

5,000 m speed skating records

Women

Men

outdoor natural ice

outdoor artificial ice

indoor artificial ice

Improvement of ice quality Indoor 400-m rinks (1986)

Clap skate (1996)

Development of tight-fit suits

FIGURE 2. Innovations that contributed to the progress in the development of world records over time (light blue for women, dark blue for men).

Speed skating is one of many cases in which the progression of world records is driven by innovations (63). For example, the invention to improve ice

quality (natural vs artiﬁcial ice) by refrigerated ovals (ﬁrst 1958), spraying tiny droplets of water to smoothen the surface (ﬁrst 1960), followed by the ice

resurfacer “Zamboni”(Olympics 1960) and eventually indoor rinks all contributed to new records. Additionally, the development of gear such as tight-ﬁt

suits to improve aerodynamics and the invention of the clap skate that enabled a longer contact with the ice as well as further enhanced aerodynamics

due to the crouched posture pushed the progress in world record development (http://www.speedskatingstats.com/index.php?ﬁle=records). Image on

left was taken at the 1932 Winter Olympics and is from Henriksen & Steen (public domain, via Wikimedia Commons); image on right was originally

posted to Flickr by adrian8_8.

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1696 Physiol Rev VOL 103 JULY 2023 www.prv.org

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coaches, and athletes in training design and implementa-

tion, and the inherent and acquired differences between

world-class athletes and the general population (sect. 2).

Such concepts are linked to a discussion of the cellular,

morphological, and functional training-induced adaptations

in athletes (sect. 3). In sect. 4, our understanding of the mo-

lecular mechanisms that underpin the responses to acute

exercise is outlined, although these insights have largely

been obtained in non-athletes and/or animal models and

their translation to elite performance remains to be vali-

dated (78). In contrast to several previous reviews, we

address these issues for both endurance- and resistance-

based exercise training. Wherever possible, direct links

between training strategy, cellular adaptation, and molec-

ular mechanisms are discussed in an attempt to integrate

these features. Finally, we provide a discussion on

whether all individuals can become gold medal ath-

letes (sect. 5).

Gut microbiome

Education

Equipment & facilities

Sleep

Chronotype

Genetic predisposition

Epigenetic factors

Me Me

Coaches

Family

Team

Knowledge

Specificity

Recovery

Intensity

Time

Lifestyle

Family history

Hallmarks

of athletes

Nutrition

Ergogenic aids

Training and recovery

Injury prevention and

rehabilitation

12:

Social environment

Socio-economic status

Motivation,

willpower,

perseverance,

body perception

Prior athletic

experience

FIGURE 3. Elite athletic performance is determined by the complex interaction of intrinsic and extrinsic factors. Undisputedly, genetic predisposition,

even though poorly deﬁned and understood, contributes to athletic prowess and trainability. In fact, the “right”genes might even be a prerequisite for

elite, world-class performance. The epigenetic landscape is at least in part inherited but, in contrast to the genome, can also be inﬂuenced by behavior,

including prior athletic experience, nutrition, and other lifestyle factors. A higher-than-average motivation and drive, the willpower to overcome obstacles,

adversities, and setbacks, perseverance, and the willingness to forgo activities common for non-athletic peers are essential. These factors as wellas

daily training are shaped by body perception and prior athletic experience, including a multidisciplinary/multisport practice in youths. Most likely, nutri-

tion, ergogenic aids, and gut microbiomes mutually interact in an intimate manner, collectively affecting trainability and performance. Optimal training

strategies not only comprise personalized planning but should also integrate adequate consideration of recovery and injury prevention and, if the situa-

tion arises, rehabilitation. State-of-the-art equipment and facilities are part of a permissive environment, which is also strongly shaped by socio-economic

status and social interactions with coaches, medical and other staff, team members, parents, siblings, friends, and rivals. This network of supporting peo-

ple helps to optimize knowledge and education for proper planning and implementation. Finally, peak performance also relies on proper and personal-

ized sleep patterns, matched to the individual chronotype. The use of doping might confer performance enhancements in the short term but is linked to

long-term healthdetriments and is counter to the ethos of a fair and clean sport. Figure created with BioRender.com, with permission.

THE MOLECULAR ATHLETE: FROM MOLECULES TO MEDALS

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Volume

Intensity

Form

Specific

preparation Competitions Transition

Mesocycles / Phases

Macrocycle

Training focus

Periodization

HIIT

Blood flow

restriction

UndertrainingOptimal training

Functional overreachingOvertraining

Improvement

Decline

Exercise

Supercompensation

Time

Progression

Volume

80%

Intensity

20%

75%

20%

Zone 1

Zone 2 Zone 3

Polarized

Pyramidal

Performance

Functional overreaching

Performance

peak Training

Recovery

Nutrition

Psychology

Skill

General

preparation

Heat

training

Chrono-

exercise

Altitude

training

"Train low"

(glycogen)

Lactate/gas

exchange

thresholds

Critical power/

lactate turnpoint

Heterochronism of adaptations:

different systems, training paradigms, intensity,...

Performance

Fitness level

Fatigue

Homeostatic

disruption

Recovery

Repair

Regeneration

Adaptation

Involution

Adaptive

dissipation

Undertraining

Overrecovery

Optimal training

and recovery

Non-functional

overreaching

Underrecovery

Overtraining

Underrecovery

Increasing training load

Reduced recovery

Performance

Fitness level

Time

Performance

Fitness level

Time

Performance

Fitness level

Time

Performance

Fitness level

Time

Performance

Fitness level

Retrogression Taper

Recovery

Rest

Plateau

Maintenance

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2. OPTIMIZING TRAINING ADAPTATIONS TO

ENHANCE ATHLETIC PERFORMANCE

2.1. Principles of Exercise Training: Speciﬁcity,

Progressive Overload, Reversibility

A reductionist view of training for elite sport perform-

ance identiﬁes a range of interdependent adaptations

that enable an athlete to sustain the highest rate of

energy production for the duration of their event, opti-

mize economy of motion, defend cellular homeostasis,

and delay the onset of fatigue (9,54,55,79,80). In addi-

tion to undertaking workouts that promote these adap-

tations, an athlete needs to attain the optimal physique

and technical skills speciﬁc to their event(s). To achieve

these goals, elite athletes engage in periodized training

techniques involving long-term systematic planning for

major events and undertake prolonged, intense work-

outs fueled by optimal nutritional practices, while build-

ing resilience against illness and injury (55,81,82).

Coaches integrate a series of workouts that individually

target important competition performance traits into a

periodized training program composed of short (7–21

days) microcycles and longer (3–8 wk) mesocycles, cul-

minating in targeted competition peaks within a season

or year (macrocycle) (FIGURE 4). There is a ﬁrm belief

that the training-induced changes in skeletal muscle

resulting from the high-volume, high-intensity training

undertaken by elite athletes over several years is largely

responsible for the observed improvements in perform-

ance over time.

Elite athletes present a narrow range of values in many

morphological, biomechanical, physiological, metabolic,

perceptual, psychological, and other traits, depending on

their specialized event (83). Although there are multiple

and varied approaches to optimize adaptation to enhance

sporting performance based on a multitude of mechano-bi-

ological descriptors, the general principles of exercise train-

ing focus on three main concepts: progressive overload,

speciﬁcity, and reversibility. These principles of training can

be applied to individuals with a wide range of abilities

because the physiological response to speciﬁc stimuli is

largely predictable. However, the magnitude of response

of one athlete to a standardized training protocol may differ

substantially from that of another because of innate genetic

predisposition, environmental factors, access to training

facilities and sport science support, socio-cultural and eco-

nomic factors, and the interactions between these compo-

nents (FIGURE 3). The question of whether all individuals

respond to exercise training (i.e., demonstrate a measura-

ble improvement in a speciﬁed physiological outcome

measure) is discussed subsequently.

The principle of progressive overload states that once

an athlete has adapted to a given training load, the sub-

sequent training stimuli must be progressively increased

to perturb the homeostasis and thereby promote further

adaptation (FIGURE 4). Overload can be quantiﬁed

according to the volume of training (how much), the inten-

sity (how hard), and the frequency (how often), with the

magnitude of adaptation dependent on the interaction

between these variables, the prevailing ﬁtness level of

the athlete, and their genetic ceiling. In addition, cellular

and whole body homeostasis can be ampliﬁed by expo-

sure to altitude, heat, or altered fuel availability (55). Such

approaches are based on the premise that by imposing

greater “metabolic stress”and provoking extreme distur-

bances to homeostasis, intracellular responses in skeletal

muscle (and other tissues and organs) will be maximized,

thereby invoking superior training adaptation and

enhancing one (or more) of the factors underpinning per-

formance (84). Several training strategies are currently

practiced by competitive athletes in the belief that they

amplify adaptation and lead to improved performance

capabilities. Here, we describe a selection of training

strategies that have high uptake by elite athletes and

have plausible biological mechanisms that might explain

current practices (85–87).

The principle of speciﬁcity states that any training-

induced adaptations that accrue to an athlete are unique

to the type of exercise mode performed; this is most evi-

dent when contrasting the divergent phenotypes that

result after undertaking either prolonged endurance- or

FIGURE 4. Training principles and strategies. A: to achieve peak performance at the timeof competition, training volume, intensity, and form/speciﬁc-

ity have to be adapted in different cycles/phases. Speciﬁc paradigms, e.g., high-intensity interval training (HIIT), “train low,”and others, are likewise

periodized and matched to the prevailing volume/intensity/form requirements. Importantly, the periodization of training has to be matched to that of

nutrition (e.g., low glucose vs. carb loading), recovery, psychological aspects, and skill acquisition. B: within shorter cycles, e.g., weekly planning, polar-

ized or pyramidal partitioning of training volume at different intensities (e.g., deﬁned by lactate/ventilatory thresholds between zones 1 and 2and the

critical power/lactate turnpoint between zones 2 and 3) helps to improve performance and reduce overtraining. C: training adaptation is initiated by a

homeostatic disruptioninduced by exercise. After exercise cessation, recovery and repairmechanisms not only result ina return to baseline but trigger

adaptive mechanisms, optimally in a supercompensatory manner, which should help to protect muscle better from future perturbations. However, in

the absence of continued stimuli, i.e., detraining, this supercompensatory response is abolished by an adaptive dissipation. The amplitude and tempo-

ral aspects of this curve are strongly inﬂuenced by the training paradigm and related parameters. Moreover,within the same system, biochemical proc-

esses, cell types, or tissues can react in a different manner (heterochronism of adaptation). D: performance gains are controlled by the balance

between training load and recovery. A suboptimal planning can result in either undertraining with little or no gains or overtraining, in which performance

decreases (retrogression) and the risk for injuries increases. In proper conditions, a functional overreach helps to maximize progression and overcome

training plateaus. Figure created with BioRender.com, with permission.

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strength/resistance-based training (86,88). The principle

of speciﬁcity states that the closer the training routine is

to the requirements of competition, the greater the likeli-

hood of successful outcomes. For this reason, the foun-

dation of any training program should reﬂect the desired

training adaptation necessary to enhance sports-speciﬁc

performance. The principle of speciﬁcity should operate

with regard to not only the modality of training but also

the intensity and speed/power output at which an athlete

performs training (discussed below). The principle of re-

versibility states that there will be a decline or complete

loss of training-induced adaptations when an athlete

reduces or stops training for a substantial time (i.e., sev-

eral weeks up to several months). Reductions in both

training volume and intensity diminish many of the adap-

tations that accrue from daily or twice-a-day training, with

such a response leading to concomitant performance

decrements. The time courses of loss of adaptations af-

ter both well-trained endurance athletes and recreational

sportspersons stop daily training are rapid: declines in

whole body maximal and submaximal responses to exer-

cise occur during the ﬁrst 7–21 days of inactivity, becom-

ing somewhat stable after 2 mo of detraining (89–93). In

athletes who predominantly train for strength and power,

and depending on the type of strength test performed,

there is a limited decline in muscular strength during

short-term (up to 21 days) inactivity, but decay rates

increase substantially after 4 wk and longer (89,93–95).

It is important to highlight that the principle of reversibility

differs from a competitive “taper”before a major event/

competition: during a taper, the volume and frequency of

training are deliberately reduced but the intensity is

maintained or even increased, resulting in a performance

enhancement of 1–2% (96,97).

2.2. Intensity vs. Volume to Optimize Training

Adaptation

2.2.1. High-intensity, low-volume vs. low-intensity,

high-volume training to maximize endurance

training adaptation.

Recently, there has been renewed scientiﬁcinquiryalong

with widespread public interest in the potential for high-in-

tensity interval training (HIIT) to induce physiological adap-

tations that are similar or even superior to a traditional,

continuous endurance-based exercise prescription for

health and performance (98–100). HIIT broadly refers to

exercise that is characterized by relatively short bursts of

vigorous activity interspersed by periods of rest or low-in-

tensity exercise for recovery. A common classiﬁcation sub-

divides this type of training into 1) sprint interval training

[SIT, supramaximal efforts performed at power outputs/

speeds >peak oxygen uptake ( _

VO2peak), for 30–60 s,

with 1- to 3-min rest or active recovery], 2) high-intensity

interval training (HIIT, comprising near-maximal efforts per-

formed at the power output/speed that elicits _

VO2peak for

1–4 min, with 1- to 2-min rest or active recovery), and 3)

moderate-intensity continuous interval training (performed

at power output/speed that elicits between 85% and 90%

of _

VO2peak performed for 5–10 min, with 1-min rest or

active recovery). In untrained and recreationally active

individuals, both short-term SIT and HIIT are potent stimuli

to induce physiological remodeling similar to that attained

after traditional prolonged endurance training, despite

markedly lower total exercise volume and training time

commitment (101,102).

The notion that interval training is a new, groundbreak-

ing scientiﬁc approach to physical conditioning, espe-

cially for athletic performance, needs to be placed in

historical context. Coaches and athletes have appreci-

ated the value of this form of training since the early twen-

tieth century, with many notable cases in which a range

of different work to rest intervals were trialed, tested, and

reﬁned to prepare for competition (99). Interval training

was widely used by a Finnish coach, Lauri Pikhala, who

worked with many champion runners including Paavo

Nurmi and Hannes Kolehmainen. Between 1920 and

1930, Nurmi was the most dominant distance runner in

the world, winning a total of nine Olympic gold medals.

The foundation of Pikhala’s training methods focused on

running a high number of repetitions (20–30 efforts) at

close to the athlete’s race pace interspersed with short

(<60 s) rest intervals. Subsequently a German physician

and coach, Woldemar Gerschler, working with cardiolo-

gist Herbert Reindel, ﬁne-tuned a similar interval training

approach focusing on the manipulation of the work:recov-

ery periods, based on an athlete’s heart rate. An athlete

would run over a distance fast enough to elicit a heart

rate close to 180 beats/min, after which they rested until

the heart rate dropped to 120 beats/min; at this time,

the next work bout was performed. Gerschler and

Reindel proposed that the rest or recovery interval was

the most important aspect of their approach because it

was during this phase that the heart adapted, allowing it

to grow larger and stronger (99). In the 1960s, the New

Zealand running coach Arthur Lydiard advocated a shift

away from high-intensity interval-based training to high-

volume, continuous training for endurance performance.

Lydiardadvocatedrunningasmuchas160km/wkduring

the preseason conditioning or “base”phase, with both

middle- and long-distance runners undertaking similar

volumes of work (103). Although there was a perception

that such a high volume of training could only be per-

formed at low intensities (i.e., high volume, low intensity),

this was not the case: running during this phase of condi-

tioning was prescribed at speeds that corresponded to

an athlete’s best 16 km race pace (for middle-distance

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athletes) or best marathon pace (for long-distance run-

ners). This conditioning phase could last from as short as

8 wk to half a year. Lydiard’sathleteshadmajorsuccess

over two Olympiads (Rome 1960 and Tokyo 1964), win-

ning medals across a wide range of distances including

triple Olympic gold medalist Peter Snell (800 and 1,500

m), John Davies (bronze medal 1,500 m), Murray Halberg

(gold medal 5,000 m), and Barry Magee (bronze medal,

marathon).

Despite these successful coach-driven approaches to

conditioning for elite athletes, it was not until the 1960s

that the ﬁrst scientiﬁc publications on the physiological

bases of training for human performance appeared, and

even today the scientiﬁc literature on the unique effects of

speciﬁc training interventions on the performance of

highly trained athletes is sparse. Indeed, although the

foundation of all training programs for the enhancement of

sport performance is the volume, intensity, and frequency

of exercise, the relative importance of these interdepend-

ent variables has not been established for many of the

key physiological adaptations to training, nor their impact

on performance outcomes (104,105). This is because train-

ing prescription is inﬁnitely variable, with countless permu-

tations around the core tenets of the general principles of

training (FIGURE 4). Adding to the complexity of training

prescription is the multiplicity of the physiological/technical

demands of many athletic events, with many requiring

components of both endurance and strength/power, as

well as different modes of exercise (i.e., swimming, cycling,

and running in the triathlon). Potential “interference

effects”between endurance- and strength/power-based

training regimens are discussed below.

There has been spirited scientiﬁc debate as to whether

training volume or training intensity promotes the greatest

adaptation in skeletal muscle (104,105), with this dialogue

focusing predominantly on exercise-induced changes in

mitochondrial content, typically assessed by quantifying

the maximal activity of citrate synthase, the ﬁrst step of the

tricarboxylic acid cycle, or skeletal muscle respiratory

capacity (see sects. 3.4.1 and 4.5). Although higher inten-

sities of exercise generally elicit greater increases in mito-

chondrial content than lower exercise intensities per unit

of time or work (104), such a narrow perspective ignores

any functional outcomes, such as athletic performance.

Perhaps more to the point, the data used to support one

or the other position (i.e., volume vs. intensity overload)

have come from studies that employed untrained or rec-

reationally active subjects participating in short-term inter-

ventions (2–6 wk) undertaking one-dimensional training

programs consisting of either HIT or continuous, submaxi-

mal endurance-based training. It is not clear how these

results can be extrapolated to elite athletes with a pro-

longed history of periodized training that includes a vari-

ety of workouts with different goals, performed within

well-deﬁned training cycles, at volumes, frequencies, and

absolute exercise intensities/power outputs that far

exceed those capable of being attained by their less ge-

netically gifted counterparts. In this regard, a recent study

reported reductions in mitochondrial respiration in skeletal

muscle in response to 4 wk of intensiﬁed HIT in moder-

ately trained individuals (106). The impairment in mito-

chondrial function occurred during the week of heaviest

training load but was dissociated from both mitochondrial

activity and mitochondrial protein abundance, which both

peaked at that time (106). Despite the transient impair-

ments to mitochondrial respiration, performance parame-

ters all increased after the intensiﬁed HIT regimen.

Furthermore, the training undertaken by the participants

in that study consisted exclusively of maximal HIT (106)

and can only be tolerated by highly trained athletes for

more than a few successive days (107).

Since the classic model of training periodization was

ﬁrst proposed over four decades ago (108), there has

been widespread discussion about how best to imple-

ment training stimuli to optimize adaptation and athletic

performance (109). Although several long-term period-

ization approaches have been described (110), con-

trolled studies comparing the impact of these different

protocols on performance outcomes are lacking. As

noted, anecdotal testimonies from top athletes and their

coaches (111), case studies of elite performers (112,113),

and reports of small cohorts of top athletes from speciﬁc

sports (53,114,115) provide insights into the training

practices of elite performers, but such studies merely

document what successful athletes did; they do not

reveal what made those athletes successful or prove

that the program they followed was optimal (116).

Indeed, there may have been many athletes who fol-

lowed similar programs who were not successful, fell ill,

suffered injury, or dropped out of the sport completely.

Notwithstanding these limitations, detailed analyses of

the training methods of elite athletes enable sport scien-

tists to examine relationships between training inputs

and variables directly or indirectly related to perform-

ance (FIGURE 5). This information can also provide a ba-

sis for hypothesis testing with respect to training load

and physiological adaptation. There have been multiple

empirical descriptions of the distribution of training in-

tensity in highly trained/elite athletes competing in en-

durance-based sports (110,114,117–121). Depending on

the speciﬁc loading characteristics of the sport (i.e.,

weight bearing vs. non-weight bearing), international

athletes competing in endurance events typically train

for between 500–600 h (distance running) and up to

1,000 h per year (rowing, swimming, cycling, triathlon),

performed during 400–800 training sessions (122–124).

This training volume is undertaken for a minimum of 11

mo a year, with the overall goal of achieving peak

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performance throughout a speciﬁed time frame (usually

4–6 wk) in the competitive season. However, there is

signiﬁcant variability between sports, with professional

cyclists frequently racing 100 days and riding in excess

of 30,000 km during any 12-mo period (125,126).

Longitudinal data suggest that the development of a

world-class endurance athlete may take up to a decade

of speciﬁc training, with highly successful athletes often

following a 2- or 4-yr cycle of preparation for world

championships or Olympic events (110,125). To maxi-

mize adaptation and reach one’s genetic potential,

champion athletes must therefore be able to tolerate

prodigious training loads. However, a high training vol-

ume alone does not guarantee sporting success.

A quarter century ago, Mujika et al. (127)studiedthe

relationships between training variables and performance

variations over the season in a group of elite swimmers.

They reported that training intensity, rather than volume

or frequency, was the key variable inducing a training ad-

aptation that led to subsequent performance improve-

ments. These workers also observed a training intensity

distribution that placed emphasis on volume-overload

training conducted at submaximal intensities for most of a

season, with the inclusion of supramaximal high-intensity

sprint workouts nearer to a competition. A decade later,

this approach would be described as a “polarized training

intensity distribution”by Seiler and colleagues (121)asdis-

tinct from a pyramidal training paradigm (FIGURE 4).

Since then, there have been several reports that elite ath-

letes follow both approaches to their competition prepa-

ration (128). Coetzer et al. (129) reported that elite

distance runners with superior race performances trained

at a higher average intensity than a group of sub-elite run-

ners: the sub-elites spent 13% of their total weekly training

volume running at speeds eliciting >80% of _

VO2peak,

whereas the elite runners spent signiﬁcantly more time

(36%) at this higher intensity. These observations agree

with others (118,119) who have observed that elite Kenyan

distance runners complete a greater volume of training

as fast-paced “tempo”runs and short-interval training

compared to their non-elite counterparts. Guellich and

colleagues (130) reported that elite endurance ath-

letes from a range of sports including rowing, running,

cycling, and cross-country skiing perform only a small

portion of their training at competition/race-pace

intensities, with the bulk of their workload comprising

low-intensity, high-volume workouts and exposure to

extreme HIT sessions.

It has been hypothesized that a polarized approach to

training, in which 75–80% of total training volume is

FIGURE 5. Periodization of training for an elite athlete. Schematic representation of periodization of training along with physiological data collected

during preparation for the 2016 Rio Olympic Games for a gold medal-winning female rower. BLa, blood lactate; BM, body mass. See GLOSSARY for other

abbreviations. Figure created with BioRender.com, with permission.

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performed at low intensities with 10–15% performed at

supramaximal intensities, may be the optimal training in-

tensity distribution for elite athletes who compete in

intense endurance-based events (131). However, this prac-

tice has recently been questioned and debated (116,132–

134). Alternative approaches to “polarized training”have

been proposed, such as pyramidal or “threshold”training

intensity distributions. At present, and to the best of our

knowledge, there are no studies that demonstrate that

adherence to a polarized training program produces

superior outcomes compared with the pyramidal training

programs athletes typically practice or other possible

training models (116,132–134). Indeed, polarized training

per se seems totally incompatible with the principle of

training speciﬁcity, a cornerstone of any training program.

Although it is tempting to attribute the superior perform-

ances of elite athletes from a range of endurance sports

to the adoption of a speciﬁc training regimen (i.e., polar-

ized training, HIT), the principle of individuality dictates

that the same training program will not equally beneﬁtall

those who undertake it. Furthermore, the molecular and

cellular mechanisms that underpin performance enhance-

ment after polarized and various other training interven-

tions are not well understood. Directly linking exercise-

induced molecular signaling events in skeletal muscle to

deﬁned metabolic responses and speciﬁc changes in

gene and protein expression that occur after diverse train-

ing regimens may provide clues as to why certain training

methods (i.e., polarized training, HIT) are such potent

interventions both for promoting health outcomes and

enhancing athletic performance.

2.2.2. High-intensity, low-volume vs. low-intensity,

high-volume training to optimize resistance

training adaptation.

Analogous to endurance-based training, periodization is

frequently used to promote muscle hypertrophy and

strength gains in response to a program of resistance

training (135). Indeed, when resistance training volume is

similar, periodized training protocols induce greater

gains in strength [i.e., one-repetition maximum (1RM)]

than non-periodized resistance training, at least in

trained individuals (135). The process of skeletal muscle

ﬁber hypertrophy and the concomitant gains in strength/

power (discussed in sects. 3.2, 4.3–4.5, and 4.8) are the

result of the conﬂuence of a net positive muscle protein

balance, with the addition of satellite cells to muscle

ﬁbers a possible mechanism. Muscle hypertrophy only

occurs when net positive muscle protein balance is

maintained over several weeks/months and when the

rate of muscle protein synthesis (MPS) exceeds that of

muscle protein breakdown (136). Resistance training vol-

ume can be deﬁned as the number of sets repetitions,

sets repetitions load (expressed as a percentage of

1RM), sets repetitions load (kg), load sets repeti-

tions for each exercise, or number of sessions repeti-

tions sets (137). Resistance training intensity is typically

deﬁned as a percentage of maximal strength (%1RM).

Resistance training frequency represents the number of

resistance training sessions performed in a speciﬁed

time period (i.e., per week) and for each muscle group.

The frequency of resistance training sessions is impor-

tant when considering resistance exercise prescription,

as the recovery time between sessions must allow for

muscle adaptation (i.e., net protein synthesis). The num-

ber of training sessions provides an indication of the total

resistance training work over a program’sduration,

whereas including load describes the total work of a sin-

gle training session. Other parameters (e.g., load, num-

ber of repetitions and sets, range of movement, time

between sets, time under tension, and volitional muscle

failure) provide a comprehensive description of resist-

ance training programs (138), even though the effect of

manipulating these variables on athletic performance

remains unclear (139).

To maximize muscle hypertrophy, the American

College of Sports Medicine (ACSM) recommends resist-

ance training intensities corresponding to a load of

70–80% 1RM for 8–12 repetitions (140). Although such

loading is unlikely to be undertaken by elite athletes

competing in strength/power events, such advice is

largely based on the observation that higher loading

induces greater force development, an increased mus-

cle electromyography activity (141), and a greater recruit-

ment of muscle ﬁbers. Evidence to support a dose-

response relationship between external loading and

maximal rates of MPS comes from the work of Kumar et

al. (142), who showed that a plateau in MPS was reached

at intensities approaching 90% of 1RM. However, results

from other studies suggest that maximal rates of MPS

can also be achieved by low-intensity, higher-volume

loading. Burd et al. (143) studied 15 recreationally active

males who performed four sets of unilateral leg exten-

sion exercise at different exercise loads and/or volumes:

90% of 1RM until volitional failure (90FAIL, 5repeti-

tions), 30% 1RM work-matched (WM) to 90%FAIL (30WM,

14 repetitions), or 30% 1RM performed until volitional fail-

ure (30FAIL, 24 repetitions). Low-load, high-volume re-

sistance exercise (30FAIL) was equally effective at

increasing rates of MPS as high-load, low-volume resist-

ance exercise (90FAIL), eliciting increases in rates of

myoﬁbrillar protein synthesis similar to those induced by

the 90FAIL protocol in the postexercise recovery period.

Furthermore, only the 30FAIL protocol sustained higher

rates of MPS 24 h after exercise. Although these data

from a single bout of resistance training are intriguing,

there is support for the concept that measures of acute

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postexercise MPS are qualitatively predictive of the

chronic training-induced phenotypic changes driven by

repeated resistance exercise stimuli. In a study from the

same laboratory, Mitchell et al. (144) studied 18 untrained

males who completed 10 wk of unilateral knee extension

resistance training. Each leg of a participant was randomly

assigned in counterbalanced fashion to one of three possi-

ble unilateral training conditions: one set of knee extension

performed to voluntary failure at 80% of 1RM (80%-1); three

sets of knee extension performed to the point of fatigue at

80% of 1RM (80%-3); or three sets performed to the point

of fatigue with 30% of 1RM (30%-3). Each participant

trained both legs and was therefore assigned to two of

the three possible training conditions. The strength of

this design is that both limbs are exposed to the same

nutrient and hormonal milieu and therefore any pheno-

typic changes can be ascribed solely to the training stim-

ulus. There were signiﬁcant training-induced increases

in muscle volume [measured by magnetic resonance

imaging (MRI)], but these were not different between the

training protocols. These results are in accordance with

previous acute measurements of muscle protein syn-

thetic rates and demonstrate that a lower load lifted to

failure results in muscle hypertrophy similar to a heavy

load lifted to failure. An important feature of this study

was that the training program was underpinned by

adequate nutrition (i.e., sufﬁcient amino acid availability)

to support the increases in MPS that occur after each

training session. These results support earlier ﬁndings

demonstrating that signiﬁcant increases in muscle ﬁber

area can be achieved after 16 wk of isometric training at

30% of maximal voluntary contraction (MVC) (145).

As is the case for most studies that have examined

various endurance training protocols, most investiga-

tions of different strength/resistance training programs

have been undertaken with recreational and/or moder-

ately trained male college students. How such ﬁndings

translate to elite athletes who are likely to have reached

an upper limit in muscle hypertrophy and strength gains

after many years of training is unclear. Elite athletes

competing in events that require strength/power will

also be undertaking additional forms of training to maxi-

mize muscular force output such as plyometrics, which

involves rapid and repeated stretch/contractions of the

muscle of the lower limb (146–148), or hypoxic/blood

ﬂow-restricted training (149–151). This makes it difﬁcult to

determine the precise contribution of any single inter-

vention to improvements in muscle hypertrophy and

strength. Inherent variability in the individual response

to resistance training is also a factor to consider in any

training protocol (discussed below). In summary, there is

currently little consensus on how the variables related to

resistance training (training load, volume, and fre-

quency, muscle time under tension, lifting cadence,

contraction mode, and interset rest interval) are most

effectively periodized to maximize both MPS and

improvements in strength and other functional meas-

ures (135,139,152,153).

2.3. Exercise Interference Eﬀects and Concurrent

Training Responses

The inverse relationship between muscle ﬁber size and

oxidative capacity highlights the principle of the speciﬁc-

ity of training when comparing muscles of endurance

and strength/power athletes (154,155). Accordingly,

simultaneously training for both endurance and strength

results in a compromised adaptation compared with

training for either exercise modality alone, at least in pre-

viously untrained individuals. This phenomenon was ﬁrst

described by Hickson (156), who reported impaired

strength development in training naive males when they

incorporated both strength and endurance workouts

versus single-mode exercise into a short-term (10 wk)

training program. Hickson (1980) coined this the “inter-

ference effect,”and since that seminal observation, a

number of animal and human studies have been con-

ducted in an effort to elucidate a molecular basis to

explain this outcome (discussed in sect. 4.5.1). Of note

was that training-induced gains in aerobic capacity in

that study (156) were not compromised by concurrent

strength and endurance training. In fact, in contrast to

the impaired strength gains observed when endurance

training is undertaken simultaneously with resistance

training (156), there is potential for combined strength

and endurance training to amplify endurance perform-

ance (157).

The study of “concurrent training”has received less

scientiﬁc enquiry than single-mode training for endur-

ance or strength/power. Indeed, studies of concurrent

training interventions pose several unique experimental

challenges. The inability to match total work as well as

the type of stimulus and/or exercise mode makes com-

parisons between the results of studies of concurrent

training problematic. Differences in experimental design

and dependent variable selection also limit any mecha-

nistic insights in those studies that have determined

only performance-based outcomes. Finally, the majority

of studies of concurrent training to date have focused

exclusively on acute molecular responses in moderately

trained individuals, employing modest workloads; the

training practices of elite/professional athletes undertak-

ing concurrent training far exceed those reported in the

literature for less well-trained subjects and are likely to

induce complex molecular proﬁles (88,158). Over the

past two decades, the mechanisms that generate the

adaptive response to both endurance- and strength-

based exercise training have undergone intense

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investigation (9,55,85–87,159–166). There are multi-

ple stimuli associated with endurance- and resistance-

based exercise and various signaling kinases that

respond to these different perturbations, in concert

with numerous downstream pathways and targets of

these kinases. These events involve the increased

expression and/or activity of key proteins mediated by

an array of signaling events, pre- and posttranscrip-

tional processes, regulation of translation and protein

expression, and modulation of protein/enzyme activ-

ities and intracellular localization (9,55,85,87,159).

These molecular processes are described in detail in

sect. 4. Finally, there are complex spatial and temporal

interactions between the various elements that ulti-

mately combine to produce the integrated response

to an exercise challenge that, when repeated over

months and years, results in functional improvements

in performance and alterations in phenotype.

Although it is convenient to classify athletic events

as either “endurance-based”or “strength-/power-based,”

with skeletal muscle from endurance- and strength-

trained individuals representing diverse adaptive

states in response to selective activation and/or

repression of signaling pathways that underpin these

adaptations (9,88,159,160,166), such a one-dimen-

sional perspective ignores the fact that the majority of

athletic disciplines require a combination of both mus-

cular endurance and strength/power for successful

outcomes. As such, both endurance- and resistance-

based training are frequently undertaken concomi-

tantly as part of a periodized training program. These

practices encompass several scenarios: 1)asingle

training session during which an athlete performs

both endurance- and resistance-based exercise; 2)

two independent training sessions undertaken by the

athlete on the same day, in one of which the focus is

endurance adaptation (i.e., performed in the morning)

and in the other strength/power adaptation (i.e., per-

formed in the afternoon/evening); or 3)whenanath-

lete incorporates both types of training on different/

alternate days as part of a periodized training program

(88). Currently, little is known about the effects of con-

current training in elite athletes on performance pro-

gression, and it is conceivable that the degree of

interference may be discipline- and training paradigm-

speciﬁc(1,167). For example, in sports where endur-

ance as well as high peak power/forces are required

(such as in 2,000 m rowing), athletes aim to maximize

both muscle mass and oxidative capacity. Indeed, the

peak power of Olympic rowers is positively correlated

with thigh muscle volume but negatively correlated

with _

VO2max (168). Similarly, sprint and endurance per-

formance are inversely related in highly trained

cyclists (169).

2.4. Altitude and Hypoxic Training to Enhance

Adaptation

Of all the practices currently used to enhance training

adaptation and elite athletic performance, “altitude train-

ing”or exposure to hypoxic environments is the most

widespread (55,97). The stimulus for a new era in

research of high-altitude training practices was the 1968

Olympic Games held in Mexico City at an elevation of

2,240 m above sea level. In the middle- and long-dis-

tance track events, runners who were born and trained

at altitude were dominant: in the men’s10,000m,the

ﬁrst ﬁve runners resided and trained at altitude. The

world record holder at the time for both the 5,000 and

10,000 m events going into the Mexico Games,

Australian Ron Clarke, who was born and trained at sea

level, collapsed after ﬁnishing 6th in the 10,000 m and

had to be administered oxygen to recover. Since those

Olympics, male and female athletes from Kenya and

Ethiopia have dominated middle- and long-distance run-

ning events, with elite athletes and coaches steadfastly

believing in the beneﬁts of hypoxia-induced adaptive

responses to optimize performance (97). This is despite

the paucity of scientiﬁcevidencesupportinganaltitude-

induced performance-enhancing effect (55,170,171).

The mechanisms that underpin the adaptive response

to reduced oxygen availability are discussed below.

2.4.1. Into thin air: altitude training strategies to

enhance endurance performance.

There are several common approaches that athletes

adopt with regard to altitude training, involving several

days to several weeks of exposure to some form of alti-

tude or hypoxic challenge (172). Regardless of the differ-

ent approaches used to induce hypoxic living/training

conditions, the underlying physiological basis for alti-

tude training is that the reduced barometric and partial

pressure of oxygen results in lowered oxygen availabil-

ity causing an increase in erythropoietin (EPO) produc-

tion in the kidney that stimulates erythropoiesis and

thereby leads to enhanced hemoglobin (Hb) mass. As

acute exposure to hypoxia over several hours does not

improve aerobic or anaerobic performance, these studies

are not discussed here (173). The original altitude training

strategy involved athletes spending up to 6 wk living and

training at a moderate altitude (2,000–2,500 m) and

returning to sea level just before a major sea-level com-

petition (“live high, train high,”LHTH). The LHTH

approach boosts EPO and Hb mass, which results in an

increase in _

VO2max. Such adaptations usually persist for

1–2 wk upon return to sea level, with the athlete partici-

pating in several major competitions during this period. A

limitation of the LHTH strategy is that training intensity is

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often compromised, which is in line with the linear reduc-

tion in _

VO2max with increasing altitude (6–8% reduction

per 1,000 m) (174). A second strategy involves athletes

continuing to reside at sea level but training at altitude

(“live low, train high,”LLTH). Adaptations resulting from

LLTH are mainly conﬁned to the trained musculature (i.e.,

skeletal muscle mitochondrial volume density), with little

effect on EPO or Hb mass. As with the LHTH approach,

the intensity of training is typically reduced with LLTH. A

third protocol, and the one that is most widely used and

has received widespread interest among scientists,

coaches, and athletes, is the “live high, train low”(LHTL)

approach, whereby athletes reside at altitude for several

weeks but return to sea level to undertake the majority of

their training sessions. Compared with LHTH or LLTH

approaches, the LHTL approach permits athletes to main-

tain their absolute training loads (volume and intensity)

while concomitantly gaining the physiological adaptations

that accrue with exposure to chronic hypoxia. Indeed,

when competitive runners completed 4 wk of supervised

training as either LHTL, LHTH, or LLTH, performance of a

5kmtimetrialatsealevelwasimprovedonlyintheLHTL

athletes despite similar gains in the athletes’_

VO2max in all

intervention groups (175). No muscle biopsies were taken

in that investigation, so it was not possible to determine

whether the different altitude-training regimens resulted

in changes in hypoxia-mediated signaling pathways or if

there were changes in major training-induced signaling

proteins. A model pioneered by the Australian Institute of

Sport (AIS) requires that athletes gain exposure to alti-

tude/hypoxia by either living in a custom-built altitude

house under conditions of simulated altitude (14 h/day) or

using altitude tents or intermittent hypoxic exposure with

hypoxic breathing devices (176). However, even though

altitude paradigms increase Hb mass (172), the purported

performance gains from living at simulated moderate alti-

tude and training at low altitude have been questioned

(177,178). Therefore, whether training in hypoxia while liv-

ing in normoxia or living under hypoxic conditions while

training at sea level (or low altitudes) is superior to living

and training in normoxia for enhancing performance of

elite athletes near sea level is unclear and warrants fur-

ther investigation. There are also many challenges when

assessing the effect of altitude exposure on performance

in elite athletes (179). For example, the scientiﬁcgold

standard design of a double-blind, placebo-controlled,

crossover trial has seldom been conducted in studies of

altitude training in elite athletes. A recent systematic

review, albeit incorporating individuals with a wide range

of athletic abilities, concluded that placebo and nocebo

effects can exert a small to moderate effect on sports per-

formance (180). Yet despite equivocal scientiﬁcevidence

to support a performance-enhancing effect of altitude/

hypoxic training practices, elite endurance athletes

and their coaches continue to believe that some form

of altitude training will confer a performance advant-

age when competing at sea level. Guidelines and

measures to improve altitude acclimatization, toler-

ance, and safety have been reviewed elsewhere (181).

Interestingly, preconditioning with hyperbaric oxygen

has also been proposed to enhance performance,

however with similar equivocal underpinnings (182).

2.4.2. Resistance training under hypoxic

conditions.

Acute hypoxia has been proposed to potentiate resist-

ance training-induced hypertrophy by activating satellite

cell-dependent myogenesis rather than an improvement

in net protein balance. To test this hypothesis, van

Doorslaer et al. (183) recruited 19 physically active male

subjects who performed 4 wk of resistance training (6

sets of 10 repetitions of a 1-leg knee extension exercise

at 80% 1RM 3 times/wk) in either normoxic [fraction of

inspired oxygen (FIO2): 21%; n= 9] or hypoxic (FIO2:13.5%,

n= 10) conditions. At the end of the intervention, the

strength gain was higher in individuals who trained

under hypoxic compared with normoxic conditions, de-

spite no changes in muscle thickness and the rate of

MPS. Although these results suggest that training under

hypoxic conditions may be a potent intervention to

increase muscle strength, at least in the early phase of

training, additional studies in well-trained athletes incor-

porating long-term protocols are urgently needed to

determine whether hypoxic resistance training can fur-

ther maximize strength gains. Other protocols with

potential additive training effects due to reduced local

muscle oxygen availability and exacerbated vascular

shear stress that leverage hypoxic stimuli (i.e., blood

ﬂow restriction) are currently being investigated (150,

151,184) yet hampered by the heterogeneous responses

to ischemic preconditioning (185).

2.5. The Lowdown on Training with Reduced

Muscle Glycogen Stores

Agrowingﬁeld of interest that has directly risen from a

better understanding of the molecular bases underlying

training adaptation is how nutrient availability has the

capacity to modify the regulation of many contraction-

induced signaling networks in skeletal muscle (sects.

3.4.2 and 4.5) (9,186–193). The interaction between exer-

cise training-induced responses and nutrient availability

has long been recognized (194), and today it is well

accepted that carbohydrate-based fuels are critical for

prolonged, intense training and in the competition setting

where optimal endurance performance is desired (195).

However, this premise does not address the issue of

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whether training adaptation is driven by a surplus or lack

of substrate (i.e., carbohydrate). During the past decade,

there has been a growing appreciation that commencing

selected training sessions with reduced muscle glycogen

stores may promote training adaptation and enhance en-

durance performance (196–198). Acutely manipulating

substrate availability (by either altering the composition

and/or timing of meals before training/competition or

depleting endogenous fuel stores by exercise) rapidly

alters the concentration of blood-circulating substrates

and hormones that modulate several receptor-mediated

signaling pathways. The release of cytokines and growth

factors from contracting skeletal muscle in response to

the altered hormonal milieu also stimulates cell surface

receptors and activates many intracellular signaling cas-

cades (described in sect. 4). These local and systemic fac-

tors cause marked perturbations in the storage proﬁle of

skeletal muscle (and other insulin-sensitive tissues) that,

in turn, exert pronounced effects on resting fuel metabo-

lism and patterns of fuel utilization during exercise. When

repeated over weeks and months, such nutrient-exercise

interactions have the potential to alter numerous adaptive

processes in skeletal muscle that ultimately drive the phe-

notype-speciﬁc variability observed between individuals

(55). However, linking these molecular events to direct

downstream effectors has proven elusive (199). Perhaps

more to the point, training adaptation requires an

increase in the steady-state levels of exercise-induced

proteins, and it was not until the pioneering study of

Hansen and colleagues (187) that the notion that endur-

ance training undertaken with low muscle glycogen lev-

els could augment adaptation gained scientiﬁc credibility.

These workers tested previously untrained individuals

before and after a 10-wk intervention in which both the

left and right legs of the same individual were subjected

to speciﬁc work-matched training protocols in which one

leg was trained once daily while the contralateral limb

trained twice every second day. As intended, the twice-a-

day training protocol decreased muscle glycogen content

after the ﬁrstboutofexercisesuchthatthesecondexer-

cise session of the day was commenced with lowered

(but not totally depleted) muscle glycogen content. The

activity of mitochondrial enzymes along with resting mus-

cle glycogen concentration were all increased to a

greater extent when half the training sessions were exe-

cuted with low glycogen availability. Exercise time to

exhaustion (a proxy for performance) involving a one-leg-

ged “kicking”task was elevated markedly for both legs

after training but was twice as long for the limb that

trained with low compared to high glycogen. The

strength of this study was the design that controlled for

both systemic and local effects. However, the authors

acknowledge that the controlled laboratory setting,

coupled with the training status of their subjects, may not

permit the results to be extrapolated to competitive ath-

letes. Several studies subsequently veriﬁed the ﬁnding

that, in well-trained athletes, chronic (3–10 wk) training

programs in which selected workouts were deliberately

commenced with low muscle glycogen concentration

increased the expression of genes and the abundance of

proteins involved in carbohydrate and/or lipid metabolism

while promoting mitochondrial biogenesis to a greater

extent than when all workouts are undertaken with nor-

mal or elevated glycogen stores (molecular mechanisms

underlying these observations are discussed in sect.

4.5.2) (199–201). Surprisingly, such adaptations accrued

notwithstanding a reduction of 7–8% in the athletes’self-

selected training intensity (200,201). Yet despite aug-

mented adaptations at the muscle level, studies that have

examined the “train low”glycogen model in well-trained

athletes have often (201–204), but not always (197,198),

failedtoshowaperformancebeneﬁt(forreview,seeRef.

205). Such a disconnect between changes in selected

molecular mechanistic variables (e.g., increases in the

phosphorylation status of signaling molecules and/or

increases in the expression of genes and proteins

involved in mitochondrial biogenesis) and whole body

functional outcomes (changes in training capacity or ath-

letic performance) is hard to reconcile. However, it may

well be that elite athletes with a prolonged history of train-

ing have already maximized many of the cellular path-

ways involved in energy provision and that proteins in

these and other contraction-induced pathways that are

upregulated with the train low glycogen protocol are not

rate limiting for performance.

There is a scarcity of studies that have examined the

effects of commencing resistance training with low mus-

cle glycogen stores. Nevertheless, some evidence

exists suggesting that reduced glycogen availability may

upregulate cellular pathways regulating mitochondrial

biogenesis after a single bout of exercise (206), even

though engaging in resistance training with low muscle

glycogen does not affect rates of MPS (207). These

results imply that commencing a bout of strenuous re-

sistance exercise with low muscle glycogen availability

attenuates neither anabolic signaling nor rates of myoﬁ-

brillar protein synthesis. In summary, despite no clear

evidence of a performance-enhancing effect from the

results of several well-controlled laboratory-based stud-

ies that have tested various train low (glycogen) strat-

egies, many athletes who compete in endurance-based

events continue to incorporate such practices into their

training programs. In contrast, there appears no reason

for athletes undertaking resistance training regimens to

adopt low-glycogen workouts into their daily schedules.

A challenge for future investigations is to directly link

some of the acute exercise-induced molecular signaling

events in skeletal muscle that take place in response to

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the greater metabolic loading imposed by various train-

ing interventions (i.e., altitude and low glycogen) to

deﬁned performance-related outcomes that occur after

elite athletes undertake such practices.

2.6. A Time to Train, a Time to Compete?

Since the awarding of the Nobel Prize in Physiology or

Medicine in 2017 for the discovery that the molecular

clock is the primary mechanism underlying circadian

rhythms, there has been a dramatic increase in the num-

ber of scientiﬁc publications regarding circadian biology

and its impact on various aspects of human behavior,

including sporting performance. Circadian rhythms are

24-h (circa diem) oscillations in biological and meta-

bolic pathways. The circadian clock is cell autonomous

and present in most human tissues and organs and is

organized in a hierarchical manner, with the hypothala-

mic suprachiasmatic nucleus (SCN) functioning as the

“master clock”with “ﬁne-tuning”by clocks in peripheral

tissues (208–211). Although light is the dominant zeit-

geber (time giver) for the SCN oscillator, which in turn

orchestrates rhythms in the peripheral organs/tissues at

appropriate phases, both the timing of exercise (212–

216) along with the scheduling of meals (217–220)can

impact circadian behavior (molecular underpinnings are

discussed in sect. 4.9).

Differences in the time of day for peak performance

for strength and anaerobic power as well as oxidative

capacity and endurance performance have been

reported in many, albeit not all, human studies (221–

224). However, there are large interindividual differen-

ces in circadian rhythms, and the time of day for peak

performance is affected by many additional factors

including time since awakening, timing of precompeti-

tion meals, sleep quality, body temperature, hormone

levels, psychological habituation, motivation, and prior

muscle fatigue (225–227). Accordingly, the effect of the

time of day of training on performance needs to be

placed in the context of an athlete’s chronotype. An indi-

vidual’s predisposition toward a preference for either

morning or evening can be classiﬁed into early chrono-

types (ECTs), late chronotypes (LCTs), or those in

between (intermediate chronotypes, ICTs) (228). ECTs,

sometimes referred to as “larks,”have signiﬁcantly ear-

lier sleep-wake cycles compared with LCTs (or “night

owls”), who function better later in the day. These differ-

ences are not only observed in sleep-wake cycles but

also multiple physiological (229), behavioral (228), and

genetic (230) oscillations that occur every 24-h period.

The implications for competition performance are not

entirely clear. Diurnal performance proﬁles have been

studied between ECTs and LCTs to determine whether

there is signiﬁcant variation when individual aspects of

circadian timing are considered. These investigations

show clear differences in performance proﬁles between

ECTs and LCTs, with LCTs exhibiting greater variation in

diurnal performance proﬁles, particularly in the morning

(231). Interestingly, performance peaks can be shifted by

different measures such as active and passive warm-up,

caffeine, or training-competition time-of-day synchroni-

zation (225). Moreover, individual shifts in chronotypes

or time-of-day performance are observed (i.e., in older

athletes with a higher prevalence of “morningness”in

training scheduling and work rates) (221).

The impact of exercise training at different times of the

day has been well studied in animal models and healthy

moderately trained humans, with the primary outcome

typically being a measure of exercise capacity, often a

laboratory-based task designed to mimic performance, or

a metabolic surrogate (232–234). However, studies inves-

tigating the timing of exercise training in elite athletes and

the subsequent effect on performance outcomes are

scarce. Once again, we are left to generalize from inter-

ventions in healthy, almost exclusively male, non-elite

subjects until such gaps in the literature are ﬁlled. There

are several reports of greater increases in muscle mass

and strength after training late in the afternoon versus

early morning (221,233–235), which is in line with the

generally higher peak forces attained in the afternoon/

early evening (236). Consistent with the enhanced reli-

ance on fatty acid oxidation in a fasted state in the early

morning in humans (237), there is a more robust meta-

bolicimpactofexerciseinthefastedstate(atthebegin-

ning of active phase in rodents) than in the fed state (at

the beginning of the rest phase) (214). Regardless, the

results are likely to have limited translational value for elite

athletes who typically undertake several workouts within

any 24-h period supported by round-the-clock eating pat-

terns necessary to meet the demands of training (81).

While elite athletes are informed of the venues, dates,

and times of major international competitions several

yearsinadvance,thenationsselectedtohostthe

Olympic Games and World Championships often adjust

competition times to accommodate and coincide with

prime-time viewing hours for North American television

audiences. At the recent Tokyo Summer Olympics, the

entire swimming program was “ﬂip-ﬂopped”such that

qualifying heats and semiﬁnals (normally held in the

morning) were scheduled for the evening and all ﬁnals

were swum in the morning. As circadian oscillations affect

physiological, psychological, and molecular mechanisms

resulting in varying physical performance capacities over

the day, both the timing and relative size of these effects

are important for optimizing sport performance at the elite

level. To determine the extent to which elite athletes are

affected by circadian ﬂuctuations in physical performance,

Lok et al. (238) assessed data from four Olympic Games

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(Athens 2004, Beijing 2008, London 2012, and Rio de

Janeiro 2016). The authors analyzed swimming perform-

ances, as these races are less likely to be inﬂuenced

by confounding environmental effects (i.e., temperature,

humidity, wind speed) and have little reliance on equip-

ment that could induce variation within and between ath-

letes. Additionally, the water temperature in the pool is

required to be within a narrow range across Olympic ven-

ues, providing a “clean”signalofdailyvariationinphysical

performance (238). Their analysis revealed that perform-

ance in Olympic swimmers was signiﬁcantly affected by

the time of day, with best performance occurring in the

late afternoon/early evening. The amplitude of the effects

of time of day was 0.37%, and in 40% of the ﬁnals this

effect was larger than the time difference between gold

or silver medal ﬁnishing times. Furthermore, time-of-day

effects exceeded the time difference between the silver

and bronze medals in 64% of the ﬁnals and the time differ-

ence between bronze and fourth place in 61% of the ﬁnals

(238). These data indicate that despite athletes incorpo-

rating both morning and evening workouts, endogenous

circadian clocks still exert a time-of-day effect on elite

swimming performance. Whether the application of circa-

dian or time-of-day principles can optimize training and

improve performance of these elite athletes remains to

be determined.

2.7. Training Strategies and Paradigms: Good,

Bad, or Indiﬀerent?

The identiﬁcation of training strategies that consistently

enhance performance remains challenging because of

the multiple interdependent factors contributing to athletic

success. Consensus emerging from observational studies

reﬂects the current practices in long (239), middle dis-

tance (146), or sprint (240) disciplines, but these are likely

to be modiﬁed with technological advances and

insights from coaches and “science-driven”initiatives,

such as the “sub-2 hour”marathon project. However,

training intervention studies are often limited to low partici-

pant numbers, with a reliance on a restricted pool of

young, male, college-educated, recreational or untrained

cohorts. Extrapolation to other demographics, including

women, underrepresented ethnicities, or elite athletes is

problematic. For example, signiﬁcant sex differences exist

in the response to both acute exercise and chronic training

adaptation (241–243), and the effects of reproductive sta-

tus, endogenous and exogenous hormones, and the men-

strual cycle are underappreciated not only in research

studies but also in training program design and application

(244). Importantly, sex differences extend to many

other training-related factors, including muscle mass

and strength, injuries, and even training participation

rates (245). On occasion, understudied approaches

can lead to detrimental outcomes, as observed for the

transient hype surrounding the so-called beneﬁts of

cold-water immersion, whole body cryotherapy, and

other passive recovery strategies that in certain con-

texts can adversely affect recovery or performance

outcomes (246,247). New training strategies are often

based on observations of athletic performance in

extreme conditions, such as the high altitude of the

1968 Olympic Games held in Mexico City or the high

temperatures that were expected for the Tokyo 2020

Olympic Games (held in 2021 because of the coronavirus

pandemic). The former contributed to the widespread

study and adoption of high-altitude training, whereas the

latter was a primer to explore heat training as a modality

to improve performance not only in hot environments but

also in mild or cold temperatures. The potential mecha-

nisms for enhanced performance in thermoneutral envi-

ronments after heat exposure, improved thermotolerance,

enhanced heat dissipation, expanded plasma volume, ele-

vated hemoglobin mass, and other adaptations triggered

by heat exposure, are discussed in sect. 4.6.1 (248,249).

Safety is an obvious concern for such an intervention,

necessitating close monitoring of core body temperature

and cardiac-related parameters (250). In most cases,

many of the reservations about speciﬁc training strategies

stem from an inadequate understanding of the systemic,

organ/tissue, cellular, and molecular events that occur in

response to an acute exercise bout and how such infor-

mation translates into long-term adaptation. In sects. 3

and 4, we summarize the current knowledge of the physi-

ological, cellular, and molecular underpinnings of muscle

plasticity triggered by both endurance- and resistance-

based exercise.

3. PHYSIOLOGICAL AND CELLULAR

ADAPTATION TO EXERCISE TRAINING:

FUNCTIONAL RESPONSE

The cellular, tissue/organ, and whole body adaptations

that occur when exercise bouts are repeated over

months and years drive the phenotypic changes

observed in highly trained athletes. Such adaptations

include alterations in energy ﬂux and metabolism, ﬁber

type transformations, enhanced mitochondrial and capil-

lary density, and muscle hypertrophy, highlighting the

enormous plasticity of skeletal muscle (TABLE 1).

Although endurance training predominantly induces

numerous metabolic adaptations that match muscle

energy supply to demand and improve economy of

motion, athletes engaging in sports that require high peak

forces demonstrate marked changes in muscle morphology

and cross-sectional area (CSA). When training adaptation is

maximized in the face of favorable genetic predisposition,

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extraordinary performances can be achieved, such as the

ﬁrst sub-2-h marathon by Eliud Kipchoge in 2019 (unofﬁcial

record of 1:59:40.2), the 100 m time of 9.58 s in 2009 by

Usain Bolt, or the current world record holder Hafþ

or Júlíus

Bj€

ornsson, who was able to deadlift 501 kg. These perform-

ances highlight the remarkable potential of skeletal muscle

to generate huge amounts of energy (adenosine triphos-

phate, ATP) for a sustained period in order to run at a speed

of 21.2 km/h for 2 h, to rapidly contract muscles to be able

to run at speeds exceeding 37 km/h for several seconds, or

to lift 500 kg. In this section, we discuss the adaptations

observed in elite athletes that allow such extraordinary

efforts.

3.1. Oxygen Transport and Maximal Oxygen

Uptake

Exercise of prolonged duration and/or high intensity

presents a major challenge to whole body homeostasis

and is associated with extensive perturbations in numer-

ous cells, tissues, and organs that are caused by, or are

a response to, the increased metabolic activity of con-

tracting skeletal muscles. To meet this challenge, multi-

ple integrated responses are rapidly engaged to blunt

the acute homeostatic threats generated by exercise-

induced increases in muscle substrate turnover and

oxygen demand (9). When repeated over time (i.e., exer-

cise training), there is a coordinated process of adapta-

tion that can be broadly categorized as either “central”

(nervous, respiratory, and cardiovascular systems) or

“peripheral”(skeletal muscle). However, such a simplis-

tic classiﬁcation does not completely characterize the

interdependent nature of these processes. For example,

pulmonary oxygen diffusion, Hb levels, cardiac output,

vascularization of the muscle, as well as oxygen extrac-

tion and utilization by the muscle during oxidative phos-

phorylation (OXPHOS) all contribute to the endurance

training-induced increase in maximal oxygen uptake

VO2max)(FIGURE 6)(291). _

VO2max therefore is a measure

of the combined capacities of the central nervous sys-

tem to recruit motor units, the pulmonary and cardiovas-

cular systems to deliver oxygen to contracting muscles

(including erythrocyte number and heme loading), along

with the ability of those muscles to extract and use oxy-

gen via oxidative metabolic pathways (9). At rest, whole

body oxygen consumption is 3.5 mL/kg/min, with

25% of this being taken up by skeletal muscle (251). In

untrained humans, _

VO2max is 10- to 15-fold greater

than resting values (i.e., 30–50 mL/kg/min). In elite en-

durance-trained athletes, _

VO2max can be twofold higher

compared with non-athletes, with the highest _

VO2max

values being 96 and 80 mL/kg/min for male and female

endurance athletes, respectively (252,292,293). The

Table 1. Reference values of sedentary individuals and elite endurance athletes

Sedentary Elite Athlete References

Men WomenMen Women

VO2max, mL/min/kg <45 <40 70–85 60–75 (122,251–265)

VEmax, L/min 120–140 95 165–185 125 (261,263,266–273)

Stroke volume, mL/beat (251,253,265)

At rest 65 55 110 70

Maximum 100 70 150–200 125

Cardiac output, L/min (251,253,265,274–276)

At rest 5–63.5–4.5 5–63.5–4.5

Maximum 20 15 30–40 25

Lactate threshold, % _

VO2max 60 60 75–85 75–85 (80,122,264,277)

Fiber type, % type I 40–50 40–50 >60 >60 (169,254,256,278–284)

Capillary-to-ﬁber ratio 1.5–2 Similar or slightly lower 2.5–3 insufﬁcient data (169,254,255,278,285–288)

Mitochondrial volume density, % 4–5 Similar or slightly lower 7.5–9 insufﬁcient data (254,255,285,286,289,290)

Sedentary men and women are between 20 and 30 yr of age. All values of muscle tissue originate from vastus lateralis biopsies. _

VEmax, maximal exer-

cise-induced pulmonary ventilation; _

VO2max, maximal oxygen uptake. Less data are available for female athletes and sedentary control subjects.

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lower _

VO2max values for women are reﬂected in the

female world records for endurance events, which are

typically 10–12% slower (294). Such differences are mainly

due to the lower absolute and relative muscle mass in

women and the lower Hb levels (294). Differences in

VO2max are also observed based on the demands of the

sport and the associated mode of training. Elite male

cross-country skiers and rowers engage a larger propor-

tion of their muscle mass (upper and lower body) than

cyclists or distance runners during training and exhibit

higher _

VO2max values. The training-induced increases in

VO2max are largely conﬁned to athletes competing in en-

durance-based events: power/strength-trained individuals

often have _

VO2max values similar to non-athletes (266).

Therefore, parameters affecting _

VO2max are differentially

impacted by the training prescription.

In most contexts, the limits of maximal oxygen con-

sumption are multifactorial and not attributable to any

single parameter (295). However, in general, exercise

performance is not limited by the respiratory system, as

its capacity exceeds demand during maximal exercise

(296). However, functional training-induced changes still

occur in athletes, including a greater strength and fa-

tigue resistance of the respiratory muscles resulting in

higher maximal voluntary ventilation (MVV) and forced

vital capacity (FVC) (266,296–298). Maximal tidal vol-

ume is similar in athletes and non-athletes, with the

higher maximal exercise-induced ventilation brought

about by an elevated breathing frequency (266). Hb lev-

els are similar in highly trained endurance athletes and

untrained individuals (266) and are only elevated by alti-

tude training interventions, discussed in sect. 2.4. (299).

However, because of a training-induced increase in

blood volume, total Hb mass may be higher (300,301). In

addition to the increased strength of respiratory muscles,

endurance athletes have cardiac hypertrophy that is char-

acterized by greater left ventricular mass and relative wall

thickness resulting in a higher maximal and resting stroke

volume and a corresponding lower resting heart rate

(253,266). Although maximal stroke volume plateaus at

40–50% of _

VO2max in untrained individuals, stroke vol-

ume increases until volitional exhaustion, contributing to

the augmented _

VO2max in elite endurance athletes (253).

In these individuals, maximum stroke volumes of 200 mL/

myonuclei ↑

MPS ↑

glycogen ↑

IMCL ↑

mitochondrial biogenesis ↑

capillary density↑

glucose↑

GLUT4 CD36

myoglobin↑

Whole body adaptation Skeletal muscle adaptation

fatty acids ↑

β-oxidation↑

OXPHOS ↑

Respiration

↑ strength & endurance of respiratory muscles

↑ breathing frequency

↑ maximal ventilation

Heart

cardiac hypertrophy

↑ resting/maximal stroke volume

↑ cardiac output

Blood

↑ Hb mass

↑ capillary density

Muscle

↑ slow oxidatve muscle fibers

↑ myoglobin

↑ substrate uptake and storage

↑ mitochondria

↑ OXPHOS

VO2max and endurance performance

Neural

↓ intracortical inhibitory interneurons

↓ antagonistic activity

Heart

cardiac hypertrophy

↑ resting stroke volume

Muscle

fiber hypertrophy

↑ myonuclei

Peak power

fiber hypertrophy

 



        







FIGURE 6. Whole body adaptations that contribute speciﬁcally to higher peak power or endurance performance. Although mainly neural and muscular

adaptations improve peak power, for endurance performance various organs and tissues show major changes. To maximize _

VO2max and thereby endur-

ance performance, changes in respiratoryand cardiovascular function as well asadaptations in skeletal muscle are required. In skeletal muscle, the high

mitochondrial density, elevated substrate (i.e., fatty acids and glucose) uptake and storage, myoglobin content, and increased vascularization all contrib-

ute to the elevated performance of endurance athletes. Strength training-induced adaptations include increased muscle protein synthesis (MPS) result-

ing in ﬁber hypertrophy and optimally myonuclear accretion. CD36, platelet glycoprotein 4; GLUT4, glucose transporter type 4; IMCL, intramyocellular

lipids. See GLOSSARY for other abbreviations. Sport icon vectors were created by ibrandify/Freepik. Image created with BioRender.com, with permission.

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beat have been reported, indicating that a cardiac output

of up to 35–40 L/min could be reached, a ﬁgure almost

double that observed in non-athletes (251,274). Whereas

left ventricular mass and resting stroke volume are similar

in power and endurance athletes, _

VO2max is not elevated

in power athletes, likely because of the increased maximal

stroke volume and oxygen pulse per stroke volume after

endurance but not resistance training (266). Finally, vascu-

larization of skeletal muscle also contributes to _

VO2max

(154). Capillary density in all ﬁber types is 50% higher in

elite endurance-trained compared with nontrained individ-

uals (254,278), and athletes with superior muscle vascula-

rization are even more fatigue resistant compared to

athletes with similar _

VO2max values (80). The endurance

training-induced vascularization occurs rapidly, with 6 wk

of intense training being sufﬁcient to elevate capillary den-

sity and capillary-to-ﬁber ratio (molecular mechanisms driv-

ing this adaptation are described in sect. 4.5.3) (255,302).

In contrast, capillary density in power/strength-trained ath-

letes does not increase with training and may be lower

than that in untrained individuals because of the ﬁber hy-

pertrophy (278,303). Collectively, central adaptations

occur at multiple levels and play an important role in the

high _

VO2max in elite athletes.

3.2. Neuromuscular Control and Force Generation

In contrast to the high _

VO2max required for optimal en-

durance performance, many sports require high power

generation, including sprint events (running, swimming,

cycling, and rowing) and weightlifting, powerlifting, and

throwing events. Maximal performance in elite strength/

power athletes is 15–20% lower in females than in

males (304), because of differences in lean body mass

between men and women (168,305). In line with the

lower lean mass, fat mass of female athletes is about

twofold higher compared to men with similar body mass

(304). With increasing age, differences in maximal per-

formance in terms of world records in female and male

masters athletes become greater, and records are

30–50% lower in women, mirroring the sex differences

observed in untrained and recreationally trained individ-

uals (304).

Voluntary muscle contraction is a complex task requir-

ing a highly coordinated interplay on multiple levels

including supraspinal structures, spinal cells, afferent

feedback and efferent input, and the motor unit (306).

The motor unit consists of the soma, dendrites, and

axon of the motor neuron as well as the innervated mus-

cle ﬁbers. The force-generating capacity of the muscle

is determined by the number of activated motor units,

the discharge rate (also described as ﬁring frequency

or rate coding) of the motor neuron, and the size and

contractile properties of the activated muscle ﬁbers. To

initiate muscle contractions, the central nervous system

sends commands to the motor neurons located in the

ventral horn of the spinal cord (307). Motor neurons inte-

grate the signal from a number of different regions and

nuclei in the cortex and brain stem, interneuron circuitries,

as well as the peripheral sensory input from afferent ﬁbers

located in the muscle spindles and Golgi tendon organ

into an action potential. The action potential propagates

along the axon of the motor neuron to the innervated

muscle ﬁbers and, through acetylcholine receptor activa-

tion and excitation-contraction coupling (ECC), results in

mechanical output by the muscle. In comparison to central

nervous system synapses, the neuromuscular junction

(NMJ) has a very high safety factor, and a nerve action

potential results in an end-plate potential (EPP) of a local

depolarization of 30–40 mV, which is higher than

required to elicit an action potential in the muscle. Several

morphological and functional parameters also contribute

to this high safety factor (308–310): ﬁrst, an extraordinarily

large size of the synapse, 100- to 200-fold bigger com-

pared with central nervous synapses in the mouse, and

thus ample interaction surface; second, a high density

of voltage-gated Ca

channels in the active zones,

coupled to a high concentration of acetylcholine in a syn-

aptic vesicle; third, the number and density of acetylcho-

line receptors, and the concentrated localization at the

crest of postsynaptic folds, adjacent to voltage-gated Na

channels (Nav1.4) in the corresponding troughs; and fourth,

the strong enzymatic activity of acetylcholinesterase in the

synaptic cleft for rapid removal of acetylcholine and

thereby prevention of repeated activation of individual ac-

etylcholine receptor channels in response to a single

action potential in the motor neuron. Together, these prop-

erties lead to an “all-or-none”activation (as ﬁrst described

by Henry Pickering Bowditch in 1871 for cardiac muscle,

later expanded to skeletal muscle), meaning that once the

stimulus threshold for an action potential in the motor neu-

ron is reached (based on the integration of different incom-

ing signals), an action potential and contraction in the

muscle ﬁber is inevitably triggered. The frequency of acti-

vation (rate coding) of the muscle ﬁberisimportantforthe

generation of force (311). In a single muscle twitch, Ca

reenters the sarcoplasmic reticulum and ﬁber relaxation

becomes complete. A more frequent stimulation results in

wave summation, and thus greater force, ultimately maxi-

mizing in a tetanus, in which twitches overlap and no

relaxationcanoccur.Inrodents,exercise-induced

NMJ remodeling has been observed affecting mor-

phology and function of this synapse (312,313). For

example, endurance training boosts the amount of

neurotransmitter released per action potential, con-

comitantly with an upregulation of acetylcholinester-

ase (313,314). Furthermore, an enlargement in the

interaction surface is achieved by a modulation of the

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number and length of nerve terminal branches, coupled to

an elevation in the total area occupied by presynaptic neu-

rotransmitter vesicles and postsynaptic acetylcholine recep-

tors (314). Similar adaptations are observed in genetic

mouse models of endurance training, with corresponding

changes in neuromuscular transmission properties (315).

Notably, however, size, complexity, and fragmentation of

murine and human NMJs can differ substantially (316). Data

describing training-induced NMJ plasticity can therefore

only be extrapolated to humans with caution, in particular

since corresponding interrogations in humans are lacking.

Whereas hand muscles have fewer motor units than

large limb muscles, the number of motor units of different

limbmusclesvariesandisnotalwaysrelatedtomuscle

size (317). In contrast, the average innervation number

(number of muscle ﬁbers innervated by a single motor neu-

ron, also called motor unit size) strongly correlates with

muscle size (317). Innervation numbers, even within one

muscle, can range from tens to thousands, and thereby

enable diverse actions such as ﬁne-tuning of the move-

ment or high force generation, respectively (317,318).

Whereas slow type I muscle ﬁbers (discussed in sect. 3.3)

are mostly part of motor units with a low innervation num-

ber, motor units with a high innervation number often con-

nect to fast type II ﬁbers (317). The motor neurons of these

different motor units exhibit considerable morphological

and functional differences (FIGURE 7). For example, motor

neurons innervating type II muscle ﬁbers in general have

larger somas and more dendrites as well as a larger axonal

diameter sizes, the latter enabling faster conductance ve-

locity (306,319). The physical dimensions of the motor

neuron somas contribute to the determination of the

recruitment threshold (320). Thus, the larger surface area

and high number of ion channels in fast motor neurons

result in a lower input resistance compared with the small

surface area with fewer ion channels of slow motor neu-

rons (320). According to Ohm’slaw(V=IR), the same

synaptic input thus induces greater changes in the mem-

brane potential of small motor neurons (with a higher re-

sistance) compared with large motor neurons (with a lower

resistance). Consequently, small motor neurons reach the

ﬁring threshold with less synaptic input compared with

theirlargercounterparts.Thisorderlyrecruitmentwas

showninanimalpreparationsbyHenneman(320), and

according to Henneman’s size principle small motor neu-

rons innervating slow type I muscle ﬁbers are recruited

ﬁrst, subsequently followed by larger motor neurons inner-

vating type IIA and ﬁnally IIX ﬁbers (306). This leads to a

gradual and smooth increase in muscle force (graduation

of contraction) and a predominant activation of slow and

↑

antagonists ↓

motor unit recruitment ↑

↑

↓

↑

inhibition of

afferent feedback

and/or

spinal interneurons

intracortical

inhibition

corticospinal

excitability

excitatory

drive low threshold

motor unit

high threshold

motor unit

NMJ

remodeling

fiber size

firing frequency

agonists

synergists

stabilizers

FIGURE 7. Neuromuscular adaptation totraining. The number of activated motor units, their ﬁring frequency, as well assize and contractile properties

of the muscle ﬁbers determine total force-generating capacity. In trained individuals, neural adaptations include an increased excitatory drive that can

lead to an elevated ﬁring frequency and higher number of activated motor units. In addition, the enhanced activation of agonists, synergists, and stabil-

izers together with the reduced coactivation of antagonists contribute to the increased force production after training. For many of these adaptations

only data in rodent models exist, and/or controversial ﬁndings in humans have been reported. NMJ, neuromuscular junction. Illustration of person was

created by kjpargeter/Freepik. Image created with BioRender.com, with permission.

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fatigue-resistant small motor units until these are over-

whelmed by strong, powerful movements necessitating

the recruitment of fast-twitch, high peak force-generating

ﬁbers (306). Although the size principle holds true for spe-

ciﬁc laboratory conditions, physiological systems that

include excitatory and inhibitory inputs are much more

complex, and it is debatable whether motor units are

always recruited in a graded manner (319,321). Recent evi-

dence suggests that during slow, ramping movement

orderly recruitment occurs, whereas high-frequency, sinu-

soid types of contractile activity are not following the size

principle (322). Moreover, motor unit recruitment is

affected by the length of the muscle (322). This implies

that, during ballistic training, recruitment is observed in a

more selective manner corresponding to the functional

movement according to the neuromechanical matching

principle (319,321). However, even during slow ramping

movement, as might be encountered in weightlifting, fast

motor units can be recruited with submaximal load (138,

323,324). In fact, a number of studies have demonstrated

that even low-load exercises such as 30% 1RM result in

recruitmentoftypeIandIIﬁber if completed until failure,

inducing a hypertrophic response similar to high-load train-

ing (138,323–325). This ﬁnding might be explained by the

observation that with increasing muscle fatigue more

motor units are being recruited to meet the same force

output,evenwhenlowerloadsareused(138,323,324).

Therefore, the recruitment of slow and fast motor units is

dependent not only on the applied load and generated

force but also on the fatigue state, contraction velocity,

and length, as well as potentially other parameters that are

extracted from skeletal muscle in different exercise proto-

cols and paradigms. Some of these factors, such as velocity

and length, might induce selective rather than the orderly

recruitment of motor units postulated in Henneman’ssize

principle. In summary, motor unit engagement, recruitment,

and fatigue are still poorly understood. Moreover, the plas-

ticity of this structure in training and the speciﬁcadaptations

in elite athletes are largely unknown. Of note, based on the

transcriptional proﬁle, even more distinct motor neuron

pools exist than the classically deﬁned three types, fast fati-

gable, fast fatigue-resistant, and slow (326). The functional

relevance of this more ﬁne-grained speciﬁcation remains

unknown.

3.2.1. Neural adaptations.

Increased force generation can be achieved by neural

adaptation, muscle hypertrophy, and/or intrinsic changes

in contractile properties (strength/power per unit of muscle

mass). MVC is substantially elevated in resistance training

beforeanyincreaseinmuscleCSA,suggestingthatneural

adaptations mainly contribute to the strength gains in the

initial phase, followed by structural changes within the

muscle. The activity of intracortical inhibitory interneurons

is lower in trained individuals, whereas data on corticospi-

nal excitability are equivocal and likely unaffected by train-

ing (327–329). The reduction in intracortical inhibition in

response to strength training induces a higher excitatory

drive, which may contribute to elevated strength in these

individuals. With augmenting force generation, the number

of active motor units as well as their activity in terms of dis-

charge rate increase (318,330). Accordingly, the higher de-

scending neural input in strength-trained individuals could

explain the elevated discharge rate and adequate activa-

tion of motor units, culminating in the observed enhanced

voluntary activation and maximal force (318,331,332). In

addition, the elevated neural drive might be important for

explosive power, as a fast recruitment and a high discharge

rate of motor units are important for the rate of force devel-

opment (330). The lower recruitment threshold observed

after strength training suggests that, in addition to the

changes in neural drive, intrinsic properties of motor neu-

rons may be altered by training (331). The timing of the

action potentials discharged by concurrently active

motor units of strength athletes appears to exhibit

greater synchronization than that in untrained individ-

uals, even though it is debatable whether these adap-

tations in intramuscular coordination contribute to

strength gains (333). Intermuscular coordination is

also improved at several levels. Besides the recruit-

ment of agonists, stabilizers/ﬁxators, and neutralizers/

synergists, reducing the coactivation of antagonists

signiﬁcantly contributes to the maximal voluntary acti-

vation and force generation in highly trained athletes

(332–334). Whether these training adaptations

evoked by intermuscular coordination are primarily

mediated by disinhibition of supraspinal signals,

altered activity of Renshaw cells and other spinal inter-

neurons, and/or adaptations in afferent feedback,

such as decreased stretch inhibition by the proprio-

ceptive system, is unclear. Nevertheless, the impor-

tance of early neural and neuromuscular adaptations

and the concomitant optimization of intra- and inter-

muscular coordination before structural changes of

themuscleinresistancetrainingadaptationisirrefuta-

ble (FIGURE 7)(329,335,336). The corresponding

neural changes in endurance training are less well

characterized but could contribute to improved run-

ning economy, decreased fatigability, and other inter-

related parameters (337–339).

3.2.2. Muscle hypertrophy.

Powerlifting or hammer throw athletes rely on the gener-

ation of instantaneous maximal peak forces, whereas

sports that involve short-duration sprints require high

contractile velocity of muscles over several seconds.

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Nonetheless, an increase in muscle mass to generate

high contractile forces is a common goal for these ath-

letes. Indeed, the muscle volume of the lower limbs of

both sprinters and other strength-trained athletes is

higher compared with endurance athletes and untrained

individuals (340,341). The training-induced gain in mus-

cle CSA is not evenly distributed along the length of the

muscle ﬁber but occurs predominantly in the midbelly

region of the muscle, which explains why the percent

increase in CSA can exceed that of muscle volume (335,

342). In humans most muscles are pennate, in which the

increase in physiological CSA of the muscle, reﬂecting

the radial growth of the myoﬁber, can diverge from the

increase in anatomical CSA. To optimize the limited

space of the aponeurosis, a larger CSA is usually accom-

panied by a steeper pennation angle, which is greater

in highly trained strength athletes compared with

untrained individuals (343) and strongly correlates with

muscle thickness (344). In contrast, in elite sprint athletes

(100 m sprinters and sprint cyclists), muscle thickness is

increased without changes in the pennate angle (345,

346). As these observations in elite athletes are all cross

sectional, it remains to be determined whether the archi-

tectural differences contributing to peak performance

are the result of long-term training adaptation or genetic

predisposition. Despite these ﬁndings, the contribution

of the pennation angle and other architectural proper-

ties to muscle functionality and power generation

remains contentious (347,348).

Of note, hypertrophy of myoﬁbrillar and sarcoplasmic

compartments has been described, and the relative

impact on muscle mass and strength gains remains equiv-

ocal, similar to the importance of “conventional”hypertro-

phy with a proportional increase in myoﬁbrillar protein

content and tissue growth compared with “unconven-

tional”hypertrophy, for example achieved by myoﬁbrillar

packing preceding an increase in ﬁber size (349).

Nevertheless, in most cases resistance training induces

radial growth of the muscle, resulting in a higher CSA

(mechanisms underlying this response are described in

sects. 4.1 and 4.3–4.5) (342,350). The expansion of myoﬁ-

brillar protein resulting in ﬁber hypertrophy might contrib-

ute the most to enhanced force-generating capacity of a

muscle ﬁber. Within the muscle ﬁber, 80% of the volume

consists of myoﬁbrils that are composed of sarcomeres,

the contractile units of the myoﬁbril (351). The thin actin

and thick myosin ﬁlaments constitute the two major active

components of the sarcomeres responsible for muscle

contraction. Upon Ca

binding to troponin C (TnC), tro-

pomyosin conformation changes to expose the myosin-

binding site on the actin ﬁlament. The thick myosin ﬁla-

ments, the force-generating elements of the sarcomere,

bind to actin and induce the sliding of actin ﬁlaments

along the myosin, resulting in muscle shortening. The

addition of sarcomeres in parallel rather than in series

causes an increase in ﬁber diameter (342). In line with the

high potential of type IIA ﬁbers to increase CSA and force

generation (352), hypertrophy predominantly occurs in

type IIA ﬁbers in elite strength-trained athletes (303,350).

Besides radial growth, inclusion of additional sarcomeres

in series leading to increased fascicle strength has been

reported (342). Limited data are available regarding the

longitudinal growth of the muscle in response to resist-

ance-based training, although there is evidence that fasci-

cle length can increase (335,343). For example, a longer

fascicle length is observed in elite sprinters (345,346),

which is positively correlated with performance times

(343,353,354). The longer fascicles could contribute to a

greater shortening velocity of a pennate muscle and

thereby enhance sprint performance (353). However, the

totalnumberofsarcomeresinseriesinamuscleﬁber and

the effects of training are difﬁcult to determine in humans,

and the few studies in rodents revealed mixed results

(342). Moreover, recent evidence indicating a mesh-type

network of branching sarcomeric structures instead of

individual sarcomeres existing in separated tubes further

complicates the interpretation of changes in sarcomere

numbers in series and in parallel (355).

Despite the fundamental contribution of radial muscle

growth to maximal power output, the relationship between

force generation and muscle CSA is not linear, emphasiz-

ing the contribution of other factors (356). One possibility

could be that muscle quality rather than size is enhanced,

resulting in a higher speciﬁc force (force per CSA) (352).

For example, the speciﬁc force of type I ﬁbers has been

shown to increase in response to resistance exercise

(352). Additionally, changes in ﬁber type distribution could

enhance speciﬁc force capacity, since both the force-gen-

erating capacity per myosin head as well as the fraction of

attached myosin heads are higher for fast myosin heavy

chain isoforms (357). Despite these changes, the increase

in overall muscle strength is superior compared with the

integration of single-ﬁber strength gains, indicating that

optimalstrengthgainsoccurwhenbothneuralaswellas

muscular adaptations take place (352).

The increase in myoﬁbrillar proteins is often, but not

always, accompanied by elevation of the number of myo-

nuclei, potentially to optimize the hypertrophic response.

The syncytial nature of muscle cells has been hypothe-

sized to be due to the limited capacity of (myo)nuclei to

provide transcripts for a certain volume of the cytoplasm,

deﬁned as the myonuclear domain (358). According to

this hypothesis, the upper limit of the myonuclear domain

is determined by the maximal transcriptional capacity of

myonuclei. Once this ceiling is reached, the number of

myonuclei was thought to be increased by the fusion of

satellite cells to muscle ﬁbers to maintain a relatively con-

stant DNA-to-cytoplasm ratio (reviewed in Ref. 358), a

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concept that has subsequently been reﬁned and cor-

rected (359). Moreover, in humans hypertrophy has also

been reported in the absence of myonuclear accretion

(360,361). Furthermore, although the addition of myonu-

clei is greater when hypertrophy exceeds 22% of size

gain, it also occurs when hypertrophy is <10% (362).

According to a recent meta-analysis, a deﬁnitive “hypertro-

phy threshold”required for myonuclear accretion remains

tenuous, and thus the threshold hypothesis appears prob-

lematic (362). Nevertheless, cross-sectional data from ath-

letes often show hypertrophy to be positively correlated

with myonuclear number (363). For example, in elite

powerlifters, both the size of the muscle ﬁbers as well as

thenumberofmyonucleiarehighercomparedwithnon-

athlete control subjects, and the gradient of the correlation

curve suggests that the myonuclear domains are higher in

largetypeIImuscleﬁbers of powerlifters compared with

those of untrained individuals (364). The use of anabolic

steroids and testosterone in powerlifters results in a dispro-

portional increase in muscle size and number of myonu-

clei, thereby leading to a larger myonuclear domain (365).

Although these data indicate a certain degree of myonu-

clear domain plasticity that could be explained by the

reserve capacity of the myonuclei to boost transcriptional

output (366), in most cases the myonuclear domains are

still within the reported range, also highlighting individual

heterogeneity.

In summary, strength-trained athletes have a pro-

nounced increase in muscle volume largely underpinned

by the speciﬁc hypertrophy of type IIA ﬁbers and accom-

panied by an increase in pennate angle, resulting in sub-

stantial gains in force-generating capacity. In addition to

the elevated muscle volume, the fascicles of sprint ath-

letes are elongated, contributing to higher shortening

velocity of the muscle and greater power generation.

Although neuromuscular adaptations together with mus-

cle hypertrophy explain the enhanced muscle perform-

ance in highly trained athletes, these adaptations differ

among athletes in a discipline-dependent manner. For

example, the musculature of strength-trained athletes has

a larger CSA and can produce greater maximal forces,

whereas power-trained athletes have slightly lower peak

forces but display a faster rate of force development (341).

These differences are most pronounced within the ﬁrst 50

ms of a contraction (341,367). The enhanced explosive

(i.e., high shortening velocity) and maximal forces in ath-

letes result in remarkable power output. In male power

athletes, mean peak power, as assessed by a counter-

movement jump, ranges between 50 and 65 W/kg, with

maximal values up to 85 W/kg for men and 70 W/kg for

women (252,303,368,369). The acceleration power

attained at the start of a 100 m sprint was estimated to be

2,392 W or 30.3 W/kg for men and 1,494 W or 24.5 W/kg

for women (252). It was calculated that Usain Bolt

reached a power output of 2,750 W (29.3 W/kg) during his

100mworldrecordin2009(252). In contrast to these re-

markable power metrics for strength/sprint-trained athletes,

power output (as measured by jump performance) remains

largely unchanged in endurance-trained athletes (266). It

is clear that the adaptive response to training stimuli is

event-speciﬁc in terms of muscle hypertrophy and neuro-

muscular adaptation, resulting in distinct performance

characteristics between different sporting disciplines.

3.3. Fiber Type Distribution

Distinct properties of the muscle further contribute to

the performance of elite athletes, such as ﬁber type dis-

tribution. In addition to distinct innervation and recruit-

ment (as described in sect. 3.2), intrinsic properties of

muscle ﬁber types diverge in a multifaceted manner

(155,357,370–372). Muscle ﬁber types can be classiﬁed

according to their predominantly expressed isoform of

the myosin heavy chains, which are the molecular

motors of the myoﬁbrils and vary in the relative actin-

activated ATPase activity that correlates with contraction

velocity (357). Differences in ﬁber type distribution are

accordingly observed in muscles of endurance- or

strength-trained athletes and considerably contribute to

sports-speciﬁc performance. The three myosin heavy

chain isoforms expressed in human muscle, type I

(encoded by the MYH7 gene located on chromosome

14, 14q11.2), type IIA (encoded by MYH2, on chromosome

17, 17p13.1), and type IIX (encoded by MYH1,adjacentto

MYH2 on chromosome 17, 17p13.1), have distinct me-

chanical properties conferring differences in contractile

velocity and force production. Type IIX ﬁbers generate

the highest force and have the fastest shortening veloc-

ity, resulting in high peak power, and are classiﬁed as

“fast-twitch”ﬁbers (357,373). The enhanced force-gener-

ating capacity is attributable not only to the larger size of

type II ﬁbers but also to intrinsic differences (i.e., higher

force-generating capacity of fast myosin heavy chain iso-

forms and a larger fraction of attached myosin heads),

resulting in a higher speciﬁc force of type II ﬁbers, which

is observed in untrained individuals as well as elite ath-

letes (357,374–376). In addition to greater power-gener-

ating capacity, fast type II muscle ﬁbers exhibit shorter

half-relaxation time due to differences in Ca

transient

kinetics (357). In response to an action potential, Ca

release in fast murine muscle ﬁbers is threefold higher

compared with slow ﬁbers, likely because of the greater

abundance of the Ca

release channel ryanodine recep-

tor 1 (RYR1) (357). The inhibitory effect of intracellular

concentrations on Ca

release is lower in slow

muscle ﬁbers, possibly contributing to the higher fatigue

resistance of these ﬁbers, as Mg

levels rise during fa-

tigue (357). Fiber type-speciﬁc differences in Ca

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transient related to the faster decline in cytoplasmic con-

centrations are determined by the sequestration of Ca

tobindingandbufferproteinssuchastroponinC(TnC),

parvalbumin, and calmodulin, as well as the reuptake of

into the sarcoplasmic reticulum (SR) by the sarco-

plasmic/endoplasmic reticulum Ca

-ATPase (SERCA)

pumps (357). As the TnC isoform expressed in fast muscle

ﬁbershasfourCa

-binding sites compared with the

three in the isoform expressed in slow ﬁbers, Ca

bind-

ingisenhancedinfastmuscleﬁbers. Moreover, the faster

uptake of Ca

by the SR is determined by the increased

SR volume and surface area as well as the higher density

of SERCA pumps in fast ﬁbers. Of note, the SERCA iso-

form expressed in fast ﬁbers (SERCA1 vs. SERCA2 in slow

ﬁbers) is more sensitive to changes in ADP concentration,

which rises during muscle fatigue. As a result, Ca

-pump

and -leak rates of SERCA1 are more affected by metabolic

stress (i.e., more reduced and more increased, respec-

tively) compared with SERCA2 in slow ﬁbers (357). In addi-

tion, calsequestrin (CASQ) that binds Ca

within the SR is

found in greater abundance in fast compared with slow

ﬁbers, thereby providing an increased capacity to bind

free Ca

. Taken together, differences between Ca

transient and cross-bridge kinetics in slow and fast muscle

ﬁbers contribute to the distinct contractile properties

(FIGURE 8). Accordingly, it is not surprising that the

energy demand of these ﬁber types is different during

maximal isometric contraction. At rest, energy expenditure

in muscle is relatively low, 0.008 mM/s of ATP turnover,

and mainly used for the Na

-K

-ATPase in the sarco-

lemma as well as protein synthesis (357). However, as

muscles start to contract, the energy demand is substan-

tially elevated by the myosin ATPases of the molecular

motor for cross-bridge cycling (70% of overall ATP

glycolytic

muscle fiber

SERCA1

MyHC-IIX

RyR1 CASQ

β-oxidation

IMCL

myoglobin

glycogen

MyHC-I

SERCA2

RyR1

CASQ

Time

Force

Time

Force

oxidative

muscle fiber

Contractile characteristics

Ca2+

Ca2+-binding

proteins

ATP

glycolytic

oxidative

Ca2+

Ca2+-binding

proteins

ATP

glycolysis

pyruvatelactate

OXPHOS

Fatigue glycolysis

pyruvate

β-oxidation

OXPHOS

PPPPPP

PPP

FIGURE 8. Contractile and metabolic properties of a strength/power-trained and an endurance-trained athlete. Characteristics of fast and powerful

muscles of strength/power athletes that are accompanied by a more fatigable muscle as compared with endurance-trained muscles with elevated oxi-

dative capacity that are more fatigue resistant. ATP, adenosine triphosphate; CASQ, calsequestrin; IMCL, intramyocellular lipids; MyHC, myosin heavy

chain; OXPHOS, oxidative phosphorylation; RyR1, ryanodine receptor 1; SERCA, sarcoplasmic/endoplasmic reticulum Ca

-ATPase; SR, sarcoplasmic

reticulum. Illustrations of people were created by kjpargeter/Freepik. Image created with BioRender.com, with permission.

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consumption) and by the SERCA pumps for Ca

reup-

take (30% of ATP consumption). Hence, during maximal

isometric contractions ATP turnover rates in human type I,

IIA, and IIX ﬁbers can increase up to 1,000-fold to 1.7,

4.7, and 7.2 mM/s, respectively (357). These ﬁber-speciﬁc

differences underscore the remarkable capacity of fast

muscle ﬁbers to turn over ATP and enable the generation

of high peak power.

To meet the distinct energy demands of different

sport activities, slow and fast muscle ﬁbers exhibit diver-

gent metabolic properties. Type I ﬁbers are highly oxida-

tive, whereas type IIX ﬁbers are more glycolytic (357),

with the fast type IIA ﬁbers of an intermediate phenotype

containing high amounts of oxidative as well as glyco-

lytic enzymes. In line with the considerable energy

demand of fast glycolytic ﬁbers, glycogenolytic activity is

elevated in these ﬁbers, and during short maximal con-

tractions ATP generation via glycolysis is double that of

slow muscle ﬁbers (357), with a corresponding rapid rate

of fatigue. In contrast, rates of fatty acid oxidation via the

b-oxidation pathway are two- to threefold higher in slow

ﬁbers, with the lower ATP demand of these ﬁbers met

by mitochondrial respiration over prolonged periods

(357). The increased oxidative capacity of type I ﬁbers is

determined by the higher mitochondrial volume, account-

ing for 6% of the ﬁbervolumeintypeIcomparedwith

4.5% and 2.3% in type IIA and IIX ﬁbers, respectively, as

well as the greater density of the mitochondrial cristae

and enzymatic activity (357). Additionally, the elevated ox-

ygen demand in slow ﬁbers is met by a higher capillary

density and 50% increased myoglobin content compared

with fast ﬁbers (154,357). Along with the capillary-to-ﬁber

ratio,thepercentageoftypeIﬁbers thus is a strong pre-

dictor of endurance capacity (377). The capillary density

not only provides greater oxygen delivery and energy

substrates but also promotes rapid removal of by-prod-

ucts of sustained contractile activity (i.e., ammonia or lac-

tate). Triglyceride stores are substantially higher in type I

ﬁbers compared with type II ﬁbers (0.5% of the ﬁber vol-

umeintypeIﬁbers compared with <0.1% in type IIX

ﬁbers), whereas conﬂicting results have been reported

regarding glycogen stores (279,357,378). Although ﬁber

type-speciﬁc differences in glycogen content are not

always observed between fast and slow muscle ﬁbers

(379,380), several studies report that glycogen concentra-

tion in type II ﬁbers is 15–30% higher compared with type I

(357,381–385). It is unclear whether this is due to differen-

ces in methodology or whether the training status has an

impact on these ﬁndings, since the glycogen content is

similar in type I and type II ﬁbers in elite athletes (386).

Collectively, the ﬁber type-speciﬁc differences in con-

tractile and metabolic properties reﬂected by the inverse

relationship between force generation and oxidative

capacity of type I, IIA, and IIX ﬁbers result in low force-

generating, fatigue-resisting ﬁbers and high force-gen-

erating, fatigable ﬁbers, respectively. These properties

emphasize the important contribution of ﬁber type distri-

bution to endurance- or strength/power-based activities.

In untrained males, the vastus lateralis comprises 40–

50% type I ﬁbers (254,256,278,387), though the rela-

tive ﬁber type distribution depends on the site of biopsy

(388). Elite endurance athletes typically present with

>60% type I ﬁbers, with extremes of >90% (169,254,

256,279,280,389). These cross-sectional data, how-

ever, fail to provide evidence of whether prolonged en-

durance training induces a shift in ﬁber distribution, or if

elite endurance athletes are successful because of innate

ﬁber type patterns.

In contrast to endurance athletes, well-trained strength

and power athletes tend to have a ﬁber type distribution

that resembles that of untrained individuals, at least in

terms of overall glycolytic (type II) compared with oxida-

tive (type I) ﬁbers, with some extremes toward a lower

abundanceoftypeIﬁbers (278,303,368,390). A signiﬁ-

cant shift from IIX to IIA ﬁbers has been reported in

strength- and power-trained athletes, with the absolute

area of fast muscle ﬁbers substantially larger because of

speciﬁc hypertrophy of type IIA ﬁbers (278,303). In other

studies, a preservation of type IIX ﬁbers in response to

sprint or plyometric training has been found, together

with a shift from type I to type IIA (372). Accordingly,

sprinters seem to have a lower proportion of slow type I

ﬁbers (281,391). As for elite endurance athletes, it is

unclear whether differences in ﬁber type distribution in

power athletes and sprinters are due to preexisting ﬁber

type patterns or whether the training-induced shift is

affected by different training paradigms. It also remains

perplexing how a ﬁber type shift is brought about in terms

of the temporal and spatial coordination: is there a simul-

taneous shift in metabolic and contractile properties com-

bined with changes in the motor neuron phenotype, or

does one follow the other? Collectively, it is evident that

the unique characteristics of type I, IIA, and IIX ﬁbers

regarding oxidative and force-generating capacities are

instrumental for sport-speciﬁc demand and thereby con-

tribute to the achieved peak performances in athletes.

3.4. Energy Metabolism and Oxidative Capacity

In skeletal muscle, the three main sites for ATP consump-

tion are the Na

-K

-ATPases of the sarcolemma for mem-

brane excitability, the SERCA pumps of the SR membrane

for Ca

reuptake, and the myosin ATPases for cross-

bridge cycling. Because of the increased elevation in ATP

utilization by myosin ATPases and SERCA pumps associ-

ated with intense contractile activity, the high ATP

demand is a major bioenergetic challenge to the con-

tracting myoﬁbers (357). Given that intramuscular ATP

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stores are relatively small, metabolic pathways re-

sponsible for ATP restoration must be rapidly acti-

vated such that ATP levels closely match demand.

During sprint events lasting <20s,thecreatinephos-

phate system and anaerobic glycolysis are the main path-

ways engaged in ATP resynthesis (392). Although the

contribution to ATP provision during a 10-s sprint is similar

between the creatine phosphate system and anaerobic

glycolysis (53% and 44%, respectively), this is substantially

changedduringa30-ssprint(23%and49%,respectively,

with 28% from mitochondrial respiration) at a time when

phosphocreatine stores are mostly depleted (392,393).

In contrast, to meet the elevated and sustained energy

demand for prolonged exercise (several minutes to sev-

eral hours), large amounts of ATP are generated by aero-

bic mitochondrial respiration, with the metabolism of

glucose, fatty acids, ketone bodies, and lactate resulting

in a higher energy expenditure (392). In extreme endur-

ance events such as the Ironman triathlon (3.8 km swim-

ming, 180 km cycling, 42.2 km running), rates of energy

expenditure 8- to 10-fold above resting metabolic rate

(RMR) can be sustained for 10–15 h (394). To enable such

performances, adequate oxygen uptake, delivery, and

extraction concomitant with skeletal muscle ATP genera-

tion using large amounts of fatty acids must be tightly

coordinated.

In addition to the higher _

VO2max values observed in

elite endurance-trained athletes, these individuals also

have greater efﬁciency or economy of motion (i.e., a

lower oxygen cost at any given work rate or speed of

movement) combined with a greater fractional utilization

of _

VO2max (i.e., the ability to use a greater proportion of

their higher _

VO2max). Collectively, these attributes are

associated with increased rates of fatty acid oxidation, a

slower rate of depletion of muscle glycogen stores, and

enhanced lactate kinetics (395,396). For example, maxi-

mal rates of whole body fatty acid oxidation in elite ath-

letes are twofold higher at submaximal workloads

compared with untrained individuals (0.6 g/min vs. 0.3 g/

min) (254) and can be reached at much higher intensities

(both relative and absolute) compared with untrained indi-

viduals (45–60% vs. 35% of _

VO2max). A “retooling”of

themusclebyadaptationtoahigh-fatdietwhileunder-

taking vigorous training can more than double these rates

in world-class endurance-trained athletes to values

exceeding 1.5 g/min at work rates of 70% of _

VO2max

(397). During exercise exceeding 80% of _

VO2max,the

availability or rate of appearance of fatty acids in the cir-

culation limits the oxidation of fat-based fuels by skeletal

muscle (398). In line with a superior ability to oxidize fat-

and spare carbohydrate-based fuels during exercise, the

onset of blood lactate accumulation, ﬁxed at a concentra-

tion of 4 mM (sometimes arbitrarily deﬁned as “lactate

threshold”)(255), is observed at both higher relative and

absolute exercise intensity in endurance-trained athletes

compared with untrained individuals (80,257). Therefore,

in addition to the higher _

VO2max and improved capillary

density, training-induced adaptations in skeletal muscle

(i.e., the ability to oxidize fat-based fuels and spare muscle

glycogen along with a concomitant reduction in lactate

appearance) enable elite endurance athletes to sustain

high absolute work rates or speeds and resist fatigue

for prolonged periods (80,267,395). These adaptive

changes are discussed in sects. 3.4.1 and 3.4.2.

3.4.1. Mitochondrial adaptations.

During prolonged submaximal exercise with adequate

oxygen availability, ATP is synthesized by OXPHOS in the

electron transport chain located in the cristae of the inner

mitochondrial membrane. To optimize mitochondrial bio-

energetics and meet the increased energy requirements

during prolonged exercise, highly coordinated adaptive

processes enhance the quality as well as the quantity of

mitochondria. For example, mitochondrial number and

morphology are altered by replication of mitochondrial

DNA (mtDNA), synthesis of mitochondrial proteins, trans-

port and incorporation of nuclear-encoded proteins into

the corresponding substructures and supercomplexes of

mitochondria, and dynamic fusion and ﬁssion events

(399). Mitochondrial dynamics are essential to maintain

quality and are sensitive to physiological and pathological

stimuli (400). Whereas fusion leads to elongated mito-

chondrial tubular networks (401), ﬁssion induces fragmen-

tation of the mitochondria allowing the sequestration

of damaged or dysfunctional organelles by mitophagy

(discussed in sect. 4.6.2) but also mitochondrial biogene-

sis (402). More speciﬁcally, ﬁssion at the periphery of the

mitochondria enables the degradation of damaged com-

ponents of the network, whereas ﬁssion at the midzone

of the mitochondria seems to be instrumental for the pro-

liferation of mitochondria, which cannot be generated de

novo (403). The fusion of the outer and inner membrane

of the mitochondria is regulated by the transmembrane

proteins mitofusion 1 (MFN1) and MFN2 and optic atrophy 1

(OPA1), respectively (401), and important proteins involved

in the ﬁssion process include dynamin-related protein 1

(DRP1), mitochondrial ﬁssion 1 (FIS1), and mitochondrial ﬁs-

sion factor 1 (MFF1) (399,402). How mitochondrial dynamics

are altered in muscles of highly trained athletes is not com-

pletely understood (404),andmostdataarebasedon

changes in the abundance of proteins regulating ﬁssion

and fusion dynamics (289,405). It has been suggested

that ﬁssion is elevated after acute exercise to promote

the removal of damaged organelles, whereas fusion

events are increased during the recovery phase (399,

400,406), leading to the elongation of mitochondria

(407). A functional mitochondrial reticulum is important for

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ATP generation as well as energy distribution within mus-

cle cells (408). In line with these observations, mitochon-

dria of oxidative muscle ﬁbers are highly interconnected,

forming substantially larger mitochondrial networks,

whereas glycolytic ﬁbers have more fragmented mito-

chondria (407,409). Recently, it has been suggested that

the two distinct subpopulations of mitochondria (subsar-

colemmal and intermyoﬁbrillar) are physically connected,

building a large mitochondrial network (410,411). These

interconnected mitochondrial networks enable a rapid

exchange of various factors between mitochondria to ulti-

mately improve ATP production in a spatially coordinated

manner (402). As demonstrated in murine muscles, the

enrichment of complex IV in subsarcolemmal regions

near capillaries facilitates the generation of the proton

motive force in oxygen-rich areas whereas the higher

abundance of complex V within the myoﬁber helps to

generate ATP near the site of high energetic demand

(412). Elongated mitochondrial networks are related to

enhanced oxidative metabolism (400), whereas frag-

mented mitochondria are less efﬁcient in generating ATP

(402). This dynamic remodeling of mitochondria could

make a substantial contribution to improved mitochon-

drial quality and function in trained muscle.

Closely linked to changes in mitochondrial dynamics,

mitochondrial biogenesis plays a major role in the adapt-

ive response to endurance training, with mitochondrial

volume density being strongly correlated to _

VO2max

(254,285,413). The exercise-induced pathways

including Ca

signaling and metabolic, oxidative,

and heat stress that are instrumental for mitochon-

drial adaptation are discussed in sects. 4.2.1, 4.4,

4.5.1, 4.5.2, and 4.6. In the vastus lateralis muscles of

untrained individuals, mitochondria comprise 4–5%

ofthemusclevolume,thehighestbeingintypeIand

the lowest in type IIX ﬁbers (255,289,300,302,414).

In endurance-trained athletes, mitochondrial volume

density is 50% higher and citrate synthase activity is

elevated by 74% (254,285). Accordingly, mitochon-

drial respiration is substantially enhanced in elite ath-

letes (415). The exercise training-induced increase in

mitochondrial volume density occurs in all ﬁber

types, including IIX, and ranges between 10% and

60% depending on the training impulse (414,416). In

addition to the greater mitochondrial volume density,

accompanied by an absolute increase in crista sur-

face, crista density is also higher in skeletal muscle

from elite athletes (290), resulting in a further eleva-

tion of muscle respiratory capacity. Thus, besides

improving oxygen delivery to the mitochondria,

muscles can enhance respiratory capacity to meet

the high energy demand during exercise by increas-

ing mitochondrial and crista density as well as opti-

mizing the interconnected mitochondrial networks.

3.4.2. Lipid and glycogen storage in muscle.

Skeletal muscle is a major site for both glucose (in the

form of glycogen) and lipid (intramyocellular triglycer-

ides) storage. Endurance, but not strength/power,

training substantially increases the size of these

depots: lipid content is approximately twofold higher in

the trained musculature of endurance athletes, which, in

part, facilitates the higher rates of fatty acid oxidation (417,

418). Although lipid droplet size is similar in muscle from

trained and sedentary individuals, the total intramyocellu-

lar lipid pool is substantially higher in endurance-trained

muscle.Thisisduetothecombinationofanincreased

number of lipid droplets along with a greater proportion

of type I muscle ﬁbers that have a greater capacity for

lipid storage than type II ﬁbers (417,419,420). These

droplets can be categorized into subsarcolemmal or inter-

myoﬁbrillar lipids, and whereas an elevated fraction of

subsarcolemmal lipid droplets is associated with insulin

resistance (421), endurance-trained individuals predomi-

nantly store lipids in the intermyoﬁbrillar fraction, often in

close proximity to mitochondria, which favors high turn-

over kinetics and confers insulin sensitivity (417,422), a

phenomenon termed the “athlete’sparadox”(423).

Glycogen, a branched glucose polymer, is found in

three distinct subcellular compartments, with the major-

ity (75–85%) located between the myoﬁbrils (intermyoﬁ-

brillar) near the SR and the mitochondria (424). Between

5% and 15% of the glycogen granules are located

beneath the sarcolemma (subsarcolemmal) and 5–15%

between the contractile ﬁlaments within the myoﬁbrils

(intramyoﬁbrillar) (424). Whereas type I ﬁbers have more

subsarcolemmal and intramyoﬁbrillar glycogen, type II

ﬁbers are enriched in intermyoﬁbrillar glycogen (424).

The ﬁber type-speciﬁc location of glycogen favors the

functional characteristics of type I and II ﬁbers (i.e., fa-

tigue resistance and fast contraction time, respectively)

(351). Intermyoﬁbrillar glycogen content is associated

with faster relaxation time and, at least in the type II ﬁber,

is necessary to sustain the high rates of ATP turnover by

the SERCA pumps (351). In contrast, intramyoﬁbrillar gly-

cogen is correlated with Ca

release from the SR and

fatigue resistance (256,425). Accordingly, in type I

ﬁbers of endurance-trained athletes, intramyoﬁbrillar gly-

cogen content is 60–65% greater, and in both ﬁber

types subsarcolemmal and intermyoﬁbrillar glycogen is

increased by 60–65% and 20–25%, respectively, com-

pared with non-athletes (351). During prolonged exercise

to fatigue, muscle glycogen concentration decreases in

all subcellular compartments, with a preferential deple-

tion of intramyoﬁbrillar glycogen (underlying molecular

signals are described in sects. 4.1 and 4.5.1). As pre-exer-

cise muscle (and liver) glycogen content is strongly corre-

lated with prolonged (>90 min) submaximal exercise

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capacity, higher muscle glycogen in trained muscle plays

an important role for maximal performance (386,424,

426). In addition, glycogen stores are not only replen-

ished more rapidly in trained muscle but also to a

greater extent (“supercompensation”) compared with

untrained muscles (described in sect. 4.8.3) (427,

428). The restoration of muscle glycogen can be

accelerated by high carbohydrate availability in the

ﬁrst 3 h after exercise and can reach rates of synthesis

of >10 mmol/kg wet muscle weight/h (428). Despite

the capacity for high rates of fatty acid oxidation dur-

ing submaximal exercise, when highly trained athletes

compete in endurance events lasting up to 3 h carbo-

hydrate-based, not fat-based, fuels are the predomi-

nant energy substrate for the working muscles.

Accordingly, carbohydrate and not lipid availability

becomes rate limiting for performance in this context

(194).

3.5. Muscle Memory

Skeletal muscle mass, _

VO2max, and other endurance

training-induced adaptations rapidly decline upon ces-

sation of a training stimulus (i.e., detraining, decondition-

ing), with many structural, metabolic, and performance-

related parameters returning to pre-training values

within weeks to months, even in athletes with a lifelong

history of training. However, prior strength training

seems to facilitate the regain of muscle mass, surpass-

ing the gains that were achieved when training was

commenced from the naive state (429). This phenom-

enon is referred to as “muscle memory”(430,431)and,

in part, is based on motor learning, intra- and intermus-

cular coordination, prior experience of body perception,

resilience to give into pain and fatigue, and anticipation

of exertion. In addition to these central mechanisms,

there is evidence for a cellular memory in muscle ﬁbers

(432). According to the myonuclear domain theory, myo-

nuclei should be lost during detraining-induced muscle

atrophy. However, at least in animal models, the number

of myonuclei remains elevated after a short period of

disuse despite a loss in muscle mass (433). Thus, the

greater myonuclear density and high transcriptional

potential could facilitate muscle growth during retrain-

ing, contributing to muscle memory. In humans, this phe-

nomenon has received little scientiﬁc enquiry, and it is

not known whether muscle memory exists, or for how

long accrued myonuclei might be preserved (361). A

large interindividual heterogeneity of the number of

myonuclei elevated after detraining has been reported,

and in most cases the pre-training number of myonuclei

is similar to that after detraining (434). Of note, athletes

with a history of abuse of testosterone or other anabolic

steroids, which boost myonuclear accretion, could still

beneﬁt from the elevated number of myonuclei even af-

ter doping cessation, leading to a potential unfair

advantage in competitions long after bans have been

served (435).

Although the enhanced growth rates of muscle mass

during retraining suggest the presence of some kind of

muscle memory (430), many of the training-induced

adaptations in muscle are the result of the complex tran-

scriptional response to repeated bouts of exercise,

which necessitates accessible genomic regions for the

transcriptional machinery. An open chromatin state is

generally indicative of enhanced transcriptional activity

(360), with the accessibility of chromatin associated with

modiﬁcations of nucleotides in the DNA and posttransla-

tional modiﬁcation of histone proteins (histone code)

(436,437). Transcriptionally silent genes exhibit closed,

condensed chromatin (heterochromatin), an enrichment

of hypermethylated DNA (5-methylcytosine instead of

cytosine), deacetylated histones, and methylation of dis-

tinct histone residues [e.g., histone 3 lysine residue 9

(H3K9) or H3K27]. Gene transcription requires a state of

open chromatin (euchromatin), linked to demethylated

DNA, acetylated histones, and the methylation of

other histone residues (e.g., H3K4 or H3K26). Besides

stable epigenetic markers that can be passed on to the

next generation, DNA methylation also occurs as a

dynamic process and is inﬂuenced by numerous stimuli

including habitual level of physical activity, nutrient avail-

ability, and (psychological) stress (360,435,438).

Accordingly, promoter regions of genes involved in meta-

bolic pathways, myogenic processes, or oxidative stress

responses are hypomethylated and more accessible in

lifelong physically active compared with inactive men

(439). Inversely, the promoter region of the peroxisome

proliferator-activated receptor (PPAR) ccoactivator 1a

(PGC-1a) is hypermethylated, and thus less accessible, af-

ter bedrest and associated with reduced mRNA expres-

sion (440). In recent years, a growing body of evidence

suggests the involvement of altered chromatin landscape

in response to exercise training as a possible contributor

to muscle memory (360,430). For example, after endur-

ance or resistance training, widespread changes in DNA

methylation status have been reported in muscle (438).

Thus, exercise-responsive genes such as PGC-1aare

hypomethylated before their induction in response to an

acute bout of high-intensity endurance exercise (441).

Despite these observations, the contribution of DNA meth-

ylation to training adaptation and muscle memory is con-

troversial. In some studies, endurance training promoted

the demethylation of genes involved in angiogenesis or

oxidative metabolism, associated with increased gene

transcription (442,443), whereas in others there was little

effect of HIIT or resistance training on DNA methylation

(444). A recent study reported that despite divergent

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contractile stimuli (HIIT, endurance and resistance exer-

cise), changes in DNA methylation and mRNA expression

in skeletal muscle were largely conﬁned to the late (4–8h)

recovery period and similar between the different exercise

challenges (445). Many of the discrepancies between

investigations can likely be explained by the timing of the

biopsy (446), with time course studies suggesting that

some DNA methylation changes are retained for up to 48

h after the last training bout (442,443), returning to base-

line levels after 72 h (444). It is not known whether DNA

methylation changes are retained after detraining and

thereby contribute to muscle memory. Finally, the differ-

ence of the transcriptional response of an untrained com-

pared with a trained muscle and the involvement of

epigenetic changes therein are currently unexplored.

In contrast to endurance training, the evidence for

long-term epigenetic remodeling triggered by resistance

training is more robust. In response to a training protocol

of loading, unloading, and reloading, several CpG islands

remained hypomethylated during unloading, likely con-

tributing to the elevated transcriptional response of the

associated genes during reloading (430). These results

suggest that chronic changes in DNA methylation may

contribute to the transcriptional memory (430), although

only a small fraction of the differentially methylated genes

displayed a distinct expression pattern (443,447).

Nevertheless, epigenetic regulation of a few regulatory

genes might be sufﬁcient to induce a faster and/or

greater response to recurring challenges.

Collectively, our understanding of the epigenetic

changes in a trained state and the contribution to mus-

cle memory is rudimentary. Findings pertaining to epige-

netic remodeling in human muscle are heterogeneous

regarding the training protocols employed, the study

design/methodology, and the caliber of subjects under

investigation. Individuals described as “low respond-

ers”to a training intervention may show attenuated epi-

genetic modiﬁcation compared with “high responders,”

although further work is needed to corroborate this hy-

pothesis (448). In elite athletes, data on epigenetic pro-

ﬁles are almost exclusively from circulating blood cells

but not skeletal muscle (449,450). However, the pres-

ence of polymorphisms of genes encoding proteins

involved in DNA methylation in elite athletes implies a

possible epigenetic predisposition (451).

3.6. How Are Physiological and Cellular Training

Adaptation Brought About?

Many of the training-induced morphological, biochemical,

physiological, and functional adaptations are the culmina-

tion of long-term (weeks to months) exposure to training

stimuli (FIGURE 6). Many of the transcriptional changes

that underpin these adaptations are the transient effect of

repeated bouts of acute exercise that accumulate over

time and result in new steady-state transcript and protein

levels (87,198), even though disparate outcomes for tran-

script and proteins can occur (452). For example, the tran-

scription of many mitochondrial genes is transiently

induced after a single bout of endurance exercise, leading

to mitochondrial biogenesis, improved mitochondrial func-

tion, and elevated oxidative metabolism when the stimuli

are repeated over time (87,405). This response, how-

ever,isnotuniformacrossalltranscriptsandthepro-

teins they encode. For example, in contrast to the

change in trained muscle, robust transcriptional regu-

lation of myosin heavy chains is not observed after

acute exercise bouts (453), whereas other genes

show an attenuated expression after repeated exer-

cise exposure (438). Few studies have simultaneously

investigated contraction-induced changes in mRNA

levels and subsequent training-induced changes in

protein levels in human skeletal muscles following

chronic interventions, and it is clear that exercise-

induced increases in mRNA levels do not always pre-

cede increases in the proteins they encode (405,452,

454). Clearly, several mechanisms regulate the train-

ing response/adaptation, and in the case of transcrip-

tional networks there may be additive or attenuated

responses over time. In sect. 4 we discuss our current

understanding of the molecular mechanisms that are

involved in the acute response of muscle to endur-

ance or resistance exercise bouts.

4. ACUTE MOLECULAR MECHANISMS

UNDERPINNING ENDURANCE- AND

RESISTANCE-BASED EXERCISE

In this section, the sensors and major signaling path-

ways involved in the response of skeletal muscle to a

single bout of endurance and resistance exercise are

summarized. We review the downstream effects of

these stimuli (e.g., transcriptional regulation and transla-

tional control) that promote muscle adaptations in

response to two distinct training paradigms. In addition

to the well-described pathways such as Ca

-depend-

ent pathways, AMP-activated protein kinase (AMPK),

and mammalian target of rapamycin (mTOR) complex 1

(mTORC1) signaling reviewed above, we delineate the

important roles of other transducers such as mechano-

sensing and transduction, for which there is a scarcity of

data on athletic populations. A brief discussion of the

common signaling pathways activated by both endur-

ance and resistance training is provided, followed by a

comprehensive overview of the molecular events that

occur after an acute bout of exercise and underpin the

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differential responses to divergent contractile stimuli

described in sects. 2 and 3.

A single bout of exercise sets in motion a complex pro-

gram of interconnected signaling events, along with the

activation of numerous biochemical pathways and tran-

scriptional networks that orchestrate the spatio-temporal

responses to muscle contraction and coordinate a pleio-

tropic response in other tissues and organs to control

energy substrate provisioning, oxygen availability, and

heat dissipation (9). These perturbations are initiated by

numerous inputs, which can occur in parallel, overlap, or

be completely independent. Several critical regulatory

“nodes”provide the hub for signal integration and subse-

quent control of transcription and enzymatic activity (9,

55,455).Repeatedboutsofexerciseoverseveralweeks

or months result in a continuous modulation of this

response and, over time, ultimately contribute to provoke

chronic adaptations (456). Although the molecular mecha-

nisms underpinning many of the chronic responses to

exercise training remain undeﬁned, numerous insights

regarding acute exercise response have been described

in recent years (9,39,41,55,163,393,455,457). A caveat

is that although the focus of this review pertains to data

obtained from exercise-trained humans, many of our cur-

rent mechanistic insights have originated from rodent and

other in vivo and in vitro model systems. It is important to

make a distinction between voluntary, whole body in vivo

responses to exercise and those elicited by other experi-

mental models. Ex vivo electrical stimulation of an isolated

skeletal muscle, for instance, evokes an action poten-

tial and “contraction”and triggers intracellular path-

ways with putative roles in training adaptation. However,

whole body, voluntary exercise induces a range of addi-

tional physiological responses that are critical for muscle

performance (and movement). Accordingly, many effects

observed in animals and isolated systems can differ from

those seen in humans in vivo, and care should be taken

when extrapolating responses from one set of conditions

or a given experimental model to another (9). Here, we

describe the signaling pathways and mechanistic events

that are principally involved in the response to an acute

exercise bout and culminate in the subsequent training

adaptation. Mechanisms that are important in muscle at-

rophy and pathological situations are not discussed in

detail, and because of space limitations we cite recent

reviews that serve as starting points for further reading

and collections of primary literature. The following sec-

tions are structured based on the putative engagement

oftherespectivepathwaysinmusclecontraction,from

pre (anticipation)- to peri (start of activity, during the exer-

cise bout)- to post (muscle fatigue and exercise cessation

and ﬁnally recovery, repair, and regeneration)-exercise

(FIGURE 9). It should be noted, however, that the exact

temporal sequence of engagement and the interactions

between and integration of these processes are not fully

understood.

4.1. Neuroendocrine Signaling in the Anticipatory

Phase and During Muscle Contraction

Anacuteboutofexerciserepresentsa“one-off”stressor

to whole body homeostasis, provoking widespread pertur-

bations in numerous cells, tissues, and organs that are

caused by or are a response to the increased metabolic

activity of contracting skeletal muscles (9,55,455).

Induction of the “ﬁght or ﬂight”response, including activa-

tion of the sympathetic nervous system in parallel with the

motor system, responds to feedback from the exercise

pressor reﬂex via group III/IV skeletal muscle afferents

(458,459). This reﬂex encompasses feedback that is

evoked from mechanically (muscle mechanoreﬂex) and

metabolically (muscle metaboreﬂex) sensitive afferents

during contractions, leading to parasympathetic depres-

sion and sympathetic activation (460). Consequently,

blood ﬂow to skeletal muscle is increased as a result of

elevated heart rate, blood pressure, and rate of ventilation.

Theexercisepressorreﬂex can be complemented by

“central command,”in which stimulation of medullary

and spinal circuitries by higher brain centers likewise

evokes respiratory and cardiovascular modulation (460).

Importantly, the sympathetic nervous system can also be

engaged by anticipation and other emotional factors pre-

ceding motor activation. Exercise leads to a substantial

increase in circulating catecholamines, a response that is

greater in trained compared with untrained individuals

exercising at the same relative intensity (458,459). In part,

centrally controlled modulation of the sympathetic nervous

system is required for a systemic activation of events that

support muscle contraction, such as increased pulmonary

and cardiovascular output or various metabolic pathways

to liberate energy substrates. Importantly, muscle tissue is

also innervated by the sympathetic nervous system

through the activation of b

-adrenoreceptors by catechol-

amines, with epinephrine having a higher afﬁnity than nor-

epinephrine for these receptors, and a higher density of

-adrenoreceptors on type I compared with type II muscle

ﬁbers (458,459). Besides affecting the microvasculature,

the adrenergic system exerts other functions in this tissue,

including direct effects on the neuromuscular system

(FIGURE 10)(458,459). Initially, adrenergic action on the

presynaptic side of the NMJ helps synchronize neurotrans-

mitter vesicle fusion and augment acetylcholine release.

Then, b

-adrenoreceptor action on the muscle ﬁbers acti-

vates the Na

-K

pump and thereby ﬁber excitability,

potentially attenuating fatigability. Muscle contractility, in

particular twitch force and relaxation rate, is modulated by

the adrenergic effect on Ca

release and reuptake via

RYR1 and phospholamban, the latter of which is exclusively

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expressed in slow muscle ﬁbers. Metabolically, b

-adreno-

receptor activation antagonizes insulin to stimulate glyco-

gen breakdown and inhibit glycogen synthesis. Moreover,

-adrenoreceptor agonism represses proteolytic proc-

esses, leading to a transient anabolic effect on muscle

mass. As members of the G protein-coupled transmem-

brane receptor family, b

-adrenoreceptors engage numer-

ous signaling pathways and effectors in muscle cells (461).

The exchange of GDP for GTP at the astimulatory sub-

unit of guanine nucleotide-binding regulatory protein

(Gas)resultsinanactivationofadenylatecyclase,the

cyclic AMP (cAMP) signaling pathway, and ultimately

elevated transcriptional activity of the cAMP response

element-binding protein (CREB), which stimulates the

modulation of additional control genes, including

PGC-1a, or myogenic factors such as myoblast deter-

mination protein 1 (MyoD) (461). The inhibition of the

Forkhead box 3 (FOXO3) by PGC-1a, and hence of pro-

tein degradation and ﬁber atrophy (462), is potentiated

by the effect of the Gbc subunit of the b

-adrenoreceptor,

which modulates the activity of phosphoinositide 3-ki-

nase (PI3K) and, via downstream activation of protein

kinase B (PKB/Akt), exerts a negative effect on FOXO3

function as well as a positive modulation of protein syn-

thesis by activation of mTORC1 (461).

4.2. Motor Neuron Activation of Muscle Fiber

Contractions

Muscle ﬁber contraction can be initiated via different

mechanisms: neuronal activity in the motor cortex for

voluntary movement, sensory neuronal input for involun-

tary reﬂex contractions such as elicited in proprioceptive

or vestibular control, or hypothalamic activation of ther-

mogenesis-promoting neurons for shivering (463–465).

Regardless of the origin of the signal and upstream cir-

cuitry, neuronal input converges on a-motor neurons in

the ventral horn of the spinal cord (466). These motor

neurons, their descending axons, and the innervated

muscle ﬁbers form a motor unit that transforms synaptic

input into muscle contractions (318). Motor units differ in

size, with one motor neuron interfacing with from a

handful to many thousands of individual muscle ﬁbers

(318). Collectively, the motor units of one muscle are

Anticipation

Initiation

Activity

Recovery

Exercise

Time

Stress response:

mechanical

redox

heat

proteostatic

energetic

substrate availability

oxygen availability

Motor neuron

signaling

Sympathetic nervous

system activation

Muscle fiber repair and regeneration

Substrate refueling and proteostasis

Functional retrieval

Central and peripheral

processes, e.g., redox signaling

Circadian

rhythms

Fatigue/

Exhaustion

FIGURE 9. Temporal engagement of different pathways and processes in skeletal muscle in exercise. Anticipation of activity is linked to elevated

sympathetic nervous system tone. Motor neuron ﬁring triggers muscle contractions at the start of and during an activity. While contracting, muscle will

be affected by different stressors and the related reaction/mitigation, for example, mechanical stress, reactive oxygen and nitrogen species (redox) pro-

duction, heat, altered proteostasis and protein unfolding, metabolic changes, substrate availability, and oxygen provisioning. The exact temporal

sequence of engagement of and interactions between these pathways are unknown. Different mechanisms contribute to muscle fatigue, exhaustion,

and exercise cessation. Subsequently, muscle repair, regeneration, and refueling are important for functional retrieval. Many of these processes are

modulated by circadian input. Images: triathlon anticipation from Wikimeda Commons (CC-BY-SA 3.0, creator: Wiech), triathlon start from Wikimedia

Commons (CC-BY-SA 2.0, creator: IQRemix), triathlon cycling from PxHere.com (CC0 Public Domain), exhaustion from Wikimedia Commons (CC-BY-SA

4.0, creator: Wallco26), massage from Freepick.com (author: javi_indy), waking up from Freepik.com (author: diana.grytsku).

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referred to as the motor unit pool (318). At the synapse

between motor neurons and muscle ﬁbers, the NMJ, an

axonal action potential, results in the release of the neu-

rotransmitter acetylcholine, which, after traversing the

synaptic cleft, binds to nicotinic acetylcholine receptors

that cluster at the entry points of subneural clefts on the

muscle membrane (FIGURE 11A)(467,468). Activation of

these ligand-gated ion channels results in inﬂux of Na

and a process called ECC, leading to depolarization of

the muscle membrane and, on the intracellular side of T

tubules, the release of Ca

from the SR, which ultimately

initiates and maintains muscle contractions (469). Thus,

one of the ﬁrsteventstooccurinresponsetoasingle

bout of exercise is initiation of Ca

-dependent signaling.

4.2.1. Ca

signaling.

Besides binding to troponin C and initiating the interac-

tion between actin and myosin, intracellular Ca

acti-

vates a multitude of signaling pathways in myoﬁbers,

modulating numerous physiological functions (470). For

example, Ca

signaling is associated with the control of

glycolysis, mitochondrial function, and the rates of protein

synthesis and degradation (471). The different Ca

tran-

sients that are evoked by activation of muscle ﬁbers by

slow and fast motor neurons contribute to the speciﬁcity

of different muscle ﬁber types (472,473). Mechanistically,

the protein phosphatase calcineurin A (CnA) and Ca

calmodulin-activated protein kinase II (CaMKII) are Ca

activated mediators involved in controlling gene tran-

scription linked primarily to a slow ﬁber phenotype (471).

In this context, CnA and CaMK activities converge on the

cAMP-dependent binding protein (CREB) and activating

transcription factor 2 (ATF2, also called CREB2), which

are activated by phosphorylation and dephosphorylation

of respective Ser/Thr sites, subsequently binding to the

promoter of the PGC-1agene PPARGC1A and inducing

transcription of this coregulator protein, among others

(474). Once synthesized, PGC-1acompetes with histone

deacetylase 5 (HDAC5) to coregulate myocyte enhancer

factor 2 (MEF2) family members on its own promoter and,

using this positive autoregulatory loop, ensures robust

transcriptional expression (475,476). Consistent with ele-

vated levels in slow and exercised muscle ﬁbers, PGC-1a

mediates a broad remodeling of skeletal muscle, result-

ing in a slow-twitch, oxidative, fatigue-resistant phenotype

(477)thatalsoincludesextramyoﬁber adaptations such

as at the microvasculature (478)orthepresynapticside

of the NMJ (315). Mice with a skeletal muscle-speciﬁc

ablation of PGC-1adisplay abnormal glucose and insulin

homeostasis (479), contraction-induced ﬁber damage,

impaired endurance capacity, and other characteristics

indicative of pathological inactivity (480).

The mechanisms that underlie the broad integration

of a vast number of signaling pathway that are engaged

in contracting muscle, and which mediate a tightly chor-

eographed modulation of broad transcriptional pro-

grams by PGC-1a, are unclear. Gene expression from

different promoters and transcriptional start sites (474,

481,482), various isoforms (481,482), context-speciﬁc

posttranslational modiﬁcations (474,482), and the RNA

binding-dependent assembly of speciﬁcmultiprotein-

containing transcriptional complexes and DNA regula-

tory elements in sequestered nuclear condensates (483)

could all contribute to a coordinated spatio-temporal

control of PGC-1a-mediated network control (482,484).

Indeed, PGC-1afunctionally and/or physically interacts

with multiple transcription factors and coregulators that

affect the exercise phenotype of skeletal muscle in

a dynamic manner (482,485,486). Thereby, spatial

β2 AR

symp. NS

Afferents

RYR1

SERCA PLN

Proteolysis

cAMP

PGC-1α

PI3K-Akt-mTOR

FOXO3

Synchronization of vesicle fusion

Augmented acetylcholine release

Action

potential

Na+/K+ pump

Fiber

excitability

Ca2+

Fiber

contractility

Ca2+

Glycogen

breakdown

FIGURE 10. Neuroendocrine signaling by

the sympathetic nervous system in exer-

cise anticipation and muscle contraction.

Sympathetic activation of the motor neuron

and skeletal muscle cells results in modula-

tion of ﬁber excitability and contractility,

metabolic and proteostatic remodeling,

and the activation of a transcriptional pro-

gram. These events prepare muscle cells for

upcoming contractions and help to maintain

contractile activity upon engagement. b2AR,

-adrenoreceptors; Akt, protein kinase B;

cAMP, cyclic AMP; FOXO3, forkhead tran-

scription factor O3; mTOR, mammalian target

of rapamycin; PGC-1a, peroxisome prolifera-

tor-activated receptor ccoactivator 1a;PI3K,

phophoinositide 3-kinase; PLN, phospholam-

ban; RYR1, ryanodine receptor 1; SERCA, sar-

coplasmic/endoplasmic reticulum Ca

ATPase;symp.NS,sympatheticnervoussys-

tem; TF, transcription factor. Image created

with BioRender.com, with permission.

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speciﬁcation, and the expression of synaptic genes in

subsynaptic but not extrasynaptic myonuclei (487), or a

temporal speciﬁcation, such as the activation of cata-

bolic and anabolic pathways like fatty acid b-oxidation

and de novo lipogenesis to increase intramyocellular lip-

ids (488), might be achieved (474,489). Of note, Ca

signaling also activates a number of additional transcrip-

tion factors with unclear epistatic relationship to PGC-1a,

including family members of the nuclear receptor 4A

(NR4A) family, of which NR4A2/NURR-1 and NR4A3/

NOR-1 in turn regulate target genes involved in oxidative

metabolism and improved muscle endurance (490,491).

As Ca

signaling is activated in response to both en-

durance- and resistance-based exercise, it is still unclear

whether and how this pathway is affected in a training

mode-speciﬁc manner. For example, training intensity

and duration may be one of the factors that inﬂuence

ﬂuctuations in the muscle and thereby inﬂuence

-mediated signaling.

4.2.2. (Neuro)endocrine factors, exerkines, and

myokines.

Besides neurotransmitter-mediated activation, motor neu-

rons and skeletal muscle ﬁbers engage in a bidirectional

cross talk through several secreted factors (FIGURE 11B).

Some of these, such as motor neuron-derived agrin, are

important for the development and stabilization of the

NMJ (468). This synapse, however, also exhibits remark-

able plasticity in the mature state, with exercise providing

β2 AR

symp. NS

Afferents

ECC

NTs

Fiber contraction

CaMK, CnA

CREB

ATF2

PGC-1α

Lactate IL-13

GDF3

Paracrine

Endocrine

Paracrine

Autocrine

Action

potential Retrograde

signaling

Ca2+

Retrograde

signaling

Endocrine:

Adipo-, Hepato-, Osteokines

Corticosteroids

Testosterone

Growth hormone => IGF-1

...

Myokines

Myobolites

FIGURE 11. Motor neuron signaling and (neuro)endocrine

effectors of contraction. A: motor neuronal signaling triggers

excitation-contraction coupling and thereby evokes a rise in

intramyocellular calcium (Ca

), which enables ﬁber contrac-

tions, activates various signaling pathways, and modulates a

transcriptional response, including retrograde feedback to the

motor neuron. Motor neuron activity is modulated by sympa-

thetic tone and includes various neurotrophic factors besides

the neurotransmitter acetylcholine. B: exerkines, originating

from tissues including muscle (myokines), liver (hepatokines),

adipose tissue (adipokines), and bone (osteokines) as well as

other hormones coordinate a systemic response to contractile

activity. Many of these factors exert auto-, para-, and endo-

crine effects. In addition, signals can be propagated by exer-

cise-linked changes in different metabolites (myobolites or

myometabokines). b2AR,b

-adrenoreceptors; ATF2, activat-

ing factor 2; CaMK, calcium/calmodulin-dependent protein ki-

nase; CnA, calcineurin A; CREB, cAMP-responsive element

binding protein; ECC, excitation-contraction coupling; GDF3,

growth differentiation factor 3; IGF-1, insulin-like growth factor

1; IL-13, interleukin 13; NTs, neurotrophic factors; PGC-1a,per-

oxisome proliferator-activated receptor ccoactivator 1a;

symp. NS, sympathetic nervous system; TF, transcription fac-

tor. Image created with BioRender.com, with permission.

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a strong stimulus to alter morphology and function (312).

Neuregulin-1 is secreted by the motor neuron and acti-

vates signaling pathways in the muscle ﬁber that lead to

the phosphorylation of PGC-1aand the GA-binding pro-

tein B [GABPB, also called nuclear respiratory factor 2b

(NRF-2b)] subunit of the GABP transcription factor com-

plex (487). These local events, which primarily affect sub-

synaptic myonuclei close to the NMJ, could provide the

mechanistic basis of the spatial speciﬁcation of PGC-1ato

exclusively regulate the transcription of postsynaptic NMJ

genes in these, and not extrasynaptic, nuclei (487).

Intriguingly, active muscle PGC-1atriggers a remodeling

process of the NMJ that extends to the presynaptic side

with altered mitochondrial and synaptic vesicle numbers

in the active zone and a quantal content reﬂecting slow

NMJ function (315). These observations go beyond the

current view of a unidirectional control of muscle ﬁber

type by the respective activity patterns of motor neurons,

in that elevation of muscle PGC-1a,observedinslow-type

or exercised ﬁbers, affects motor neuron function, at least

at the NMJ. Neurturin could be a mediator of this PGC-1a-

dependent retrograde signaling, acting on the NMJ (492)

and even on motor neurons in the spinal cord (493).

Another example of such a factor, brain-derived neurotro-

phic factor (BDNF), a signaling factor secreted from neu-

rons but also cells and tissues such as skeletal muscle

ﬁbers (494), functions as a myokine, a hormonal entity

produced and secreted by muscle cells. BDNF expres-

sion is elevated upon contractile activity, the protein

secreted, and besides a potential effect on the motor

neuron affects NMJ morphology and function postsynap-

tically in an autocrine manner (495).

Several other (neuro)endocrine factors have also been

identiﬁed in the context of exercise. For many of these,

particularly testosterone and other classical steroid and

non-steroid hormones, regulation during an acute exer-

cise bout is probably of little signiﬁcance compared with

the chronic effects such as restoration of substrate stores,

muscle repair and regeneration, and in extreme situations

overtraining/overreaching. For example, corticosteroids,

glucagon, and leptin are elevated when blood glucose

and/or muscle and liver glycogen concentrations are low

and stimulate fatty acid oxidation in muscle by activation

of AMPK (496). Testosterone, growth hormone, and the

downstream target insulin-like growth factor 1 (IGF-1) are

induced after different types of resistance training and

exert anabolic effects by stimulating MPS and ﬁber repair

(497). The regulation of these hormones in humans is

variable, and little is known about the exact molecular

mechanisms that mediate these adaptations. Indeed,

gain- and loss-of-function models of the receptors of

some of these hormones fail to reveal a clear picture

regarding their function in exercise-induced muscle plas-

ticity (486). Besides these classic hormones, a novel class

of so-called “myokines”have been discovered and stud-

ied in recent years (498). Myokines, some of which are

only produced in contracting muscle ﬁbers, sometimes

referred to as “exerkines,”elicit auto-, para-, and endo-

crine effects to coordinate local and systemic processes

(499,500).Forexample,whensecretedasamyokine,

interleukin (IL)-6 acts as a metabolic coordinator by pro-

moting lipolysis in adipose tissue, gluconeogenesis in the

liver, and, via activation of AMPK, glucose uptake and fatty

acid oxidation in muscle (501). Paracrine effects of myokines

are also instrumental for an adequate response of muscle

tissue to exercise, such as the proangiogenic effects of IL-6

or the vascular epithelial growth factor (VEGF) on epithelial

cells (501) or the activation of resident macrophage polariza-

tion by the B-type natriuretic peptide (BNP) and secreted

phosphoprotein 1 (SPP1) (502,503). Many of the endurance

exercise-induced myokines are under the transcriptional

control of PGC-1a(501,504), whereas the regulation of

those modulated by resistance training is less clear (504,

505). Paracrine signaling from different cell types to myoﬁb-

ers is also important for a normal exercise response, such

as the exercise-induced secretion of IL-13 by type 2 innate

lymphoid and other immune cells that promotes an oxida-

tive phenotype in muscle (506) or growth differentiation fac-

tor 3 (GDF3) by macrophages (507), as well as endothelial

cell-secreted lactate, both important for muscle regenera-

tion (508). A complex dialogue between muscle and other

cell types, mediated by myokines, hepatokines, adipokines,

and osteokines, ensures proper and coordinated local as

well as systemic adaptations to contractile activity, such as

for the adiponectin-mediated activation of muscle AMPK

(509,510). Collectively, however, our understanding regard-

ing hormones that affect skeletal muscle during contraction

or throughout recovery and regeneration from exercise is

rudimentary.

4.3. Mechanosensing and Mechanostress

Mitigation

4.3.1. Cell membrane mechanosensing.

Mechanical stress is exerted on muscle ﬁbers at the initia-

tion of and during exercise by passive stretching, sarco-

meric contraction, and other stimuli (FIGURE 12)(511). The

force-induced stretch and contraction/compression of mus-

cle ﬁbers in situ is not restricted to the longitudinal direction

but extends across orthogonal, radial, and tangential axes

(511). The ensuing shear, tension, and compressional stress

and cellular deformation present a high potential for dam-

age to the extracellular matrix (ECM), cell membrane, intra-

cellular scaffolds, and other structures. Therefore, a

complex system of mechanosensing exists to attenuate

damage and initiate adaptive processes that confer protec-

tion against acute and subsequent insults. Broadly,

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mechanical stress is detected by different structures at the

cell membrane or by intracellular sensors. Stretch-activated

channels (SACs) belong to the ﬁrst category in skeletal

muscle, of which the mechano-gated Ca

transient recep-

tor potential channels (TRPCs) are activated by mechanical

stress (512). The expression and function of the mechano-

sensing cation channel Piezo1 in skeletal muscle is less

understood, at least in intact ﬁbers (513). TRPC activity

results in Ca

inﬂux, and the ensuing elevations in intra-

myocellular Ca

either directly affect target structures or,

through the activation of distinct signaling pathways, result

in the activation of calmodulin, CnA, MEF2, and nuclear

factor of activated T cells (NFAT) (512). Dephosphorylation

of NFAT by CnA enables a cytoplasmic-nuclear transloca-

tion and subsequent regulation of gene expression by this

transcription factor, often together with MEF2 (512). NFAT

binds to regulatory genes involved in muscle ﬁber type

remodeling or hypertrophy, including induction of PGC-1a

and, via a positive feedback loop, transcription of TRPCs,

thereby sensitizing muscle ﬁbers to future mechanoinsults

(512). Non-genomic effects of intracellular Ca

include

direct modulation of structural proteins such as titin or

actin. Deformation of cytoskeletal structures thus medi-

ates mechanosensing by receptors at the cell membrane,

leading to a regulatory loop that reacts to changes in me-

chanical stress by adapting sensing and cell rigidity (512).

, for example, affects the assembly of actin ﬁlaments,

thereby driving a cytoskeletal rearrangement that affects

cell stiffness (512). Increases in intracellular Ca

also

result in the activation of Ras guanine nucleotide-releasing

factors (GRFs), which in turn activate the Ras GTPase (514).

In this manner, the mitogen-activated protein kinase

(MAPK) signaling pathway is engaged, leading to elevated

activity of p38 MAPKs, extracellular signal-regulated ki-

nases (ERKs), c-Jun NH

-terminal protein kinases (JNKs),

and stress-activated protein kinases (SAPKs). The MAPK

pathway integrates TRPC Ca

-derived mechanosensing

via transmembrane adhesion receptors such as integrins,

integrin-associated proteins, focal adhesion kinase (FAKs),

and other components of the focal adhesion complex

(512,515). The stress-activated kinases then execute the

phosphorylation of enzymatic effectors and transcriptional

regulators including PGC-1a(516), serum-response factor

(SRF), JUN, and FOS, forming the activating protein 1 (AP-1)

complex or early growth response gene 1 (EGR-1), and

thereby inducing the expression of immediate-early and

delayed primary response genes (517). This program

includes several transcription factors needed for second-

ary response gene transcription, some of which are

directly modiﬁed by stress kinase phosphorylation (518).

Collectively, these early primary and secondary response

genes promote processes related to cell survival, cytos-

keletal rearrangement, and elevation of small heat shock

proteins (HSPs) and other chaperones, thus mitigating

potential harmful events in the contracting muscle ﬁber on

different levels (511,512,518).

4.3.2. Cytosolic mechanosensing.

Besides these mechanosensing systems originating at

the cell membrane, at least two cytosolic signaling path-

ways are important. First, mTORC1 activity is increased

Shear stress Contraction-Relaxation

TRPC

Cytoskeleton

Titin

Hippo

mTORC1

YAP/TEAD

Integrins

FAC

Change in titin stiffness

Repair of sarcomeres

Ca2+

Stress kinases: p38 MAPK,

ERK, JNK, SAPK

Nuclear

deformation

Immediate-early and delayed

primary gene expression:

SRF, EGR-1, AP-1, PGC-1α,...

FIGURE 12. Mechanosensing and mechanostress mitigation in the contracting muscle ﬁber. Mechanical stress is sensed and translated by structures

at the cell membrane and intramyocellular components in the cytosol, cytoskeleton, sarcomeres, or nucleus. As a consequence, resistance to shear

stress is increased, stiffness and integrity of sarcomeric structures adapted, and a broad program of immediate-early and delayed primary genes initi-

ated. AP-1, activating protein 1; EGR-1, early growth response gene 1; ERK, extracellular signal-regulated kinase; FAC, focal adhesion complex; JNK, c-

Jun NH

-terminal protein kinase; mTORC1, mammalian target of rapamycin complex 1; p38 MAPK, p38 mitogen-activated protein kinase; PGC-1a,per-

oxisome proliferator-activated receptor ccoactivator 1a; SAPK, stress-activated protein kinase; SRF, serum response factor; TEAD, TEA domain tran-

scription factor; TF, transcription factor; TRPC, mechano-gated Ca

transient receptor potential channels; YAP, yes-associated protein. Image created

with BioRender.com, with permission.

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in mechanically stimulated ﬁbers (519,520). This protein

kinase is the major regulator of cellular protein synthesis

and one of the key inhibitors of autophagy, thereby con-

trolling cell size (521). In prohypertrophic states, mTORC1

is activated and contributes to the regulation of muscle

mass (522) in a controlled manner. Dysregulation of mus-

cle mTORC1 through ablation of the upstream inhibitor

tuberous sclerosis complex (TSC) results in an atrophic

phenotype (523).Incontrast,inducible,skeletalmuscle-

speciﬁc ablation of raptor, an essential component of

mTORC1, has little effect on muscle mass in sedentary

mice (524). These ﬁndings suggest that mTORC1 is an im-

portant, but not the only, regulatory factor governing skel-

etal muscle hypertrophy (525). The prototypical activators

of mTORC1 signaling are insulin and amino acids, in partic-

ular leucine, arginine, and glutamine, collectively repre-

senting an anabolic context with high nutrient availability

(521). However, in muscle contraction and mechanosens-

ing, other stimuli may be more important to activate

mTORC1, although the speciﬁc exercise-stimulated mech-

anisms have not been identiﬁed (519). Candidate path-

ways include IGF-1 signaling or that of the muscle-speciﬁc

IGF-1 splice variant mechano growth factor (MGF), whose

activity is increased by mechanical stimulation and could

engage mTORC1 via PI3K-Akt-dependent pathways.

However, even though IGF-1 exerts clear anabolic effects

in muscle, experimental evidence indicates that acute

mechanosensing and activation of mTORC1 might be in-

dependent of PI3K and Akt (519,520). mTORC1 activation

could also be achieved by cross talk with established

mechanosensing pathways such as intracellular Ca

engaging mTORC1 via activation of CaMK kinase a

(CaMKKa) or phosphorylation of TSC and raptor by ERK ki-

nases (519,520). Furthermore, different membrane-bound

phospholipases and diacylglycerol kinase f(DGKf)are

activated by stretch, in part via Ca

, and then exert vari-

ous functions related to the mechanoresponse (519).

Phospholipases activate the Raf-ERK as well as PI3K-Akt

pathways, thereby regulating two potential upstream regu-

lators of mTORC1 (519). Moreover, phosphatidic acid pro-

duced by phospholipase D or DGKfdirectly stimulates

mTORC1 activity, most likely by binding to the 12-kDa

FK506-binding protein (FKBP12)-rapamycin binding (FRB)

domain of mTOR (519). Then, a mechanosensitive integ-

rin-FAK-TSC2-Ras homolog enriched in brain protein

(RHEB) axis could also converge on mTORC1 (515).

Finally, several other mechanisms have been pro-

posed to mediate the activation of mTORC1 upon me-

chanical stress and loading, including translocation of

TSC2, the cellular redox state, in particular reactive

nitrogen species (RNS), and amino acid availability.

Regardless of the mode of upstream control, mTORC1

activity triggered by loading-induced mechanical

stress results in an upregulation of protein synthesis

and other hypertrophic programs and, in combination

with PI3K-Akt activity, a reduction in catabolic proc-

esses and apoptosis (519).

In parallel to mTOR signaling, the Hippo pathway also

contributes to mechanostress-induced muscle cell remod-

eling (526). The transcriptional coactivator Yes-associated

protein (YAP) is controlled by the Hippo pathway and is

activated upon deformation or rearrangement of actin

and the subsequent regulation of various actin-associated

proteins (526). After cytoplasmic-nuclear translocation,

YAP coactivates TEA domain (TEAD) transcription factor

family members to control the expression of genes linked

to decrease in apoptosis and increase in muscle hypertro-

phy (526). Even though the prohypertrophic function of

YAP is mTOR independent, the Hippo/YAP pathway may

engage in cross talk with the Akt/mTOR pathway to pro-

mote muscle mass gains and with the transforming

growth factor-b(TGF-b)/small worm phenotype/Mothers

Against Decapentaplegic (SMAD) pathway to coordinate

repair and regeneration, respectively (526).

4.3.3. Structural mechanosensing at the

cytoskeleton, sarcomeres, and cell nucleus.

Intramyocellular structural components also contribute

to mechanosensing, mostly ﬁlamentous actin and the

sarcomeric proteins myosin and, in particular, titin, a

giant scaffold protein that is essential for forming the sar-

comeric structure (527–529). Because of reversible

extension of speciﬁc domains, titin acts as a molecular

spring and determines the passive elastic properties of

sarcomeres and muscle ﬁbers and can even contribute

to active force and tension generation during muscle

contractions (530). During stretch, physical deforma-

tion of titin leads to the release of several ankyrin-

repeat proteins including cardiac ankyrin-repeat pro-

tein (CARP), diabetes-related ankyrin-repeat protein

(DARP), and ankyrin-repeat-domain protein-2 (ANKRD2)

that act as transcription factors to initiate sarcomerogene-

sis and ﬁber repair leading to adaptive muscle remodel-

ing and increased expression of structural proteins,

including titin, desmin, and dystrophin (527,528). At that

time, a complex formed by the muscle LIM protein (MLP)

is released from titin and interacts with NFAT signaling to

induce prohypertrophic genes. The titin-cap (T-CAP) acti-

vatestheE3-ubiquitinligasemousedoubleminute2hom-

olog (MDM2), which, together with the titin-associated

-dependent cysteine proteases calpain1 and calpain3

as well as the neighbor-of-BRCA1-gene-1 (NRB-1), promotes

protein degradation and autophagy, hence a robust sys-

tem of protein quality control to repair defective sarcomere

structures (527,528). In the active muscle, in addition to

constituting one of the major signaling hubs for mechano-

sensing, titin represents a tunable spring, acquiring

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context-dependent stiffness and thereby conferring

enhanced tension and an increased passive force to mus-

cle cells (527,528). Different posttranslational modiﬁca-

tions of the titin protein and direct binding of Ca

affect

the stiffness of this protein to improve sarcomere integrity

during exercise and promote the effectiveness of acceler-

ated contraction-relaxation cycles (527,528).

Other intracellular structural components that are

involved in mechanosensing and transduction include the

cell nucleus (531,532), often the most stiff element of the

cell (533). The perinuclear cytoskeleton transmits forces to

the Linker of Nucleoskeleton and Cytoskeleton (LINC)

complex and various proteins of the nuclear envelope

such as lamins and emerin. The LINC complex provides a

mechanical connection between the cyto- and nucleoske-

leton. Remodeling of the nuclear lamina by mechanical

force can directly affect gene expression by changing the

chromatin condensation state, histone modiﬁcations,

gene repositioning, and the binding of transcription factors

to accessible DNA regions. Inversely, the chromatin state

and histone modiﬁcations might affect nuclear rigidity.

Thereby, a bidirectional link between nuclear mechano-

sensing and transcriptional regulation is achieved (532,

533). How this is affected by exercise is unclear. Signaling

induced by mechanosensing occurs as soon as the mus-

cle contracts, but it is not known whether resistance- and

endurance-type exercise affect mechanosensing in a simi-

lar fashion and thereby activate the same pathways.

Furthermore, it is possible that speciﬁc interventions or

types of contractions (i.e., eccentric vs. concentric contrac-

tions) may enhance stretch or shear stress and thereby

promote mechanosensing-induced signaling pathways.

4.4. Oxidative Stress

Oxidative stress and the associated cellular responses

are closely linked to mechanical stress and mechano-

sensing (FIGURE 13)(534). In contracting skeletal mus-

cle cells, reactive oxygen species (ROS) are produced

by NADPH oxidase enzymes NOX2 and NOX4 and to a

lesser extent by mitochondria. Whereas NOX4 seems to

be a more constitutive enzyme important for basal ROS

production in muscle, NOX2 activity is highly regulated

by speciﬁc agonists such as angiotensin II or various

cytokines. At the onset of contraction, phospholipase A

is activated by elevated intracellular Ca

to produce ar-

achidonic acid from the cleavage of membrane phos-

pholipids. Arachidonic acid in turn increases ROS

production by NOX2 and mitochondria (534). Muscle

stretch, compression, or osmotic shock thereby results

in a rapid burst of intramyocellular ROS, which then

serves as physiological signaling agent (535). In addi-

tion, NOX2 activity might be directly modulated by

mechanosensing of the intracellular microtubule net-

work (536). NOX2-derived ROS in turn affect TRPCs

and, in a positive feedback loop, further sensitize muscle

ﬁbers to stretch. In a speciﬁc range of concentration, ROS

are important to stimulate maximal force generation,

even though the mechanistic aspects of this function are

unclear. RNS could trigger adaptations similar to ROS in

skeletal muscle. Nitric oxide (NO) is primarily produced by

thetypeIneuronalnitricoxidesynthase(nNOS)enzyme

in the contracting muscle ﬁber (537,538). Subsequently,

NO affects several systems in myoﬁbers, either by direct

nitrosylation or by activation of NO-dependent guanylate

cyclases and the ensuing increase in cGMP (536–539).

NO has a broad-ranging impact on muscle cell metabo-

lism by increasing glucose uptake or reducing the activ-

ities of creatine kinase and several glycolytic enzymes

(536–539). Together with NO produced by epithelial

(eNOS) and inducible (iNOS) NOS, positive effects on va-

sodilation and the activation of satellite cells are

achieved. Finally, both ROS and RNS engage numerous

signaling pathways and transcriptional regulators to pro-

mote a myocellular remodeling (540). MAPK signaling

pathways are redox sensitive, and an activation of JNK,

p38 MAPK, and ERK is observed upon elevated levels of

ROS and RNS (537). In terms of transcriptional regulation,

release of the redox-sensitive Kelch-like ECH-associated

protein 1 (KEAP1) enables a cytoplasmic-nuclear shuttling

of the transcription factor nuclear factor erythroid 2-related

factor 2 (NRF2, also known as nuclear factor erythroid-

derived 2-like 2, NFE2L2), which then binds to antioxidant

response elements (AREs) on regulatory sites of various

genes to promote a robust antioxidant response (541).

NRF2/NFE2L2 also induces the expression of nuclear re-

spiratory factor 1 (NRF1) and PGC-1aand increases mito-

chondrial biogenesis and substrate oxidation (541). NRF2/

NFE2L2 gene expression is controlled by an AMPK-PGC-

1aaxis, implying a robust mutual regulation of NRF2/

NFE2L2 and PGC-1a,withbothPGC-1aand NRF2/NFE2L2

being activated by MAPK pathway effectors (541).

Furthermore, PGC-1aregulates the transcription of several

genes encoding antioxidant enzymes, at least in part, in

an NRF2/NFE2L2-dependent manner (541). PGC-1agene

transcription is also controlled by NO via the activation of

cGMP-associated signaling, potentially in a bimodal fash-

ion (541). Upon redox-dependent oxidation of cysteine res-

idues (540) and a resulting stabilization of the tumor

suppressor gene p53, this transcription factor binds to and

activates the promoter of PGC-1atomediatesomeofits

protective effects in muscle during exercise (542). Nuclear

factor κB(NF-κB) and AP-1 are two additional transcription

factors that can be activated in a redox-speciﬁc manner

(537). In this context, NF-κB is a strong regulator of antioxi-

dant genes, whereas AP-1 induces a more general stress

response (537). Of note, both transcription factors interact

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with PGC-1a: AP-1, together with MEF2 family factors, con-

trols PGC-1agene expression, whereas PGC-1abinds to

AP-1 to regulate some of its target genes (474,537). In

contrast, a mutual negative interaction between NF-κB

and PGC-1amayhelptoregulatehomeostasis

between metabolism and inﬂammation in muscle

(543). The cellular redox state also affects PI3K-Akt-

mTOR signaling to control rates of protein synthesis

and muscle hypertrophy (534,539). First, ROS-medi-

ated activation of Akt results in an increase in mTORC1

function (534), whereas NO exerts a negative effect on

this pathway, presumably to keep hypertrophy in

check (539). Both redox modalities merge in the pro-

duction of peroxynitrite, formed by the reaction of

superoxide with NO, which leads to an activation of

mTORC1 (534). Thus, the redox balance modulates and

ﬁne-tunes muscle hypertrophy. Collectively, adequate

regulation of ROS and RNS is instrumental to react to

mechanical and other types of stress during exercise

and acutely affects contractility (534). Furthermore,

such a contraction-linked increase in ROS and RNS trig-

gers a hormetic response, in which an upregulation of mi-

tochondrial uncoupling proteins, antioxidant enzymes,

and compounds blunts potential damage by future insults

(534). Accordingly, higher levels of antioxidant enzymes

such as superoxide dismutase (SOD) 1 and 2, catalase

(CAT), and glutathione peroxidase (GPx), as well as non-

enzymatic antioxidants such as reduced glutathione

(GSH) that ameliorate redox homeostasis, are observed in

the muscles of trained individuals (544–547). Based on

the role of these processes, inhibition of the production of

ROS and RNS with pharmacological and/or nutritional

antioxidants could be detrimental in promoting an optimal

cellular environment to maximize training adaptation

(548). Even though excessive ROS production has been

linked to tumorigenesis, cardiovascular diseases, hyper-

tension, neurodegenerative disorders, and other chronic

pathologies, exercise training substantially reduces the

risk of these diseases, despite the contraction-induced

acute elevations of ROS and RNS in skeletal muscle (534).

These epidemiological observations highlight the impor-

tance of a well-balanced and coordinated redox produc-

tion and detoxiﬁcation system in muscle, without any

apparent pathological consequences in muscle tissue or

beyond (549).

4.5. Energy Homeostasis, Substrate and Oxygen

Sensing

4.5.1. Energy homeostasis and energetic stress.

Muscle cell contractions are strongly linked to major

metabolic remodeling (FIGURE 14A). In many situations,

Shear stress Contraction-Relaxation

TRPC

NOX

ROS NOS

RNS Glucose

Vasodilation

mTORC1

NRF2/NFE2L2

cGMP

PGC-1α

Stimulation of maximal

force generation

Enhanced stretch

sensitization

Integrins

FAC

Antioxidant and stress

response genes

Satellite cell

activation

FIGURE 13. Redox stress by reactive oxygen and nitrogen species in muscle contraction. Redox regulation of muscle contractility and stress

response by reactive oxygen (ROS) and nitrogen (RNS) species during muscle contraction. ROS and RNS are primarily produced by enzymes at the

muscle cell membrane. Subsequently, a number of downstream effects are promoted, including an increase in energy substrate and oxygen availabil-

ity, enhancement of force generation, improvement of the resilience against oxidative stress, and modulation of a transcriptional program for muscle

remodeling. cGMP, cyclic guanylate monophosphate; FAC, focal adhesion complex; mTORC1, mammalian target of rapamycin complex 1; NOS, nitric

oxide synthase; NOX, NADPH oxidase; NRF2/NFE2L2, nuclear factor erythroid-derived 2-like 2; PGC-1a, peroxisome proliferator-activated receptor c

coactivator 1a; TF, transcription factor; TRPC, mechano-gated Ca

transient receptor potential channels. Image created with BioRender.com, with

permission.

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the demand for ATP as a rapid energy source is only

partially compensated by creatine phosphate system

transfer and the subsequent increase in oxygen-inde-

pendent anaerobic and aerobic metabolism of glucose,

lipids, lactate, ketone bodies, and other energy sub-

strates. This leads to a shift in the relative concentrations

of ATP, ADP, and AMP (393). During recovery from strenu-

ous exercise, and after optimal refueling, this catabolic

energetic state will pivot into an anabolic state and muscle

and liver glycogen as well as intramyocellular lipid stores

will be replenished. In parallel to the shift in adenosine

species, the relative abundance of nicotinamide adenine

dinucleotide (NAD

) and NADH as well as other cofactors

involved in myocellular redox reactions is affected by mi-

tochondrial OXPHOS, lactate dehydrogenase activity, as

wellasotherprocesses(550,551). These fundamental

metabolic changes triggered by the increased energetic

demand of contracting muscle cells result in a complex

ATP ADP / AMP

NADH

FAD

Protein

Degradation Synthesis

AMPK

Autophagy

mTOR

SIRT1

PGC-1α

Glucose uptake

Glucose

PGC-1α

Protein

Degradation Synthesis

AMPK

Autophagy

Amino acids

mTOR

Glucose

Fatty acids

Mondo

Metabolites

Glycogen

Acute, severe hypoxia/reduced physoxia

HIF-1α

Prolonged hypoxia/reduced physoxia

HIF-2α

Mitochondrial

biogenesis and

function

Fatty acid

transport and

oxidation

Ketone body

metabolism

Lactate

metabolism

FADH2

NAD+

Metabolic

remodeling:

Transcription of

fatty acid

oxidation genes,

glucose uptake

and metabolism,

mitochondrial

genes,...

Modulation of

proteostasis

PPARα

PPARβ/δ

Amino acids

Insulin

IGF-1

PGC-1α

ERRα

Reduced PGC-1α and oxidative metabolism

Inhibition of mTORC1 and anabolic processes

Increased glycolysis and vascularization

Increased myoglobin

Increased vascularization (HIF-1α independent)

SIRT1 TF

HIF-1α

FIGURE 14. Energy homeostasis, substrate and oxygen

signaling. A: metabolic stress signaling in muscle contrac-

tion to increase energy provisioning. A decrease in energy

substrate availability leads to the activation of energy sen-

sors that reduce anabolic processes consuming ATP and

induce catabolic pathways to produce more ATP. This

broad response comprises direct modulation of protein

and enzymatic activities by posttranslational modiﬁcation

as well as the control of a broad transcriptional program.

B: energy substrate signaling senses substrate levels and

leads to metabolic partitioning. Thereby, muscle cell me-

tabolism is coordinated with substrate availability and

anabolism balanced with catabolism. C: reduced oxygen

availability in skeletal muscle is sensed by hypoxia-induci-

ble factor (HIF)-1aand HIF-2ain acute and chronic set-

tings, respectively. HIF-1arapidly reduces pathways that

consume O

, while promoting anaerobic glycolysis to gen-

erate ATP. HIF-2apromotes muscle oxygen extraction

and provisioning. AMPK, AMP-activated protein kinase;

ERRa, estrogen-related receptor a;FAD:ﬂavin adenine di-

nucleotide; IGF-1, insulin-like growth factor 1; mTOR, mam-

malian target of rapamycin; NAD, nicotinamide adenine

dinucleotide; PGC-1a, peroxisome proliferator-activated re-

ceptor ccoactivator 1a; PPARa/-b/d, peroxisome prolifera-

tor-activated receptor a/-b/d;SIRT1,sirtuin1;TF,transcription

factor. Image created with BioRender.com, with permission.

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modulation of signaling cascades and biochemical path-

ways that are crucial for training adaptation. For example,

a shift in the ATP-to-AMP ratio toward AMP leads to the

activation of a signal transduction pathway centered on

AMPK, which in turn phosphorylates downstream protein

kinase substrates (552,553). In addition, AMPK activity

is modulated by the cellular environment, in particular

upstream kinases liver kinase B1 (LKB1) in exercise of short

duration (i.e., seconds to minutes) and CaMKKbduring

prolonged exercise bouts, or by signaling induced by vari-

ous myokines such as IL-6, IL-15, BDNF, and leukemia in-

hibitory factor (LIF) (498,501,554). Although the precise

role of contraction-induced AMPK signaling in the regula-

tion of glucose uptake and fatty acid oxidation remains

controversial (555), AMPK activation leads to a general

catabolic response upon cessation of exercise, including

augmented uptake of glucose and fatty acids, reduced

rates of glycogen synthesis, elevated glycolysis, and

improved mitochondrial activity (554). Furthermore, AMPK

is a potent activator of autophagy and promotes protein

degradation via the ATP-dependent ubiquitin-proteasome

system to liberate amino acids for energy production in

muscle and gluconeogenesis in the liver (554). The regu-

lation of these two processes is tightly coordinated, with

inhibition or activation largely determined by the relative

activity of AMPK and mTOR and the balance between the

catabolic and anabolic state of the muscle cell (556). For

example, ketoacids resulting from the metabolism of the

branched-chain amino acids valine, leucine, and isoleu-

cine can be used to generate ATP via the tricarboxylic

acid (TCA) cycle in a catabolic state, whereas branched-

chain amino acids can also activate mTOR in the face of

high energy availability (557). In the former setting, AMPK

inhibits mTOR activity by phosphorylation of the mTORC1

upstream inhibitors TSC1 and 2 as well as the mTORC1

component raptor (521). Autophagy is directly stimulated

by AMPK-mediated phosphorylation of the Unc-51-like ki-

nase 1 (ULK1) (521,554), whereas protein degradation is

boosted by phosphorylation and thereby activation of

FOXO3 (554), as well as transcriptional activation of

FOXO1 and FOXO3 (558). In an anabolic context, insulin

or amino acid signaling as well as lysosomal recruitment

of mTOR strongly reduce autophagy and catabolic path-

ways so that protein synthesis and lipogenesis are

enhanced (521). S6 protein kinase (S6K) and eukaryotic

translation initiation factor 4E (eIF4E) are two important

mTORC1 phosphorylation substrates that, together with

increased transcriptional activity of RNA polymerases I

and III, subsequently coordinate ribosomal biogenesis

and protein synthesis (521,559). Insulin signaling-depend-

ent activation of Akt results in phosphorylation and nu-

clear exclusion of FOXO1 and 3, and thereby inhibition of

protein degradation, as well as activation of glycogen syn-

thase kinase 3b(GSK3b),whichinturnphosphorylates

eIF2B and b-catenin to promote protein synthesis (560,

561). The strong inhibitory effect of mTORC1 on autophagy

is exerted by phosphorylation of ULK1 and transcription

factor EB (TFEB), a key regulator of lysosomal biogenesis

(521,562). TFEB and TFE3 are activated by Ca

/calci-

neurin signaling in contracting skeletal muscle, resulting in

nuclear translocation and activation of autophagy, lysoso-

mal, and mitochondrial gene expression, in part by func-

tionally interacting with PGC-1a(562). Thus, overall, AMPK

and mTORC1 exert opposite functions, promoting cata-

bolic and anabolic processes, respectively, with a direct

inhibition of mTORC1 by AMPK; this reciprocal control is

important to regulate speciﬁc adaptations to endurance-

and resistance-based training stimuli but might also be rel-

evant in the context of concurrent training and the training

interference effect (163,521,563). The molecular basis of

the interference effect underlying the compromised

strength gains observed when individuals simultaneously

undertake both endurance and strength training pro-

grams (described in sect. 2) was investigated at the mo-

lecular level by Atherton and colleagues (564), who

studied isolated rat muscles that were electrically stimu-

lated with either low frequency to mimic endurance exer-

cise (3 h at 10 Hz) or high frequency to mimic resistance

training (6 10 repetitions of 3-s bursts at 100 Hz). They

observed selective activation and/or downregulation of

AMPK-PGC-1aor Akt-mTORC1 signaling pathways in

response to these divergent loading patterns. Speciﬁcally,

they reported that electrical stimulation that mimicked ei-

ther endurance- or resistance-based training switched sig-

naling to either an AMPK-PGC-1a-orAkt-mTOR-selective

state. They termed this activity the AMPK-Akt “master

switch”and hypothesized that such selective activation of

AMPK-PGC-1aor Akt-mTORC1 signaling could explain

speciﬁc adaptive responses to endurance or resistance

training (564). However, Coffey et al. (565)demonstrated

that in highly trained athletes prior training history attenu-

ated the “exercise-speciﬁc”signaling responses involved

in single-mode adaptations to training and that a degree

of “response plasticity”was conserved at opposite ends

of the endurance-resistance adaptation continuum.

Given that genotypes were originally selected to sup-

port diverse physical activity patterns obligatory for

human survival and that modern-day success in

many sporting endeavors requires a high endurance

capacity coupled with superior explosive power, the

conservation of multiple signaling networks to meet

divergent physiological demands seems to make

sound evolutionary and biological sense (1).

AMPK and mTOR can also synergize and converge in

certain cellular contexts (563), potentially representing

the temporal speciﬁcation of these two proteins in the

response to contractile activity of skeletal muscle, or ad-

aptation to mixed or concurrent forms of training. For

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example, after training, AMPK improves insulin sensitivity

of myoﬁbers, thereby potentiating the activation of mTOR

(554). Moreover, both AMPK as well as mTOR converge

on the activation of PGC-1ato promote mitochondrial bio-

genesis and oxidative metabolism of energy substrates

(474,521,554). The interaction between these two key

metabolic regulators, and the implications for muscle cell

plasticity, are therefore multifaceted and remain poorly

understood. In addition to mTOR signaling, AMPK also

engages redox-sensitive pathways including the NAD

dependent protein deacetylase sirtuin 1 (SIRT1), with

AMPK-mediated phosphorylation of PGC-1apreceding

SIRT1-dependent deacetylation and subsequent activa-

tion in skeletal muscle (566,567). Lysine deacetylation by

SIRT1, SIRT3, and other NAD

sensorsaswellasthe

counterregulatory effect by acetyltransferases such as

general control non-repressed 5 (GCN5) are not re-

stricted to enhancing and decreasing the activity of PGC-

1a(568) but also other targets, including histones.

Thereby, a tight coupling between the myocellular redox

state and transcriptional regulation in exercise is facili-

tated (569,570). Although the functional interaction

between PGC-1aacetylation and AMPK-dependent phos-

phorylation has been proposed, the cross talk between

phosphorylation events by other kinases, protein methyl-

ation, ubiquitination, sumoylation, or O-linked b-N-acetyl-

glucosamination is less well understood (474,482).

Posttranslational modiﬁcations of proteins can affect dif-

ferent properties, including stability or turnover, localiza-

tion, interactions with other protein binding partners, DNA

recruitment, enzymatic activity, or structural conformation

(571,572). Indeed, once activated, PGC-1ainteracts with

many different transcription factors, including estrogen-

related receptor a(ERRa), NRF1, NRF2/GABP, MEF2C,

and MEF2D, to coordinate a complex, yet poorly under-

stood transcriptional network encoding the biological

program of endurance exercise adaptation encompass-

ing vascularization, remodeling of the NMJ, or induction

of a slow-type contractile phenotype (474,573,574).

Moreover, PGC-1ainitiates a coordinated transcriptional

network encoding mitochondrial biogenesis and function,

includingTCAandOXPHOS,fattyaciduptake,transport,

and b-oxidation, ketone body and lactate metabolism, as

well as glucose uptake and use in the pentose phosphate

pathway (474,481,575–577). Other transcription factors

such as ERRcor PPARb/d, for which the epistatic relation-

ship to PGC-1aand the involvement in the exercise

response are less clear, evoke similar gene programs in

skeletal muscle (485). Finally, a multifaceted interaction

between PGC-1aand other coregulator proteins affects

the activity of PGC-1ain the control of skeletal muscle

plasticity. For example, nuclear corepressor 1 (NCOR1)

competes with PGC-1afor binding to ERRaand PPARb/d,

thereby reducing PGC-1atarget gene expression

mediated by these interactions (486). In addition, trans-

ducers of regulated CREB-binding proteins 1, 2, and 3

[TORC1/2/3, also called cAMP-regulated transcriptional

coactivators (CRTCs)] are coregulators that are strongly

modulated by environmental cues and, in turn, induce

PGC-1agene expression (486). The diversity of interac-

tions and hence the variety in PGC-1a-containing protein

complexes with different coregulators and transcription

factor binding partners likely contribute to the highly orch-

estrated and coordinated transcriptional network control

exerted by this coactivator protein in skeletal muscle in

exercise (474,481–486,578).

4.5.2. Signaling mediated by substrates and

metabolites.

Metabolites and energy substrates have additional

effectsonexerciseadaptationinskeletalmuscle,and

even transient and subtle perturbation in cellular homeo-

stasis can trigger broad downstream effects (FIGURE

14B)(84). For example, glycogen binds to a carbohy-

drate-binding module on the AMPKbsubunit to nega-

tively affect AMPK activity (579), providing a molecular

explanation for the enhanced training effect when individ-

uals commence exercise with low muscle glycogen

stores, as in “train low”(glycogen) protocols (81,579).

Mondo transcription factors are activated by binding of

glucose, leading to a modulation of the expression of

genes involved in glucose homeostasis by MondoA in

muscle, while concomitantly reducing fatty acid oxidation

by PGC-1a, thereby providing an important metabolic

switch between glucose and lipid oxidation in contracting

ﬁbers according to the Randle cycle (580). Fatty acids are

ligands for various nuclear receptors, including the

PPARs, and liver X receptors (LXRs), leading to an

increase in rates of lipid oxidation and lipogenesis in skel-

etal muscle, respectively (485). Furthermore, as noted

above, amino acids are potent activators of mTOR and

thus contribute to mTORC1-mediated control of muscle

proteostasis that promotes ﬁber hypertrophy in response

to resistance-based training (522). The requirement for

mTORC1 in inducing exercise hypertrophy seems to

depend on various factors, including temporal aspects or

training stimuli, with considerable mTORC1-independent

contributions (581). Moreover, amino acid supplementa-

tion to activate mTORC1 without concomitant resistance

training is clearly insufﬁcient to induce gains in muscle

mass and strength (582). Succinate, a citrate cell cycle in-

termediate, accumulates in muscle, the interstitial space,

as well as the circulation during exercise. Signaling trig-

gered by succinate binding to succinate receptor 1

(SUNCR1) induces adaptations in the gene expression pro-

grams for axon guidance, neuronal projection, and muscle

regeneration that collectively contribute to endurance

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exercise capacity (583). In addition to NAD

, other cofac-

tors at the intersection of metabolism and transcription

are likely affected by contractile activity in skeletal muscle,

including ﬂavin adenine dinucleotide (FAD) in the TCA

cycle and OXPHOS, a-ketoglutarate in the citrate

cycle, and acyl-CoA and acetyl-CoA in substrate oxi-

dation and the citrate cycle (393). These cofactors are

directly involved in epigenetic gene regulation by

modulating histone and DNA demethylation and his-

tone acetylation (584). Whether such an epigenetic

coupling to metabolism exists in skeletal muscle dur-

ing exercise is unknown, even though epigenetic

mechanisms contribute to exercise-induced muscle

plasticity (578,585). Finally, the extensive metabolic

remodeling in muscle and other tissues during and af-

ter exercise is likely to include many other metabo-

lites with important signaling and regulatory functions

in the training response (586,587), collectively

referred to as myobolites or myometabokines (588,

589). In addition to muscle-intrinsic effects, inter-tis-

sue communication is also mediated by such circulat-

ing metabolites including b-aminoisobutyric acid

(BAIBA)thathelptocoordinatethegeneralsystemic

response (590). In a similar manner, altered muscle

metabolic capacity can affect the circulating levels of

endogenous metabolites and, in the case of aberrant

levels of such metabolites, thereby contribute to a

“detoxiﬁcation”by lowering hyperketonemia (575)or

the conversion of kynurenine into kynurenic acid,

which is unable to cross the blood-brain barrier (591).

One of the ﬁrst studies to propose a link between sub-

strate availability and molecular signaling in exercising

human muscle was that of Wojtaszewski and colleagues

(592). They measured muscle signaling responses and

substrate utilization during and after an acute bout of

steady-state cycling in well-trained subjects under condi-

tions in which exercise was commenced with either low or

high muscle glycogen content. After exercise started in a

low-glycogen state AMPKa2andAMPKa1 activity was ele-

vated to a greater extent compared to when the same

exercise bout was commenced with high glycogen con-

tent (592). However, exercise commenced in the lowered

glycogen state was associated with elevated catechol-

amine concentrations compared with the glycogen-loaded

trial, making it difﬁcult to determine whether fuel availabil-

ity and/or humoral factors contributed to the observed

boosted AMPKa2andAMPKa1 activity. Subsequently, the

results of several other investigations demonstrated that,

compared with normal glycogen levels, commencing en-

durance exercise with reduced glycogen availability

increases the phosphorylation of p38 MAPK and transcrip-

tional activation of IL-6, pyruvate dehydrogenase kinase 4

(PDK4), hexokinase, and HSP72 (188). PGC-1amRNA was

also induced to a greater extent (8- vs. 3-fold) after highly

trained cyclists performed a standardized bout of submaxi-

mal endurance exercise with low versus normal glycogen

concentration (191). Even in response to resistance exer-

cise, commencing exercise with low glycogen seems to

promote mitochondrial adaptation, as demonstrated with

increased phosphorylation of p53 and mRNA expression

of PGC-1a(206). Although “train low”(glycogen) protocols

boost the training response in well-trained athletes, this

training paradigm failed to be superior to conventional pro-

tocols with regard to performance enhancement.

4.5.3. Oxygen sensing.

If oxygen consumption exceeds oxygen availability and

uptake, “physiological hypoxia”(or “reduced physoxia”)

occurs, corresponding to a drop of mean oxygen ten-

sion from 30 mmHg to 2–3 mmHg in contracting skeletal

muscle ﬁbers (593–595). This drop is already observed

at relatively low exercise intensities, implying that addi-

tional mechanisms might be contributing to oxygen

availability for different structures in the muscle cells,

such as myoglobin function or local intracellular oxygen

levels and gradients (596–598). Hypoxia-inducible fac-

tor (HIF)-1aand HIF-2aare the major mediators of

hypoxic stress (FIGURE 14C). Upon reduced oxygen

availability, HIF-1aproteolysis by prolyl-hydroxylases 2

and 3 (PHD2/3) is alleviated and the HIF-1aprotein stabi-

lized (593). HIF-1athen controls gene programs involved

in anaerobic glycolysis to sustain energy production in the

absence of adequate oxygen supply and represses those

programs that are oxygen dependent, such as mitochon-

drial OXPHOS. This is brought about by inhibiting PGC-1a

expression and activity while promoting gene expression

related to vascularization to improve oxygen supply via

the myokine VEGF (593). Furthermore, the hypoxia-re-

sponsive gene DNA damage inducible transcript 4

(DDIT4) encoding the REDD1/RTP801 protein, an activator

of TSC1/2, inhibits mTORC1 and downstream anabolic

pathways, thereby limiting ATP-consuming processes

(599). The paralog HIF-2aplays a permissive role in the

acute hypoxic response compared with HIF-1abut a

greater function in long-term adaptation in which HIF-1a

activity is repressed (593). In this context, PGC-1ainduces

the expression of HIF-2a,ERRa,theAP-1complex,and

VEGF to promote angiogenesis and vascularization in a

HIF-1a-independent manner (474,600). With regard to

training, the temporary hypoxia in muscle can be exacer-

bated by vasoconstriction of capillaries in muscle tissue,

for example by vascular occlusion or peak contraction

(149). Accordingly, the exercise-induced increase in

mRNA expression of all four postulated PGC-1aisoforms

is blunted when endurance exercise is performed with

blood ﬂow restriction (601). However, in the long term,

training under hypoxic conditions may boost the adaptive

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response in the muscle. It remains to be determined

whether such training paradigms are more effective in

enhancing the performance of elite athletes than training

under normoxic conditions.

4.6. Thermotolerance, Protein and Organelle

Quality Control

4.6.1. Heat stress.

Contractile activity is linked to the production of heat, with

only a small fraction of chemical energy (25% depending

on the type of muscular activity performed) being con-

verted into external force production (FIGURE 15A)(602).

Elevated muscle temperature has several advantages in

terms of enzyme kinetics and activity and contributes to

vasodilation and increased blood ﬂow, permitting a better

supply of oxygen and energy substrates, as well as more

efﬁcient removal of by-products. Nevertheless, excess

contraction-induced heat production must be dissipated

through vasodilation and sweating. Thermal stress can

result in misfolding of proteins, impairing cellular function.

To mitigate the potentially damaging effects of heat, exer-

cise induces elevated activity and levels of HSPs, most

notably HSP72 of the HSP70 family (603,604). The

upstream mechanisms of HSP activation in exercise are

poorly understood and likely depend on various meta-

bolic, biochemical, and physical factors as well as training

status. Upon heat stress, HSPs are released from binding

to heat responsive factor 1 (HSF1) and act as chaperones

to refold misfolded proteins and control proteasomal deg-

radation and autophagy (603,604). HSF1 in turn promotes

the transcription of PGC-1a, and together these two pro-

teins induce gene expression of HSPs and PGC-1ain an

autoregulatory loop (603,604). This cross talk with

PGC-1amediates heat shock-boosted oxidative me-

tabolism and mitochondrial function (603,604). In

addition to acting as chaperones and inducing an oxi-

dative phenotype, HSPs exert various other effects in

muscle. For example, by inhibiting JNK through direct

interaction and upstream signaling pathways, there is

Heat

Contractile activity

HSF1

Increased chaperone activity

PGC-1α

HSPs

PGC-1α

Mitochondrial activity

Shear stress

Proteostasis

ATF4, ATF5, CHOP

ATF6α, IRE1α, PERK

PGC-1α

Ca2+ Ca2+ release and reuptake

UPRER

UPRmt

Increased mitochondrial

dynamics

Initiation of mito-

and autophagy

Activation of protein

degradation

Inhibition of gene expression

and protein synthesis

Activation of chaperones

for protein refolding

Proteasome

HSF1

FIGURE 15. Heat and proteostatic stress. A:ther-

mosensing and the heat stress response mitigate

misfolding of proteins. Heat is produced by various

processes in the contracting muscle ﬁber, including

shear stress, mitochondrial activity, Ca

release

and reuptake, and ATP metabolism in contraction

cycling. Heat is sensed in the cell and a broad tran-

scriptional program engaged to increase mitigating

measures, e.g., chaperones to reduce thermally

induced protein misfolding. B: proteostatic stress

and the ensuing response pathways reduce protein

load, misfolding, and organelle health. Dedicated

pathways in the endoplasmic reticulum and mito-

chondria are engaged by proteostatic dysbalances,

e.g., excessive protein accumulation or misfolding.

At least in part, these two pathways converge to ini-

tiate a transcriptional program aimed at reversing

protein misfolding, alleviating proteostatic stress by

reducing gene expression and protein synthesis

while enhancing protein degradation, and by ensur-

ing organelle functionality. ATF4/5/6a,activating

transcription factor 4/5/6a; CHOP, C/EBP homolo-

gous protein; HSF1, heat shock factor 1; HSP, heat

shock protein; IRE1a, inositol-requiring enzyme 1a;

PERK, RNA-dependent protein kinase-like ER

eukaryotic translation initiation factor 2akinase;

PGC-1a, peroxisome proliferator-activated re-

ceptor ccoactivator 1a; TF, transcription factor;

UPR

, endoplasmatic reticulum unfolded pro-

tein response; UPR

, mitochondrial unfolded pro-

tein response. Image created with BioRender.com,

with permission.

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a reduction in inﬂammation and enhanced insulin

sensitivity elicited by HSP72 (603,604). These effects

can be potentiated by heat application to reduce muscle

soreness, improve muscle function during recovery from

damaging exercise, or enhance muscle mass gains

in strength training, potentially triggering a hormetic

response in which the heat shock response is pre-

induced, thereby conferring earlier and/or greater pro-

tection (605). Paradoxically, cold-water immersion

and other modalities to apply cold stressors after

exercise also reduce delayed-onset muscle sore-

ness (DOMS) and inﬂammation after a single applica-

tion (606). However, unlike heat exposure, chronic

cold therapy diminishes strength training effects by

reducing muscle blood ﬂow, attenuating mTORC1

signaling and ribosomal biogenesis, and increasing

FOXO3 activity (606). Repeated cold therapy may

also interfere with the activation of HSPs by exercise

(606). Some current guidelines for the treatment of

soft tissue injuries in sports therefore completely

omit cold application (607).

4.6.2. Endoplasmic reticulum and mitochondrial

unfolded protein response.

HSPs also interact with the regular endoplasmic reticulum

unfolded protein response (UPR

), which is activated by

accumulation of unfolded or misfolded proteins in the ER

(FIGURE 15B)(605). During exercise, interaction between

PGC-1aand cleaved ATF6ainitiates the adaptive UPR

in muscle (608,609). ATF6a, inositol-requiring enzyme 1a

(IRE1a), and the RNA-dependent protein kinase-like ER eu-

karyotic translation initiation factor 2 alpha kinase (PERK)

normally reside in the ER membrane and are engaged

upon ER stress, such as in the context of dysregulated

proteostasis triggered by resistance exercise bouts (608).

Activation drives the release of BiP/glucose-regulating

protein 78 (GRP78), an ER chaperone that then binds to

misfolded ER proteins. IRE1a,PERK,andATF6asubse-

quently initiate signaling cascades aimed at constraining

gene expression and protein synthesis and providing

adequate energy availability to normalize proteostasis

and alleviate ER stress (608,609). Exercise-induced ER

stress is diminished with repeated exercise bouts, indicat-

ing either better control of proteostasis or more efﬁcient

resolution of ER protein misfolding after training (608,

609). Like the ER, upon exercise muscle mitochondria

also initiate an unfolded protein response (UPR

)to

mitigate dysbalanced proteostasis, protein import, and

(re)folding, as well as OXPHOS complex assembly by acti-

vating mitochondrial chaperones and proteases (610). If

overwhelmed, a retrograde signaling is engaged to boost

the activities of the transcription factors ATF4, ATF5, and

C/EBP homologous protein (CHOP), which in turn regulate

the transcription of genes encoding mitochondrial

chaperones and proteases, as well as the integrated

stress response (610). Mitochondrial and cellular pro-

tein quality control are highly coordinated. Initially, cy-

tosolic processes only permit transport-competent

folding conﬁgurations of proteins to be imported into

mitochondria, supported by the ubiquitin-proteasome

system that degrades damaged, mislocalized, or

improperly imported proteins at the outer membrane

(611). Then, mitochondrial chaperones and proteases

ensure proper folding and removal of misfolded proteins

within mitochondria (611). The next step in escalation of

damage results in a remodeling of the mitochondrial net-

work by ﬁssion and fusion (402), removal of defective

parts of mitochondrial by mitochondrion-derived vesicles

or piecemeal mitophagy (612,613), ultimately culminating

in wholesome mitophagy (610,614). Mitochondrial dy-

namics, the balance between ﬁssion and fusion, are

instrumental not only for mitochondrial biogenesis but

also for proper morphology of the mitochondrial net-

work (615): fusion leads to larger mitochondria and

increased ATP production, whereas ﬁssion, promoted

in response to severe cellular stress, helps induce the

degradation of dysfunctional mitochondria (402,616).

The cytosolic PTEN-induced kinase 1 (PINK1) is normally

imported into the matrix of healthy mitochondria and

rapidly degraded. Upon deterioration of the membrane

potential or the loss of ATP supply, PINK1 accumulates in

the outer membrane and phosphorylates the E3 ubiqui-

tin ligase Parkin, which in turn ubiquitinates mitochon-

drial proteins to target the organelle for mitophagy. An

acute bout of exercise might lead to elevated organelle

turnover, through both mitophagy as well as general

autophagy, by increasing mitochondrial localization of

Parkin and activation of the AMPK-ULK1 axis, respec-

tively (610,614). However, the regulation and functional

involvement of mito- and autophagy in acute exercise

and chronic training adaptations remain poorly under-

stood (617,618), especially in elite athletes.

4.7. Exhaustion, Fatigue, and Event up to

Cessation of Exercise

The completion of an exercise bout is characterized by

several processes that contribute to exercise cessation.

These can be classiﬁed and summarized as exhaustion, a

process dependent on an increasing perception of sub-

jective effort that can, to some extent, be inﬂuenced and

overcome by the individual’s willpower and motivation

(619). Physiological pathways resulting in a reduced ability

and ultimately an inability of muscles to contract, inde-

pendent of motivation and willpower, are referred to as

fatigue, in which the continuation of contractile activity

becomes impossible (619). These deﬁnitions already hint

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NOX

ROS

NOS

RNS

RYR1

Reduced fiber

excitability

Exhaustion

Fatigue

Decreased motor

neuron firing rate

Hyperthermia

Hypoglycemia

Dehydration

Relative O2/CO2 levels

Exerkines/metabolites from

muscle and other tissues

Nociception

Motivation/willpower

Upstream input

Afferent feedback

Performance

ROS/RNS levels

Modulated neurotransmisson

(catecholamine, serotonin,

dopamine, adenosine)

Compromised axonal branch point

propagation (?)

Accumulation of by-products of

contraction and damage

Energy substrate depletion

Oxygen supply

ROS/RNS accumulation

Ca2+ homeostasis dysregulation

Dampened excitation-contraction

coupling

Nociceptor

activation

Decreased

synaptic activity

Na+/K+ pump

Reduced force

production

Desensitization of

proteins to Ca2+

Reduced myosin

ATPase activity

Ca2+

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at the multifactorial and multiorgan components that con-

tribute to exercise cessation (FIGURE 16A). Central fac-

tors include catecholamine, serotonin, dopamine, and

adenosine signaling in different regions of the brain

thatevokeastateofmentalfatigue(620). Some of

these alterations in central neurotransmission might

be caused by heat sensing to prevent hyperthermia of

the brain, availability of energy substrates (in particu-

lar hypoglycemia) to prevent catastrophic contractile

failure and inadequate supply for neuronal function,

relative oxygen and CO

levels,dehydration,pain/

nociception, or metabolite signaling from contracting

muscle ﬁbers such as excess ammonia or increased

ratio of free tryptophan to branched-chain amino acids

in the circulation (619–621). Moreover, elevated cyto-

and exerkine proﬁles in exercise could modulate vari-

ous processes, including immune cell activity in the

brain, and thereby also neuroenergetics and neuro-

transmission (622). These, and potentially other cen-

tral mechanisms, most likely help to protect the brain

and other organs from detrimental outcomes trig-

gered by overexertion (623). Central fatigue can be

overcome by direct peripheral stimulation of muscles.

This is not the case for peripheral causes mostly per-

taining to the motor unit, ranging from peripheral nerv-

ous system signaling to the muscle, ECC, energy

supply, and contractility (619). Motor unit fatigue is not

well understood, even though motor neurons are clas-

siﬁed into fast and slow fatigable pools (329,624,

625). Failures in axonal propagation, in particular

across branch points, or in NMJ transmission seem of

little signiﬁcanceinexercisesettingsandmightpri-

marily pertain to pathological situations (619). The

observed decrease in motor unit ﬁring patterns and

discharge rates could be mediated by afferent feed-

back and upstream input (619). In some paradigms, fa-

tigue of speciﬁc muscles, in particular the respiratory

muscles, will limit performance (626,627). In muscle

cells, different processes have been proposed to

affect contractility and fatiguability, such as contrac-

tion-induced depletion of endogenous fuel stores to-

gether with inadequate provisioning of exogenous

energy substrates and oxygen supply (619,628). The

accumulation of intra- and extracellular by-products

of prolonged contraction or metabolites enriched

because of muscle ﬁber damage could likewise gov-

ern fatigue, such as products of energy metabolism,

oxidative stress, inﬂammation, or respiration (CO

)

(619,628). In essence, the mechanistic underpin-

nings of muscle-intrinsic fatigue are not entirely

clear. Interestingly, in contrast to the stimulating

effect of ROS and RNS on muscle contractility at

lower levels, once a critical threshold is reached,

dampening effects of accumulated ROS and RNS on

performance are observed (FIGURE 16B)(629). For

example, ROS induces muscle fatigue, mediated by a

desensitization of receptors and myoﬁbrillar proteins

to Ca

,andadecreaseinNa

-K

pump activity

(FIGURE 16C)(534). This concentration-dependent,

biphasic bell-shaped effect on muscle performance

and fatigue might be a protective mechanism against

excessive contractile activity and subsequent tissue

damage, with ROS serving as an internal rheostat for

the strain exerted on ﬁbers (534). RNS evoke a simi-

lar response by initiating processes such as muscle

pain and fatigue to mitigate overexertion and over-

load linked to excessive cellular and tissue damage.

For example, NO modulates synaptic transmission

by retrogradely affecting presynaptic structures of

the NMJ, activates nociceptor complexes containing

the NO-sensitive calcitonin gene-related peptide

(CGRP) receptor and thereby causes muscle pain, or

reduces muscle force production, at least in part by

reducing myosin ATPase activity and Ca

release

from the SR by affecting the RYR and the SERCA

pumps (536–539). Thus, for both ROS and RNS,

modulation of intramyocellular Ca

homeostasis is

central for the regulation of fatigue (629). Of note,

the beneﬁts of inhibition of the production of ROS

and RNS with pharmacological or nutritional antioxi-

dants to delay fatigue, reduce cellular damage, and

shorten the recovery period are superseded by the

dampening effects on the procontractile and per-

formance aspects of ROS and RNS during exercise,

FIGURE 16. Exhaustion and muscle fatigue. A: central and peripheral contributors to exhaustion (volitional) and fatigue (involuntary). Altered neuro-

transmission in the brain ensures protection of this and other organs from hyperthermia, hypoglycemia, dehydration, shifted O

/CO

levels, and further

potentially detrimental processes in exercise. To a limited extent, these effects can be overcome by willpower and motivation. Peripheral factors offa-

tigue involve the motor neuron and muscle ﬁbers. Although impairments in action potential propagation and neuromuscular junction transmission

seem minor in healthy individuals, input from upstream brain regions and afferent feedback modulate motor neuron ﬁring rate. Muscle-intrinsic contrac-

tility is affected by energy substrate and oxygen availability, accumulation of by-products of contraction and damage, elevation of reactive oxygen

(ROS) and nitrogen (RNS) species, a dampening of excitation-contraction coupling including the Na

-K

pump, and intramyocellular Ca

homeostasis.

B: concentration-dependent, biphasic bell-shaped effect of ROS and RNS on muscle performance. During contractions, ROS and RNS sustain and

enhance contractile activity. However, once levels exceed a poorly deﬁned threshold, a different set of processes is engaged that limits performance.

C: exceeding a certain concentration, ROS and RNS contribute to muscle fatigue by affecting ﬁber excitability and contractility, synaptic activation, and

nociception. A modulation of intramyocellular Ca

homeostasis thereby plays a central role. Putatively, this “rheostat”helps to avoid overexertion and

to minimize muscle tissue damage. NOS, nitric oxide synthase; NOX, NADPH oxidase; RYR1, ryanodine receptor 1. Image created with BioRender.com,

with permission.

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resulting in an overall reduction in training response/

adaptation (534). Chronic elevation of ROS in inac-

tive ﬁbers such as in bedrest leads to pathological

outcomes of constitutively stimulated redox signal-

ing in muscle (630). In this context, restoration of

ROS levels and redox signaling pathway activity by

exercise, pharmacological, or nutritional interventions

might confer clinical beneﬁts (630,631). However, antiox-

idant treatment with supplements or nutritional compo-

nents must be carefully tailored to the speciﬁccontext:

oxidative distress and potential antioxidant deﬁciencies

must be conﬁrmed, an evidence-based, personalized

treatment strategy designed, and the outcome of the

treatment monitored (631). Otherwise, ineffective treat-

mentsoradverseeffectsmightresult,forexamplein

blunting oxidative eustress in exercising individuals (631).

4.8. Repair and Regeneration, Multicellular Cross

Talk, and Refueling

4.8.1. Multicellular interactions in muscle repair.

Upon cessation of exercise, a pleiotropic, highly coordi-

nated program of repair, regeneration, and refueling is

initiated. Skeletal muscle tissue comprises a complex

assortment of different cell types, many of which are still

being identiﬁed with novel technical approaches such

as single-cell RNA sequencing (scRNA-seq) (632–634).

As noted above, it is well accepted that the cross talk

between different cells is involved in exercise adapta-

tion, such as the release of IL-13 from type 2 innate

lymphoid cells (506). To date, however, data describing

the processes involved in repair and regeneration of

muscle tissue have, to a large extent, come from

genetic, pharmacological, and other models of severe

physical damage (635–637), with little information

derived from physiological in vivo exercise conditions

(638). Upon damage, a cascade of events is com-

menced in which muscle ﬁber-derived and other signals

activate resident immune cells, promote the inﬁltration

of additional immune cell populations, orchestrate the

activation, polarization, and termination of immune cell

phenotypes, and engage satellite and other myogenic

cells to mediate muscle repair and regeneration

(FIGURE 17A)(635–637). In exercised human skeletal

muscle, resident and inﬁltrating neutrophils, leukocytes,

monocytes, and macrophages ﬁrst promote an inﬂam-

matory environment, phagocytose damaged tissue, and

clean up cellular debris within hours after an exercise

bout (635–637). The inﬁltration and activation of these

immune cells are at least in part orchestrated by a cock-

tail of cyto- and chemokines that is released from myo-

ﬁbers and other cells including IL-6, C-X-C motif ligand 8

(CXCL8/IL-8), C-C motif chemokine ligand 2/monocyte

chemotactic protein-1 (CCL2/MCP1), tumor necrosis fac-

tor a(TNF-a), IL-1b, and interferon c(IFN-c)(635–637).

However, the composition of this cocktail depends on

the preceding exercise modality, load, and intensity. The

release of a disintegrin, metalloproteinase 8 (ADAM8)

and other proteases and the subsequent remodeling of

the ECM facilitate immune cell inﬁltration into muscle tis-

sue (635–637). A shift of macrophage polarization from

the pro-inﬂammatory M1 to the anti-inﬂammatory M2

type is a hallmark for the second phase, in which tissue

is regenerated within hours to days (635–637). The

release of IL-10, platelet-derived growth factor (PDGF),

transforming growth factor b(TGF-b), IGF-1, angiopoietin,

VEGF, follistatin, NO, hepatocyte growth factor (HGF),

and other signaling molecules from M2 macrophages, T

cells, mast cells, ﬁbro-adipogenic progenitors, and type

2 pericytes boosts ﬁbrotic activity and other pathways to

remodel the ECM to accommodate repaired and novel

myoﬁbers and stimulate the activation of satellite cells

and the formation of capillaries and related proc-

esses that are required to reconstitute muscle tissue

(635–637,639,640). Functional retrieval is com-

pleted by the expression of mature myosin heavy

chains and subsynaptic NMJ genes to ensure proper

contraction and innervation (635–637). This tightly

coordinated process is critical for proper regenera-

tion and tissue remodeling. The absence or elonga-

tion of the pro-inﬂammatory response or a reduced

anti-inﬂammatory response impairs muscle regenera-

tion and could result in detrimental events such as ﬁ-

brosis. Regeneration is typically complete within 4–7

days for most exercise challenges (635–637). In

response to muscle-damaging exercise, the inﬁltra-

tion of neutrophils occurs within 24 h, followed by an

increase in macrophages after 2–7days(637,641).

However, the exact time course of muscle regenera-

tion in response to different exercise paradigms is

poorly understood, and it is unclear how these proc-

esses are engaged in athletes. It remains to be deter-

mined whether trained muscles differ from untrained

muscles in terms of absolute number of speciﬁc cells

such as tissue-resident macrophages, lymphocytes,

or ﬁbro-adipogenic progenitors or the relative pro-

portion of a certain cell type (i.e., M2 macrophages).

The relative amount of myonuclei compared to total

nuclearnumberislowerinsoleuscomparedwiththe

extensor digitorum longus (EDL) (40% and 60%,

respectively), indicating a higher abundance of non-

muscle mononucleated cells in oxidative muscles that

could potentially contribute to better regeneration

(642). In line with this observation, a trained muscle

might harbor a distinct cellular content and improved

regenerative capacity: for example, mice overex-

pressing muscle PGC-1aexhibit a higher proportion of

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Auto- and mitophagy

Mitochondrial dynamics

ATP

ADP

Protein

Degradation Synthesis

mTOR

Amino acids

Insulin

IGF-1

Glycogen

PGC-1α

IMCL

Glucose

Fatty acids

Contractile activity

PGC-1α

Recovery/regeneration

PGC-1α

Glucose-6-phosphateRibose-5-phosphate

Nociceptor

activation

Activation

Polarization Macrophages, neutrophils,

monocytes, FAPs, pericytes, ...

Satellite cells

Stem cell niche

Ca2+

Dysferlin

MG53

Nuclear

migration

Sarcomere repair and

sarcomerogenesis

Altered ratio of

ATP/AMP and

NADH/NAD+

Glucose uptake

Fatty acid oxidation

Mitochondrial activity

De novo lipogenesis

Refueling of

intramyocellular lipid

and glycogen stores

Adequate

energy

availability

TF FIGURE 17. Muscle repair, regeneration, and refu-

eling. A: multicellular interactions and intramyocellu-

lar processes that control muscle repair. Resident

and inﬁltrating cells of different types are engaged

by various signals in a temporally highly orchestrated

manner. Thereby, damaged material is removed,

muscle ﬁbers repaired or de novo formed, and func-

tional retrieval achieved. Activation of nociceptor sig-

naling should prevent further exertion and damage

during repair and regeneration. Moreover, the multi-

cellular processes are complemented by intramyocel-

lular pathways to restore membrane and sarcomere

integrity as well as organelle function. B:postexercise

refueling of glycogen, intramyocellular lipids (IMCL),

and protein structures. Depleted intramyocellular

energy substrate stores are replenished after exercise

depending on a systemic, anabolic context, i.e., the

availability of the corresponding substrates and

signaling of anabolic hormones. Because of the ener-

getic demand for protein, glycogen, and IMCL

synthesis, these processes are coordinated with mi-

tochondrial activity and ATP production. C: temporal

speciﬁcation of catabolic and anabolic processes by

peroxisome proliferator-activated receptor ccoacti-

vator 1a(PGC-1a). To avoid a futile cycle, the cata-

bolic activity of PGC-1aduring contractions must be

separated from the anabolic function in regenera-

tion. The mechanistic underpinnings of the tran-

scriptional speciﬁcation of this coactivator (and

other regulators with multipurpose roles) remain

unknown. FAP, ﬁbro-adipogenic precursor; MG53,

mitsugumin 53; mTOR, mammalian target of rapa-

mycin; TF, transcription factor. Image created with

BioRender.com, with permission.

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anti-inﬂammatory M2 macrophages in muscle tissue

and show improved regeneration upon muscle injury

(643,644). Whether the time course of muscle regen-

eration is accelerated in athletes with a prolonged

history of training, thereby hastening recovery, is cur-

rently unknown.

4.8.2. Fiber repair and regeneration.

Muscle damage is greater after eccentric/plyometric/

lengthening or isometric exercise undertaken with elon-

gated muscle length compared with concentric/miometric/

shortening contractions (637). Exercise-induced muscle

damage is characterized by a force reduction, systemic

increase in myocellular enzymes and proteins such as cre-

atine kinase (CK) and myoglobin, muscle soreness upon

palpation, but also swelling and a decrease in range of

motion (637). Although some of these symptoms appear

immediately after exercise (e.g., loss of muscle force),

others such as muscle soreness present 24–48 h later, of-

ten being disassociated from CK levels, which peak after

3–4days(637). Different mechanisms exist to deal with

muscle cell damage in an escalating manner (645). For

example, membrane lesions are rapidly sensed and

repaired, involving specialized features of membrane traf-

ﬁcking components, in particular the action of dysferlin

upon inﬂux of Ca

throughgapsinthecellmembrane

(646,647), as well as other mediators such as the tripartite

motif (TRIM) protein 72 (TRIM72), alternatively called

Mitsugumin 53 (MG53), that also serves as a myokine for

distal organ repair (648). The restoration of membrane

damage is furthermore facilitated by the migration of myo-

nuclei to the site of lesion (649), with this process most

likely supported by the exchange of proteins between

nuclei (650), and the microtubule-dependent transport of

RNAs and ribonuclear proteins within the myoﬁber (651).

Then, mechanical strain leads to non-uniformity and over-

stretching of sarcomeres, as well as disruption of Z disks,

resultinginimpairedforceproductionandoverloadofsar-

colemma and T tubules (637). Of note, fast muscle ﬁbers

are more susceptible to damage induced by eccentric con-

tractions, which could be due to ultrastructural differences

such as the narrow and more fragile Z disks, suggesting

that a training-induced shift toward slow muscle ﬁbers

mightprotectthemusclefromdamage(357). This

raises the question of whether muscles of athletes are

better protected against recurrent mechanical strains

and/or trained muscles have an enhanced repair and

regeneration capacity. Mechanosensing, membrane rup-

ture, stretch-activated channels, and dysregulated ECC

induce intracellular signaling pathways, such as higher in-

tracellular Ca

, which result in degradation of damaged

structures as described above. Neurotrophic factors pro-

duced by muscle ﬁbers and satellite cells, in particular

activation of the bradykinin receptor B2-nerve growth fac-

tor (NGF) and cyclooxygenase 2 (COX-2)-glial cell line-

derived neurotrophic factor (GDNF) pathways, stimulate

muscle nociceptors and thereby contribute to the pain

experienced in DOMS (637,652). Of note, interference

with the inﬂammatory cascade, even the pro-inﬂammatory

phase, can be detrimental to muscle recovery and adapt-

ive remodeling (637,653). Massage, thermal therapy (hot

or cold), compression, active regeneration, along with vari-

ous pharmacological and nutritional approaches often

have antagonistic effects on DOMS, muscle recovery, and

functional remodeling (654). Thus, probably the best prac-

tice to reduce future/subsequent muscle damage is to

repeat a similar exercise bout, albeit at reduced intensity/

loading (637). Accordingly, in resistance-trained individuals,

recovery of maximum voluntary isometric torque occurs

faster and is accompanied by reduced muscle soreness

and lower CK levels compared with untrained individuals

(655,656). These attenuated symptoms of muscle dam-

age, which also resolve after a shorter period, are hall-

marks of the “repeated bout effect”(637). A trained muscle

therefore has greater protection against contraction-

induced damage. However, it is not clear whether this

effect is conferred by better resilience against insults,

more efﬁcient repair and regeneration, or a combination of

these (637). The observation of the repeated bout effect

extends to the contralateral, non-trained muscle and sug-

gests a systemic propagation of this signal (637). However,

the underlying mechanisms are unknown. Nevertheless, it

is clear that improved functional recovery is essential to

sustain the high training intensities and volumes of athletes

without overreaching/overtraining (657).

4.8.3. Muscle refueling.

Full functional retrieval requires additional processes,

including restoration of organelle function, sarcomere

repair, and replenishment of substrate stores (FIGURE

17B). Optimally, a supercompensation is achieved, as

observed for muscle glycogen stores (428). The efﬁ-

ciency of refueling depends on promoting an optimal

anabolic environment and is dependent on providing

adequate nutritional availability (81). In this setting,

energy sensors such as AMPK remain inactivated, and

theactivityofanabolicregulatorssuchasmTORare

increased by the availability of amino acids, glucose,

and fatty acids and stimulation by insulin, IGF-1, and

other anabolic hormones (556,557,658). The ensuing

promotion of protein synthesis is instrumental to support

the restoration and de novo formation of sarcomeric and

other structures. Intracellular sensors of glucose and

fatty acids help to restore glycogen and intramyocellular

lipid stores. For example, PGC-1apositively regulates

the transcriptional program for lipogenesis, lipid droplet

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assembly, and perilipins (488,659). As noted above,

the increased intramyocellular lipid level in the mus-

cle of endurance-trained athletes resembles the

accumulation of these in muscle from patients with

type 2 diabetes (the “athlete’sparadox”). However,

although the diabetic patient is insulin resistant, the

endurance-trained athlete is insulin sensitive based

on the daily turnover and ﬂux of lipid stores (660).

PGC-1aalso increases muscle glucose uptake while

restricting the entry of glucose into glycolysis and

boosting glucose-6-phosphate activity in the pentose

phosphate pathway and glycogen resynthesis (488).

PGC-1amatches these energy-demanding anabolic

processes to adequate mitochondrial function and

ATP synthesis. Moreover, PGC-1a-mediated pentose

phosphate pathway activity produces ribose-5-phos-

phate, the building block for ATP and the other nucle-

otides (488). Intriguingly, the anabolic function of

PGC-1ain this context is opposite to that during mus-

cle contraction, in which this coactivator strongly

stimulates catabolic pathways, including fatty acid

b-oxidation (FIGURE 17C). Thus, to avoid futile cycles

atemporalspeciﬁcation of PGC-1a, including distinct

transcription factor binding and DNA element recruit-

ment, is likely, although the molecular characteristics

associated with such a speciﬁcation are unknown.

4.9. Circadian Clock

Almost all physiological processes in humans are under

the control of circadian rhythms (661). Locomotion and

physical activity belong to the most fundamental aspects

of the behavior of higher animals and in an evolutionary

context required coordination of activity with the avail-

ability of prey and food, the avoidance of predators,

along with adequate rest, sleep, and related recovery

processes (662). As described in sect. 2, external cues,

such as timing of food and physical activity, serve as

zeitgebers (time givers) to modulate the circadian clock

in cell-autonomous peripheral tissues and thereby adapt

many tissues/organs to the prevailing environmental

conditions (663). Circadian control of the muscle pheno-

type is inﬂuenced by circadian rhythmicity and executed

by a subset of the transcriptome oscillating in this tissue

(662), with a reciprocal relationship between the core

molecular clock and external stimuli such as the time of

exercise training (FIGURE 18A). Several regulatory

nodes induced by an acute exercise response poten-

tially inﬂuence muscle clock oscillations (FIGURE 18B)

(664–666). For example, activation of AMPK affects the

stability of Period2 (PER2) and cryptochrome circadian

regulator 1 (CRY1), two components of the core clock

(662,667). CRY1 and CRY2 interact with PPARb/dand

thereby reduce the oxidative phenotype of muscle cells

(662,667). Circadian Locomotor Output Cycles Kaput

(CLOCK) and Brain and Muscle ARNT-Like 1 (BMAL1),

two other core clock components, regulate SIRT1 tran-

scription in skeletal muscle. SIRT1 in turn deacetylates

PER2 and BMAL1, thus in part counteracting the acetyl-

transferase activity of CLOCK (667). Bidirectional interac-

tions between the clock, mTOR, and protein synthesis

contribute to a link between circadian oscillations and

proteostasis (667). HIF-1ainduces the transcription of

PER1 and PER2, whereas NRF2/NRE2L2 and NF-κB

reciprocally control gene expression of nuclear receptor

subfamily 1 group D member 1 (NR1D1/REV-ERBa)(667).

SIRT1-deacetylated PGC-1ainduces the expression of

retinoic acid-related orphan receptor a(RORa/NR1F1)

and coactivates RORain the transcriptional regulation of

BMAL1 (667). REV-ERBaand RORaare part of an acces-

sory arm of clock control and exert opposite effects in

core clock modulation. CREB activity is affected by CRY1

and in turn controls gene expression of PER1 and PER2

(667). Finally, PPARaand BMAL1 exert mutual transcrip-

tional regulation (662). Many of these interactions have

not been validated in human muscle skeletal, but there

is ample potential for cross talk between factors that are

modulated by contractile activity and those that entrain

and synchronize the molecular clock (662,663,665–

667). Accordingly, the gene expression of several com-

ponents of the molecular clock are affected by exercise,

such as BMAL1, PER2, and CRY1 (663). Curiously, other

clock components, including CLOCK, PER1, CRY2, and

REV-ERBb/NR1D2, were unaffected by skeletal muscle

contractile activity in these studies, which conﬂicts with

a general modulation of clock phase and amplitude by

exercise. As such, these data suggest a speciﬁc control

of a subset of clock genes and not a complete resynch-

ronization. Such a targeted interaction could imply that

some of these proteins might have additional functions

unrelated to the molecular clock such as the control of

cellular metabolism. Indeed, the consequence of the

cross talk between exercise factors and the molecular

clock for circadian rhythmicity, muscle function, and

exercise adaptation is unclear and is likely to be con-

founded by many factors including meal time, sleep,

psychological stress, and other zeitgebers (665). Animal

experiments with voluntary wheel running conducted

under a skeleton photoperiod suggest that skeletal mus-

cle clock oscillations are robust even in the face of per-

turbations induced by daytime running and feeding

(668). Moreover, studies of the transcriptome, proteome,

and phosphoproteome of skeletal muscle of mice

undergoing maximal endurance tests at different times

of the day indicate a strong association with metabolic

parameters such as muscle and liver glycogen concen-

trations, suggesting more indirect effects of circadian

oscillations (668). Thus, future studies need to determine

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the extent of the inﬂuence of the molecular clock on the

exercise responses and vice versa, including functional

consequences for acute endurance and resistance exer-

cise bouts, chronic training adaptations, and peak per-

formance at competitions.

4.10. An Integrative View of the Molecular

Mechanisms

In this section, we summarized the molecular mecha-

nisms and pathways that are activated in skeletal mus-

cle in response to endurance and/or resistance

exercise, with a focus on the putative pathways for

whichanassociationbetweentheacuteexercise

response and chronic training adaptation has been

consistently reported. Other reviews have discussed

the exercise-induced changes in various pathological

conditions such as muscle wasting, cachexia, or sar-

copenia (669–672), which may be completely distinct

or share some commonalities with those in healthy

muscle in well-trained athletes. There are also several

pathways and factors that contribute to the pathoetiology

of muscle wasting and diseases. Although voluntary and

forced muscle inactivity do not necessarily mirror con-

tractile engagement (673), some of these could play a

role in exercise training adaptation. For example, the lev-

els of myostatin, which rise in several pathological states

(15), are reduced by exercise (674), and the absence of

myostatin signaling may be an important contributor to

training adaptation. However, this might depend on fac-

tors such as baseline control, exercise modality, or the

pathological context regarding comorbidities. Related

mechanisms such as the repression of activin receptor

type II (ActRII), for which myostatin is one of the ligands,

by the m(6)A methyltransferase-like-3 (METTL3) could

also potentially contribute to muscle hypertrophy after

exercise training (675). Readers are referred to recent

reviews on muscle atrophy and disease states (560,

676–679). Finally, many studies using gain- and loss-of-

function of targeted genes have reported altered muscle

metabolism or contractile function, most of which require

validation after exercise interventions in both rodent mod-

els and humans (485,486,680,681). Many of these fac-

tors will undoubtedly add to our current knowledge

regarding human exercise-induced muscle plasticity.

Notwithstanding these limitations and caveats, we still

have a poor understanding of how exercise adaptation is

regulated. Most studies focus on individual pathways and

factors, often centered on the “usual suspects,”and pre-

cisely how the complex and interdependent network of

signaling pathways and mechanisms is spatio-temporally

coordinated and integrated is unclear (FIGURE 19). A

reductionist study of these pathways is difﬁcult because

muscle activity and plasticity are under robust control,

with numerous redundancies (overlapping or parallel

pathways that are engaged in a physiological setting),

backups/contingencies (pathways that are engaged if

other mechanisms are impaired, controlling the same

Central clock

Metabolism

Contraction

CLOCK

BMAL1

E boxE box

PER

CRY

ROR

REV-ERB

CRY PER

RORE

BMAL1

ROR

AMPK

PPARβ/δ

SIRT1

HIF-1α

mTOR

PGC-1α

CREB

PPARα

Activity levels

and food intake

Skeletal muscle

core clock

NFE2L2

NF-NB

REV-ERB

FIGURE 18. Circadian regulation of skeletal muscle function and

plasticity. A: circadian regulation of activity and muscle function.

Circadian regulation of sleep-wake cycles, feeding, physical activity,

or other zeitgebers is sensed and translated by the master clock in

the suprachiasmatic nucleus as well as peripheral clocks in almost

every cell in the human body. As a consequence, various physiologi-

cal processes, e.g., muscle cell metabolism or contractile perform-

ance, can be affected in a circadian manner. B: interactions between

core clock genes/proteins with regulators of muscle function and

plasticity. Such cross talk pertains to the regulation of gene expres-

sion, protein-protein interactions, and/or enzymatic activity. Thereby,

physiological processes in muscle might be affected by the core

clock. Inversely, muscle ﬁber metabolism, contractile activity, oxygen

availability, redox balance, and other perturbations could modulate

the skeletal muscle clock. AMPK, AMP-dependent protein kinase;

BMAL1, brain and muscle ARNT-like 1; CLOCK, circadian locomotor

output cycles kaput; CREB, cAMP response element binding protein;

CRY, cryptochrome circadian regulator; HIF-1a, hypoxia-inducible

factor 1a; mTOR, mammalian target of rapamycin; NFE2L2, nuclear

factor erythroid-derived 2-like 2; NF-κB, nuclear factor κB; PER, pe-

riod; PGC-1a, peroxisome proliferator-activated receptor ccoactiva-

tor 1a; PPARa/b/d, peroxisome proliferator-activated receptor a/b/d;

REV-ERB, nuclear receptor subfamily 1 group D member 1/2; ROR,

retinoic acid-related orphan receptor; RORE, ROR elements; SIRT1,

sirtuin 1. Image created with BioRender.com, with permission.

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biological program), and alternatives (processes that are

used when others are dysfunctional, leading to different

physiological adaptations but resulting in similar out-

comes) (18,41,682). For example, three of the most char-

acterized factors with putative roles in contraction-

inducedremodeling(AMPK,mTOR,andPGC-1a)aredis-

pensable for many training-induced adaptations. First, in-

ducible ablation of muscle AMPKadoes not affect whole

body substrate utilization, muscle glucose uptake, fatty

acid, or mitochondrial respiration during exercise (683).

Similarly, muscle-speciﬁcknockoutmiceforPGC-1astill

increase mitochondrial biogenesis with training, at least

in some studies (576). The function of mTORC1, with

roles in the early events leading to muscle hypertrophy, is

compensated by non-mTOR-dependent pathways during

recovery from exercise (581). Integrity of raptor is impor-

tant for hypertrophy induced by synergist ablation over-

load but not the related boost in the rate of protein

synthesis (684). Genetic models with inducible muscle-

speciﬁc inhibition by ablation of raptor and sustained acti-

vation of mTORC1 by disruption of TSC1 have little effect

on preserving muscle mass (524) or facilitating hypertro-

phy (685), respectively. It is conceivable that such results

are caused by ﬂawed or imperfect experimental model

systems, with many studies relying on constitutive gain-

and loss-of-function. Moreover, targeting strategies might

be imprecise, such as the use of raptor and rictor to ge-

netically ablate mTORC1 and mTORC2, respectively, lev-

eraging TSC1/2 to activate mTORC1 activity, or using

rapamycin as a pharmacological inhibitor of mTORC1.

CnA CaMKII

PGC-1α

AMPK mTOR

SIRT1

cAMP

β2-AR IGF-1, insulin

ROS

ATP/ADP/AMP

Metabolism Vascularization

Mechanosensing

Spatio-temporal signal coordination and integration?

Adipo-, hepato-, osteokines

e.g., adiponectin

Ca2+

Stress kinases

e.g., p38 MAPK

NADH/NAD+

CARP

DARP

ANKRD2

branched chain

amino acids

CREB, ATF2

NFAT

MEF2 HDAC5

NCOR1

TFEB

MEF-2

MondoA

HSF1

HIF-1α, HIF-2α

FOXO3A

ATF4, ATF5, ATF6, CHOP

PER, CRY1, BMAL1, CLOCK, REV-ERB

NR4A2 (NURR-1), NR4A3 (NOR-1)

PPARβ/δ, PPARα

ERRα, ERRγ

NRF1, GABP, TFAM

SRF, AP-1, EGR-1

TAZ/YAP/TEAD1

NRF2/NFE2L2

Contractility

Fiber type

Motor unit

remodeling Myokines

Myobolites

Proteostasis

Autophagy

Redundancies

Contingencies

Alternative pathways

Output specification and coordination?

FIGURE 19. Molecular mechanisms in contracting muscle ﬁbers. A small selection of molecular sensors and mediators as well as a simpliﬁed sum-

mary of the presumed interactions are depicted. Nota bene: the spatio-temporal integration and coordination of these pathways, functional redundan-

cies (e.g., overlapping or parallel pathways), contingencies (back-up processes with the same function), alternatives (back-up processes leadingto

similar adaptations using different functions), speciﬁcation and coordination of downstream effects and adaptations, in particular in chronic settings, as

well as many other aspects are still only understood at a very rudimentary level. b-AR, b-adrenoreceptor; CARP, cardiac ankyrin-repeat protein; CnA,

calcineurin A; CREB, cAMP-dependent binding protein; DARP, diabetes-related ankyrin-repeat protein; ERRa/c,estrogen-relatedreceptora/c; GR, glu-

cocorticoid receptor; HSF1, heat shock factor 1; NO, nitric oxide; PPARa/b/d, peroxisome proliferator-activated receptor a/b/d; ROS, reactive oxygen

species; SIRT1, sirtuin 1. See text for other abbreviations. Image created with BioRender.com, with permission.

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Even though raptor and rictor are unequivocal members

of mTORC1 and mTORC2, many other potential interac-

tions of these proteins beyond their direct function in

forming the mTOR complexes have been proposed (686)

or demonstrated (687). Similarly, TSC1/2 and the down-

stream effector RHEB clearly result in activation of mTOR

but potentially also the modulation of the function of other

proteins (688). Furthermore, physiological mTOR activity

is regulated transiently and in a pulsatile manner, quite dif-

ferent from the sustained, long-term loss- and gain-of-

function in the animal models. Finally, rapamycin is a

potent inhibitor of mTORC1 activity but at different dos-

ages and administration durations serves also as a modu-

lator of the activity of other protein complexes, including

mTORC2 and signal transducer and activator of transcrip-

tion 3 (STAT3) (689). Notably, STAT3, like mTORC1, exerts

effectsonmusclemass(690). However, these seemingly

paradoxical ﬁndings in relation to PGC-1a,AMPK,and

mTOR should not necessarily be interpreted as a sign of

their dispensability or insigniﬁcance in the physiological

exercise response but rather as proof of the resilience of

whole body systems to adapt even under adverse condi-

tions. For example, although muscle-speciﬁcPGC-1aknock-

out animals can partially adapt to exercise training, this

adaptation differs from the physiological training response

seen in wild-type animals and occurs despite a lack of vas-

cularization or metabolic adaptations in lactate and ketone

body metabolism, thus presumably relying on alternative

processesthatprovidesimilarbeneﬁts (575–577). How

such compensation is achieved is unclear, but it is conceiva-

ble that the transcription factor binding partners still regulate

the corresponding target genes even in the absence of this

and other coregulators, albeit at lower levels or altered tar-

get speciﬁcity (474,486). PGC-1acan regulate target genes

with different binding partners, such as those involved in

the hypoxic response by coactivating AP-1 or ERRa,imply-

ing functional redundancies in the transcriptional network

engaged in exercise adaptation at different levels (474).

Future studies should aim at obtaining an unbiased, holistic

picture of the molecular mechanisms that control muscle

plasticity in response to endurance and resistance training

(18,40). Such insights might also be important to better

understand training interference effects and help in the

design of concurrent training programs for athletes involved

in multisport events (i.e., the triathlon) or who require traits of

both endurance and power for successful performance.

Finally, our knowledge about the mechanisms that control

chronic adaptations to endurance- or resistance-based

training is sparse compared with that describing the

responses to a single bout of exercise. Many of the adapta-

tions in elite athletes with a prolonged history of training are

not reﬂected in the transcriptional changes that occur after

one acute exercise bout, such as the change in expression

of different myosin heavy chains (9). Therefore, it is unlikely

that a trained muscle only reﬂects the additive or sustained

changes that are induced in individual acute exercise bouts

(9). Epigenetic changes might be involved in priming and/or

altering the gene expression proﬁle of trained versus sed-

entary and of acute exercise-induced changes in the trained

versus the naive state (41,585,691). Precisely how the tem-

poral sequence of individual exercise bouts over time

results in training adaptation remains a fertile area for future

research. Together, sects. 2–4 have described training

practices and the physiological and molecular pathways

involved in the acute exercise response; sect. 5 integrates

these aspects to discuss interindividual differences and the

speciﬁc aspects that underpin elite athlete performance.

5. CAN WE ALL BECOME GOLD MEDALISTS?

5.1. Individual Responses to Training

Elite sporting performance is the result of the interaction

between genetic and training-related factors (692,693),

and although several genes or gene clusters have mod-

erate associations with performance or performance-

related phenotypes (694–696), the genomic signatures

associated with elite athletic performance across a wide

range of events/sports have yet to be identiﬁed.

Notwithstanding the lack of direct links between genetic

variants and elite performance, the notion that there exist

interindividual responses to exercise training and that

innate factors may explain a large part of the training-

induced variance in maximal aerobic capacity in previ-

ously untrained persons can be traced back to the classic

HERITAGE studies conducted in the 1980s by Bouchard

and colleagues (697). In these and other recent investiga-

tions, the most common reported primary outcome mea-

sure in response to endurance-based training programs

was an individual’s_

VO2max attained during an incremental

exercise test to exhaustion, either treadmill walking/run-

ning or ergometer cycling, usually lasting 10–15 min.

After 2–3 mo of endurance training (3 or 4 sessions

per week), _

VO2max is typically increased by 10–15% at

the group level, but the magnitude of improvement

canbeaslittleas1–2% and as great as 35% (698). A

key observation from these early human training stud-

ies was that up to 20% of subjects demonstrated little

change in _

VO2peak in response to a standardized train-

ing protocol and were considered “exercise resistant”

(699). However, individuals who demonstrate a low

training response to one outcome measure (e.g., _

VO2max)

do not always display the same response in other

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parameters. This makes the concept of responders versus

non-responders open to different interpretations. Indeed,

exercise training induces a multitude of health- and per-

formance-related beneﬁts (9,700), some of which may

even have a non-physiological basis (701).

Recently, the notion that there exist exercise-resistant

subjects or non-responders has been challenged on the

grounds that in those studies in which individuals exhibit

no meaningful change in a speciﬁed outcome variable,

the training impulse has been inadequate in terms of ei-

ther volume or intensity overload (702). To test this hy-

pothesis, Montero and Lundby (702) recruited 78 healthy

young male volunteers and ﬁrst subjected them to 6 wk of

supervised training. Individuals trained in ﬁve groups dif-

fering in the number of exercise sessions per week: they

performed 60 min of cycle ergometer exercise either one,

two, three, four, or ﬁve times a week, corresponding to

60, 120, 180, 240, and 300 min total training time. After

completing this ﬁrst phase of training, the group mean

maximal work rate sustained during an incremental cycle

test (W

max

) was increased in all groups apart from the

group who undertook just a single training session per

week. In groups one, two, three, four, and ﬁve, 69%, 40%,

29%, 0%, and 0% of individuals, respectively, were non-

responders [i.e., did not have a signiﬁcant increase in the

maximal work rate (W

max

)attainedduringanincremental

test to exhaustion]. Subsequently, individuals classiﬁed as

non-responders to the ﬁrst phase of training performed a

second 6-wk block of training in which two additional 60-

min sessions per week were included, independent of the

number of sessions completed during the ﬁrst 6 wk.

Following this protocol of volume overload, the lack of

training-induced increase in W

max

was universally abol-

ished. Although further research needs to be undertaken

to determine whether such ﬁndings can be extrapolated

to other populations, these results fundamentally chal-

lenge the notion of non-responders and suggest that if a

training stimulus is of sufﬁcient volume and/or intensity

and follows the principles of progressive overload and

speciﬁcity, then those individuals thought to be exercise

resistant or low responders can indeed become “res-

ponders”(702). In this context, Booth and Laye (703)

believe that the term non-responder should be replaced

by individuals who demonstrate “low sensitivity”to a

training stimulus and that such individuals merely require

increased training volumes and/or intensity to drive

favorable responses. At the population level, focusing on

only selected measures of training response and label-

ing an individual as a non-responder is somewhat of a

reductionist approach to exercise. Indeed, if we accept

that exercise is a “polypill”(46,704) exerting a plethora

of positive beneﬁts (700), then by focusing on a small

number of measures of response we ignore the fact that

exercise works through so many different pathways and

mechanisms that the chances of an individual exhibiting

no single biological beneﬁt is highly unlikely (701,705).

Regarding elite athletic performance, the issue of low

responders or non-responders becomes somewhat irrel-

evant: to become an elite performer, one must be initially

well endowed in the traits that have critical roles in the

athlete’s event, and one should also be a high responder

to exercise training (83). Furthermore, without a rich

genetic endowment, world-class athletic performance is

unattainable (83). In this regard, there are substantial dif-

ferences in performance-related traits measured in the

sedentary state (i.e., before any training intervention).

Individuals who have high levels of a trait before expo-

sure to exercise training are greatly predisposed to expe-

riencing early success, which also might have a big

impact on motivation and subsequent training adherence.

This is not the case in non-elite sedentary populations in

which no correlation is observed between the baseline

level of ﬁtness (i.e., _

VO2max) and the response to an exer-

cise training dose (699), suggesting a unique biology

underlying trainability. In support of this contention,

Rønnestad et al. (292) report the case of an individual

with a _

VO2max of >70 mL/kg/min in the untrained state

that increased by 30% after 3 yr of specialized training to

>95 mL/kg/min and coincided with a world championship

title. Animal studies of selected breeding for aerobic run-

ning capacity also reveal high and low responders to

standardized exercise training. To determine the inher-

ited components of acquired running capacity, a model

of two-way artiﬁcial selection for animals that were either

low or high responders to exercise training was devel-

oped (706). These two animal lines were tested for maxi-

mal treadmill running distance before and then after 8 wk

of standardized treadmill run training protocol (i.e., the

same absolute training load). After 15 generations of

selection, and 8 wk of training, the high-response rats

improved an average of 223 m in run distance, whereas

exercise capacity declined by 65 m in the low-response

animals. Taken together, a continuum of responses to

standardized exercise training protocols exists (698), yet

low sensitivity to adapt may be mitigated by revision of

exercise prescription including training frequency, dura-

tion, and intensity (701,702). Although an understanding

of how genetic factors contribute to interindividual train-

ing responses may improve personalization of training

prescription, at present genomic predictors for response

trainability are lacking (707).

5.2. Genetic Predisposition to Becoming an Elite

Athlete

An indication of genetic predisposition toward athletic

prowess could be inferred from a variety of observa-

tions. For example, people from the western parts of

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Africa (including Ghana and Nigeria) as well as the de-

scendants of the slaves that were transported from

these regions to the “New World”(the West Indies or

the United States) are excellent sprinters. In contrast,

athletes from Eastern Africa, such as Kenya and

Ethiopia, are famous for their extraordinary long-dis-

tance running feats. In fact, 90% of elite marathon

runners worldwide are of Ethiopian or Kenyan descent

(708). However, it is unclear whether different genetic,

and in extension anthropometric (709)orratherenvi-

ronmental, factors and training practice (118)explain

this phenomenon. For example, the higher altitude

plateaus of the Eastern African countries might facili-

tate endurance training adaptations in contrast to the

mostly sea-level landscape of Western Africa. Despite

these alternative explanations, it is estimated that

65% of athletic ability can be explained by genetic

factors (710). Moreover, there are data indicating that

maximal endurance capacity as well as trainability is

inherited (699,711) and that the genetic makeup accounts

for a substantial contribution to performance levels (712).

However, despite evidence that genetic components are

strongly related to the phenotypic traits of elite athletes,

knowledge of the speciﬁc genes underpinning this pre-

disposition is limited. Rare examples for extreme genetic

variants underline the genetic contribution to athlete sta-

tus. One example is the mutation in the EPO receptor

gene that resulted in a more active truncated protein in

the Finnish cross-country skier Eero M€

antyranta (713). His

Hb levels were at least 200 g/L, which is substantially

higher compared with other endurance athletes or non-

athletes (150 g/L) and could thereby have contributed

to the three Olympic gold medals and two World

Championships he won over his career (266,713). In

broader populations, the two polymorphisms that are

most described and linked to athletic performance are

located within the ACE and ACTN3 genes that encode

for the angiotensin I-converting enzyme and a-actinin-3,

respectively (714). In fact, the ﬁrst polymorphism that was

associated with athlete status was ACE I/D (715). ACE is

part of the renin-angiotensin system and is involved in

regulating blood pressure by converting angiotensin I to

the active vasoconstrictor angiotensin II. ACE activity in

serum is lower in the presence of the insertion (I) allele

containing 287 base pairs within intron 16 (716). The I al-

lele is associated with successful endurance capacity,

whereas the deletion (D) allele is associated with prowess

in strength/power events (716). However, inconsistencies

exist within this classiﬁcation: in elite endurance runners,

an association with the D allele or the I allele as well as a

lack of any association have been reported (708,714). In

comparison, data on ACTN3 polymorphisms are more ro-

bust. ACTN3 is an actin-binding protein that is exclusively

expressed in type II ﬁbers and located at the Z disk,

suggesting a role in high-velocity force contractions (717).

The single-nucleotide polymorphism (SNP) in the ACTN3

gene results in a premature stop codon (X) instead of the

arginine (R) at position 577, and the XX genotype is deﬁ-

cient in expressing the ACTN3 protein (718). The 577R al-

lele has been associated with elite sprint/power athletes

and explosive performances, RR being superior to RX

and XX genotypes (719,720). In contrast, the XX variant is

more frequently observed in elite endurance athletes

compared with non-athletes and is extremely rare in elite

power athletes (719). In line with these observations, the

absence of ACTN3 results in an increased endurance

performance and higher oxidative phenotype in the mus-

cle of knockout mice (721).

During the last two decades, at least 155 polymor-

phisms related to elite endurance (93 polymorphisms) or

power athletes (62 polymorphisms) have been identiﬁed

(722). Endurance markers that have been replicated in at

least three independent studies include ACE I, ACTN3

577X, HFE (homeostatic iron regulator), PPARA, and

PPARGC1A, and power markers include ACE D, ACTN3

577R, AMPD1 (adenosine monophosphate deaminase 1),

HIF1A, MTHFR (methylenetetrahydrofolate reductase),

NOS3, and PPARG (722). Of all 93 polymorphisms associ-

ated with elite endurance athletes, the 3 located within

the ADRB2 (adrenoceptor b2),ADRB3,orPPARGC1A

genes have also been shown to be associated with base-

line _

VO2max of a non-athlete population (723)andthe5

variants of the ACE, AMPD1, CKM, HIF1A, and PPARD

genes with _

VO2max trainability (724). However, even

though several genetic variants have been identiﬁed

in genomewide association studies (GWASs) of elite

athlete status, there is no subset of genes that allows the

identiﬁcation of elite athletes (696). Often, studies are

underpowered, which is not surprising regarding the lim-

ited number of elite athletes and accessibility of biological

samples, and therefore many results cannot be replicated

in different cohorts (696). Based on a meta-analysis

including 1,520 endurance athletes and 2,760 non-ath-

letes control subjects, a polymorphism in the GALNTL6

gene, encoding for polypeptide N-acetylgalactosaminyl-

transferase-like 6, may be a signiﬁcant marker for athletic

performance (696). In endurance athletes, the C allele is

overrepresented compared with non-athletes, whereas

the T allele of GALNTL6 is more frequently observed in

elite power athletes compared with endurance athletes

or non-athletes and is associated with higher peak power

in active men (696,725). Another recent meta-analysis in

elite endurance athletes identiﬁed polymorphisms in the

MYBPC3 (myosin-binding protein C3) and NR1H3 (nuclear

receptor subfamily 1 group H member 3/LXRa) genes that

were also correlated with _

VO2max (726). SpeciﬁcSNPsin

the HFE, NFIA-AS2 (nuclear factor I A antisense RNA 2),

and TSHR (thyroid stimulating hormone receptor) genes

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that are more frequently observed in elite endurance ath-

letes compared with controls have also been associated

with high _

VO2max among athletes (727–729). Additionally,

athletes with homozygous C alleles of NFIA-AS2, encod-

ing a long noncoding RNA, have improved hematologic

parameters such as higher Hb levels, since NFIA-AS2

may be involved in the regulation of the transcription fac-

tor NFIA and erythropoiesis (727,728). However, even if

a combination of GWAS and selected physiological

measures in elite athletes may help identify SNPs for vari-

ous genes, data including such measures are limited and

so far these candidates have not been replicated (722). In

the future, it might be possible to link polymorphisms to

the responsiveness of individuals (i.e., low vs. high res-

ponders) to standardized training interventions, as a set of

21 SNPs was able to predict almost 50% of the variation

observed in the _

VO2max training response (698). However,

as noted, replication of these data remains difﬁcult, and

not all SNPs seem to affect trainability across all popula-

tion groups (698). Importantly, the identiﬁed polymor-

phisms are based on associations, and for the large

majority of these the functional relevance and mechanistic

aspects of the gene variants in muscle biology are

unknown. Therefore, identiﬁcation of SNPs with larger

effect sizes, replication of the identiﬁed SNPs in independ-

ent cohorts, as well as studies including a larger sample

size and possibly additional physiological measures to dis-

criminate individuals (i.e., _

VO2max and performance out-

comes) are necessary to gain knowledge about genetic

factors that underpin elite athlete performance. These

studies will have to be combined with mechanistic investi-

gations of the functional effect of gene variants and SNPs

to understand how differences are brought about.

Gain- and loss-of-function studies in mouse models

have identiﬁed 31 genes associated with endurance

performance (681). For eight of these, genetic var-

iants have been reported to be associated with elite

endurance athletes (681,722). The genes associated

with an elite endurance athlete status and enhanced

endurance performance in a gain-of-function mouse

model include PPARD, PPARGC1A, PPARGC1B, and

PPP3CA (protein phosphatase 3 catalytic subunit a),

and those correlated with endurance performance in

a loss-of-function mouse model include ACTN3,

ADRB2, BDKRB2 (bradykinin receptor B2), and HIF1A

(681,722). Although 47 genes were identiﬁed in mouse

models that induce hypertrophy in a gain- or loss-of-func-

tion model, no corresponding human polymorphisms

were described for most of the genes that were associ-

ated with a strength/power muscle phenotype (680).

However, gene variants in IGF1 and ADRB2 have been

found in the phenotype of power athletes and are 2 of

the 47 genes that induce hypertrophy in a gain-of-func-

tion model (722).

Collectively, most of the identiﬁed polymorphisms dif-

fer between studies and only explain a very small frac-

tion of the interindividual differences in endurance and

strength. As a consequence, the current knowledge is

inadequate for talent identiﬁcation or prediction of train-

ing response (68). Besides the question of whether

genetic talent identiﬁcation will ever be feasible in the

future, ethical and practical issues also need to be con-

sidered (718,730). “Genetic”prediction of athletic prow-

ess and specialization disregards personal preferences

and choices, with potential detrimental consequences

on enjoyment, motivation, and ultimately adherence.

Talent identiﬁcation and premature specialization might

also preclude the multidisciplinary practice in youths

that predicts world-class performance (731). Moreover,

sensitive genetic information has potential for misuse

and unexpected outcomes, and could have psychologi-

cal consequences that could even extend to other family

members. Additionally, the reported associations are

observed at the population level and hence have a very

low predictive value at the individual level (732). In fact,

there are frequently individuals with a seemingly less

favorable genotype who achieve elite athlete status

(718). Moreover, monozygotic twin studies revealed a

strong impact of discordant leisure-time physical activity

on performance, ﬁtness, health, and well-being, to a

large extent disconnected from the genetic endowment

(733). In summary, the current scientiﬁc evidence sup-

porting the contributions of speciﬁc genetic variants to

elite athletic performance phenotypes is weak (734).

This is partly because complex traits are modulated not

by several genes with large effect sizes but instead by

polygenic systems deﬁned by hundreds or thousands of

loci, characterized by alleles with small effect sizes, plus

less frequent alleles (83). In contrast to the commercial

for-proﬁt genetic testing to predict training selection and

response, non-genetic testing, such as assessment of

physical performance, might be more useful for athlete

stratiﬁcation (68,83,692,693,735). Importantly, instead

of talent identiﬁcation, genetic information could also be

used for the screening of polymorphisms that are associ-

ated with injury risk among athletes (i.e., stress fractures

or tendinopathies) to reduce injury by individualized pre-

ventative measures (718), with much fewer ethical consid-

erations attached.

5.3. The Aging Athlete and Athletic Performance:

Slowing Down with Speed

During the past century, there has been a steady

increase in life expectancy among most countries in the

Western world. However, such enhanced longevity (life

span) has not always been accompanied by a propor-

tional elevation in healthy life expectancy, so-called

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“healthy aging”or “healthspan”(736). Thus, an objective

of medical and aging research is not necessarily to pro-

long life span per se but instead to increase the health-

span and compress morbidity later in life (737). At the

population level, aging is strongly associated with a rise

in sedentary behavior and concomitant declines in phys-

ical and mental capacity. An examination of the perform-

ance proﬁles of individuals who continue to train and

compete throughout their entire life provides insights

into the extremes of human function and the upper limits

of physiology during the human aging process (738,

739). The birth of the “masters”athlete movement (those

individuals >35–40 yr of age, depending on the sport)

can be traced back to the late 1960s and early 1970s. At

this time, there was a massive increase in the number of

people who started exercising, either for health and

pleasure or to pursue competitive endeavors. In the

United States, this escalation in structured physical activ-

ity initially centered on distance running and was

inspired by a few select individuals such as Roberta

Gibb and Kathrine Switzer, who were the ﬁrst female ﬁn-

ishers in the Boston marathon in 1966 and 1967, respec-

tively, and Frank Shorter, who won the gold medal in the

men’s Olympic marathon in 1972 and silver in the 1976

Olympics. Throughout the next two decades, there was

an explosion in the number of marathon races held in

capital cities throughout the world, with applications to

run in these events far exceeding the number of avail-

able starting places. The mid-1970s also saw the birth of

the triathlon, which consisted of an amalgamation of

three separate sports: swimming, cycling, and running.

From humble beginnings (15 men started and 12 ﬁnished

the inaugural “Ironman”triathlon in Hawaii in 1978), the

Hawaii Ironman is generally considered one of the most

difﬁcult 1-day sporting events in the world, and today

Ironman races attract almost half a million entries world-

wide each year. These competitive, mass-participation

inner-city marathons and triathlons were the motivation

for a generation of women and men to start training for

speciﬁc competitions/races and laid the foundation for a

generation of athletes who are now in their eighth or

ninth decade of life and have participated in formal exer-

cise training throughout their life span (740). As such, we

now have both cross-sectional and longitudinal data on a

cohort of masters athletes who have maintained rigorous

training schedules over many decades and have better

health outcomes than their age-matched non-athletic

counterparts. Such well-trained individuals represent the

optimum phenotype for examining the effects of aging on

performance and vice versa, as these individuals are

most likely minimally affected by the negative effects of

the age-related decrease in voluntary physical inactivity

and changes thus largely driven by an inherent aging pro-

cess (739). Although cross-sectional data on masters

athletes are easier to obtain than longitudinal data, the

former can only provide the age-related performance

decline for a population, whereas longitudinal data show

individual trajectories. A detailed analysis of the age-

related declines in performance across multiple sporting

events is beyond the scope of this review, and the reader

is referred to previous work in this area (741–746). Here,

we provide a general overview of the effects of aging on

overall physical performance declines and discuss some

of the mechanisms that underpin this decay in perform-

ance capacity.

Plotting age-group world records for males and

females across various sporting events provides insights

into the rates of decline in performance capacity across

the healthspan (FIGURE 20). Such cross-sectional data

offer the “best-case scenario”for each age band but do

not provide any information on the individual athletes’

decay curves. Several observations are noteworthy.

First, the rate of performance decline does not appear

to differ between or within sports (e.g., the various track

and ﬁeld events and multiple swimming strokes and dis-

tances) (745). Second, there are no major sex-related dif-

ferences in the deterioration in performance for most

sports (746), and although there is a greater absolute

drop-off in performance for females compared to males,

the relative decline is similar. Performance declines for

most of the running, swimming, and cycling events, inde-

pendent of distance, are not linear but curvilinear (741).

However, at 70 yr of age, there is an accelerated

increase in performance decrements for almost all sport-

ing performances. For example, world records show

rapid declines after age 70 in swimming, long-distance

running, and sprint performance (744). Although it is

unlikely that those athletes still training and competing

after the age of 70 can maintain the same absolute train-

ing volumes and intensities, there is no reason to sus-

pect that the relative training intensity has diminished. It

is worth noting that only 5% of athletes competing at

age 80 yr are still competing at age 90 yr. Therefore,

world-best performances in these latter years may

merely reﬂect a lower number of participants rather than

any underlying physiological factor responsible for the

drop in performance capacity. Nevertheless, the per-

formance decline in athletes aged 80 yr is threefold

greater compared with athletes aged 30–69 yr (1.62%

vs. 0.46% per year) and accelerates around 67 yr, espe-

cially for sprint/power disciplines (742,743).

The factors that constrain performance with aging are

event-speciﬁc, meaning that for each sport/event there

may typically be one or more physiological/mechanical

systems that limit exercise capacity. For example, the

decline in maximal running velocity (independent of dis-

tance) is likely to be underpinned by deteriorations in sev-

eral properties in skeletal muscle that include a decrease

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in the maximum strength or power output, a slower rate of

force development and transmission, and a reduction in

elastic energy storage and recovery of tendons (748).

During the normal aging process, there is a progressive

loss of muscle mass, mainly in the lower body, which

increases after the age of 45 yr, with the absolute

decline being faster in men than in women (749). Even in

masters athletes who have undertaken a lifetime of train-

ing, a reduction in size and function of muscle is observed,

which is most pronounced in the fast ﬁbers (750). This

selective loss of fast-twitch ﬁbers explains, in part, the

greater magnitude of performance decline in sprint and

explosive events compared with endurance-based activ-

ities. Cross-sectional data from 37- to 90-yr-old masters

athletes indicate that peak anaerobic power declines by

7–14% per decade, with this reduction being similar

between male and female athletes (751). Despite the

selective loss of fast muscle ﬁbers, Cristea et al. (752)have

shown that a 20-wk program that combined sprint training

with heavy and explosive strength exercises speciﬁcally

targeting fast-twitch muscle ﬁbers improved maximal, ex-

plosive, and sport-speciﬁc force production in elite mas-

ters sprinters (aged 52–78 yr). Furthermore, at a single-

ﬁber level, it seems that power output per unit size (i.e.,

muscle quality) is not reduced in muscles of aging

athletes (753), suggesting that the loss in power out-

put can mainly be ascribed to the loss of fast muscle

ﬁbers rather than muscle quality. In contrast to

sprint-based activities, men and women with a pro-

longed history (5 days/wk for 7 h/wk over the past 52

yr) of endurance-based training have capillarization

and aerobic enzyme activity similar to younger (25 yr

of age) exercisers, which in turn is 20–90% greater

than the parameters determined in elderly age-

matched non-exercisers. Although whole muscle

responses offer unique insights into age-related

muscle deterioration, they fail to provide a better

understanding regarding the potential mechanisms

underlying this phenomenon.

With endurance-based sports, there is a decrease in

VO2max of 1%peryearaftertheageof35yr(754). This

is due to a combination of factors including, but not lim-

ited to, an increase in ventricular stiffness that contributes

to worsening left ventricular diastolic function reﬂected

by reductions in early inﬂow velocity, ratio of early to late

inﬂow velocity, and early diastolic tissue velocity and

increases in the isovolumic relaxation time and the time

constant of isovolumic pressure decay (755). Although

lifelongexercisershaveagreaterstrokevolumeandcon-

sequently a superior functional capacity and cardiovascu-

lar reserve than their sedentary peers, there may be

some adverse consequences of a lifetime of rigorous en-

durance-based training. Several studies have reported

increased risk of atrial ﬁbrillation, atherosclerotic plaques,

and aortic dilation in masters athletes compared with age-

matched untrained individuals (756–758). A J-shaped

association between exercise volume and all-cause mor-

tality, cardiovascular disease, and total cancer, as opposed

to the L-shaped association with diabetes, would imply a

negative risk proﬁle at very low and very high volumes of

activities (759). These ﬁndings, however, contrast with

results of other studies in different athlete populations, in

which a J-shaped association was not observed (760,

761). In fact, many studies and meta-analyses reveal

reduced mortality in former athletes (761–763), even in

those competing at the highest level such as United

States, French, or Polish Olympians or French participants

oftheTourdeFrance(764–767). Often, assessment of

potential effects of genetic components and the beneﬁts

of lifelong training in elite athletes is confounded by

healthier lifestyle habits such as being more active or a

non-smoker (768,769).

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85-89

90-94

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85-89

90-94

Age group Age group

Time (h)

Time (s)

Marathon records 100 m records

Masters athletes

Women

Men

Women

Men

World record World record

FIGURE 20. Age-related decline in records of sprint and endurance events. Records for marathons (https://world-masters-athletics.com/

championships/non-stadia/) and 100 m sprints (747) of masters athletes represent the age-induced reduction in tissue and organ function that despite

high training loads leads to a decrease in performance. However, they also highlight the potential of the human body to achieve incredible performan-

ces at advanced age with adequate training.

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5.4. Looking Ahead: Personalized Training Using

Wearables

The application of wearable appliances/sensors to sport

is a relatively new phenomenon. In 1978, a Finnish com-

pany pioneered the ﬁrst wearable heart rate monitor,

subsequently introducing a monitor with an integrated

computer interface, which gave athletes the ability to

view and analyze their training data on a computer for

the ﬁrst time. In 2009, a professional European soccer

club used wearable devices for measuring player work-

load during games. That device was among the ﬁrst to

allow coaches real-time monitoring of each player’s bio-

metrics for signs of exhaustion or injury while on the ﬁeld

of play. The generation of real-time data during competi-

tion situations is important: athletes have long been able

to monitor their physiological status under controlled

laboratory conditions, but competition demands includ-

ing prevailing environmental factors (heat and humidity,

wind speed, altitude, other athletes/players, crowds)

impose a different set of stressors that cannot be mim-

icked in the laboratory (770). Over the last 20 years, the

growing interdisciplinary merging of technologies has

led to milestones in the ﬁeld of advanced sportswear

systems. Such systems are designed to assist athletes

to reach their desired ﬁtness and performance goals by

helping to create an optimal micro- and macroenviron-

ment and/or physiological state for comfort, to facilitate

best performances by providing real-time information on

the environment and state athlete status (770). Of note,

most sensors for monitoring athletic training loads and

sports performance have been driven by technological

advances in other disciplines, mainly clinical medicine

(e.g., continuous glucose monitoring systems) and the

military (770).

The concept of wearable sensors in sport is broad

and includes any information gathering system that an

athlete can wear/carry while participating in normal train-

ing/competition environments. Wearables can be worn

by athletes on their person, in their clothing, or within

their equipment and incorporate sensors, a microproc-

essor, and a form of communication unit that enables

connectivity within a personal area network (PAN) where

a smartphone or other appliance stores data and oper-

ates as a gateway with connectivity to the internet (771).

Sensors and devices for athletes must be small and

light, as well as ﬂexible, durable, and impact resistant.

Perhaps most importantly, any device should not neg-

atively affect normal range of motion in an athlete’s

chosen discipline. Simultaneously, wearables must

produce precise measurements of biometrics like

motion, heart rate, blood pressure, respiration rate,

oxygen kinetics, blood, saliva, and sweat markers, and

impact forces (772).

During the past decade, there has been a global

explosion in wearables in sport and other health-related

ﬁelds (772) underpinned by rapid developments in

“smart technologies”such as artiﬁcial intelligence (AI)

and machine learning. These technologies rely on sen-

sor systems that collect, process, and transmit relevant

data (such as biomarkers and other training/competition

indexes) that are crucial to evaluate an athlete’scondi-

tion and maximize performance (771). In the sports set-

ting, these platforms have several objectives: 1)to

gather valid, reliable, high-quality, data-rich sensory in-

formation from athletes in training/competition environ-

ments; 2) to apply sophisticated analytics methods to

identify patterns for determining athlete health and

training/competition status; 3)toobtainreal-timedata

regarding training-related metrics (i.e., training varia-

bles, sleep quality, diet) while assisting athletes/

coaches to manage a range of performance variables

and outcomes to detect early signs and symptoms of

overtraining (657); and 4)toestablishnovelperform-

ance outcomes that supplement subjective, manually

collected data and coach-based feedback with auto-

mated, objective data from devices. Data obtained

from wearables can furthermore be leveraged to learn

new techniques and provide real-time feedback on

this process (770). For example, Samsung developed

the Samsung SmartSuit to optimize body posture dur-

ing short-track speed skating. The suit includes ﬁve

integrated sensors and enables real-time feedback to

the coach regarding the body position of the athlete:

in this scenario, real-time feedback is transmitted to

the athlete with instructions to modify body position to

reduce drag and optimize performance. The Dutch

short-tracker Suzanne Schulting used this suit to pre-

pare for the Olympic Games in 2018 and became the

ﬁrst Dutch Olympic gold medal winner for 1,000 m, a

feat she repeated in 2022.

Training load for sport performance encompasses both

external and internal dimensions, with external training

loads representing the physical work performed during a

training session and internal loads being the associated

biochemical and biomechanical stress responses. With

regard to athlete monitoring, wearables provide informa-

tion over four broad domains (771,773): 1) internal load,

representing the psychophysiological responses to a

given external load and typically determined by measure-

ment of heart rate, oxygen uptake, blood lactate, and rat-

ings of perceived exertion; 2) external load, determined

by the physical demands associated with a given stimu-

lus, monitored by global navigation satellite systems, iner-

tial measurement units, or linear/angular transducers that

provide measures related to distance covered at certain

velocities, acceleration/deceleration, and change of direc-

tion forces; 3) well-being, monitored by subjective scales

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related to fatigue, DOMS, stress, quality of sleep, or mode

state; and 4) readiness, assessed by measures of heart

rate variability, heart rate recovery, and variations in the

test results of selected neuromuscular or submaximal/

maximal test protocols. As long-term improvements in

training adaptation and performance capacity are ulti-

mately the result of an athlete’scumulativeinternalload

over multiple acute work bouts, the measurement of inter-

nal load and the factors inﬂuencing these outcomes is of

paramount importance for the coach and athlete. A knowl-

edge of the relationships between internal and external

training loads has the potential to enhance training pre-

scription, periodization, and athlete management through

a detailed assessment of training ﬁdelity and efﬁcacy

(773). Whether such information will provide coaches with

an objective framework for evidence-based decisions

remains to be determined. Moreover, potential issues with

accuracy, dependability, or data security and privacy will

have to be considered and solutions proposed that are

acceptable for all stakeholders (774).

5.5. The Application of “-Omics”Technologies to

Exercise Biology

In the past quarter century, the ﬁeld of exercise biology

has evolved to include sophisticated analysis of multi-tis-

sues and organs through the application of established

techniques already employed in other disciplines, as

well as various -omics platforms to complement classic

approaches (775,776). Such inquiry has provided both a

greater understanding of the biological bases of the

health beneﬁts of exercise (38) as well as knowledge of

muscle bioenergetics and adaptation to training in rec-

reationally active individuals and subelite athletes (55,

160,777). The application of molecular techniques to

exercise biology has provided novel insights into the

complexity and breadth of intracellular signaling net-

works involved in response to both endurance- and re-

sistance-based exercise (55,161,777). The recent

explosion in global -omics technologies in the exercise

sciences has also provided new opportunities to map

the complexity and interconnectedness of biological

networks underlying the tissue-speciﬁc responses and

systemic beneﬁts of exercise training (161,455,586,

778–782). A “sportomics”approach (the use of -omics

sciences in sports) has even been proposed to comple-

ment existing methods of studying and monitoring an

athlete’s state of fatigue and physical performance and

aid in talent identiﬁcation (783,784). There have been

in-depth and integrated multiomics proﬁling efforts of

the response to acute exercise in subclinical populations

(785), along with longitudinal “big data”approaches to

develop prediction models for biomarkers for precision

medicine (786). However, to date, few studies have

been undertaken in elite athletic cohorts (787).

Although there is some evidence to suggest that a com-

bined -omics solution will greatly facilitate discovery of the

genetic and non-genetic inﬂuences on sporting perform-

ance, training response, injury predisposition, and other

potential determinants of successful human performance

(788), large-scale, collaborative efforts involving well-deﬁned

phenotypic cohorts will be essential for major progress to

be made in the ﬁeld of elite sport performance (782).

Indeed, integration of data from multiple -omics approaches

will require large sample sizes, big data sets, and expertise

in computational biology to resolve the complex biology

associated with the diverse exercise responses to endur-

ance- and resistance-based training regimens. This will ne-

cessitate collaborative efforts between multiple research

teams using common procedures and experimental

protocols to execute multicenter exercise/lifestyle

intervention trials with the goal of collecting sufﬁcient

functional and molecular data to further elucidate the

mechanisms responsible for adaptive response to var-

ious exercise training regimes. Issues of data privacy

and accessibility will have to be considered.

Such an approach is already underway: the Molecular

Transducers of Physical Activity Consortium (MoTrPAC)

is a multicenter study on the effects of two different

forms of exercise (endurance and resistance training)

across individuals of different ages and sexes as well as

sedentary and well-trained individuals (782). There are

two main aims of MoTrPAC: the ﬁrst is to study the

response to exercise at the whole body and cellular lev-

els and to identify the molecular underpinnings that

might be responsible for the adaptive process and varia-

tion among individuals. The second aim is to deliver

a map of the biological molecules and pathways under-

lying the systemic effects of acute and chronic exercise

(454,782). Ultimately, the knowledge gained from

MoTrPAC and other similar large-scale undertakings

(e.g., the Wu Tsai Human Performance Alliance) will give

biological science researchers and health professionals

the insights to develop personalized training protocols to

maximize performance and/or health beneﬁts based on

the unique molecular signatures and speciﬁctargets

identiﬁed. Notwithstanding the increased knowledge that

will accrue from a better understanding of these sophisti-

cated biological processes and pathways, advances in

training techniques for achieving new limits in human ath-

letic performance have rarely had their origins in science.

Part of the reason that sport science and exercise biology

has failed to inform training practices stems from a reluc-

tance of coaches to modify their methods, many of which

have been nurtured and perfected over decades and are

ﬁrmly entrenched as coaching “lore.”Donating tissue

samples for exercise biologists to gain mechanistic

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insights into various training protocols has also met with

limited success. As such, knowledge of training methods

to enhance elite sport performance has traditionally

evolved by way of trial-and-error observations of a few

pioneering coaches and their athletes, with exercise sci-

entists playing “post hoc”roles attempting to explain the

underpinning biological mechanisms (99). Although major

breakthroughs in the knowledge of how exercise acti-

vates numerous cellular, molecular, and biochemical

pathways have been witnessed, direct evidence linking

such effects to speciﬁc performance outcomes and

understanding how these effects exert their beneﬁts in

different athletic populations remains elusive and a chal-

lenge for future research. To do so, exercise biologists

who investigate training adaptation and elite athletic per-

formance will have to integrate information pertaining to

an athlete’s genetic and epigenetic background with tis-

sue-speciﬁc gene expression, proteome, and metabolo-

mic proﬁles to predict potential improvements in strength,

aerobic capacity, and other traits necessary for elite

performance.

6. SUMMARY, CONCLUSIONS, AND

PERSPECTIVES

We stand on the shoulders of giants who have unraveled

seminal and fundamental aspects of muscle biology and

metabolism (789). Today, human studies are boosted by

technological and conceptual advances that enable the

investigation of molecular mechanisms, cellular functions,

multicellular dynamics, as well as inter-tissue and inter-

organ cross talk in an unprecedented manner. For exam-

ple, the identiﬁcation of myokines resulted in the new deﬁ-

nition of skeletal muscle tissue as an endocrine organ, in

fact the largest in our body (790,791). Similarly, metabolism

of kynurenine (792) and excess ketone bodies in hyperke-

tonemia (575) in skeletal muscle, boosted by exercise,

imply a role for this tissue in the detoxiﬁcation of dysregu-

lated endogenous metabolites, analogous to xenobiotic

detoxiﬁcation in the liver. scRNA-seq has yielded novel

insights into the cellular composition of muscle, including

the identiﬁcation of previously unidentiﬁed cell types and

the ﬁrst analyses of multicellular dynamics and interactions

(632–634). Likewise, single-nucleus RNA-seq (snRNA-seq)

reveals a hitherto unsuspected coordination between

nucleiinthesamesyncytialmyoﬁber but also a surprising

heterogeneity and subspeciﬁcation of transcriptional pro-

grams that extends beyond the classically deﬁned

synaptic, extrasynaptic, and myotendinous nuclear

populations (793–795), combined with insights into

protein transfer between nuclei (650), RNA transport

in the muscle ﬁber (651), and even the movement of

myonuclei in speciﬁccontexts(649). Exon skipping,

CRISPR-Cas9-based approaches, and adeno-associ-

ated viral (AAV) vectors have been applied in different

settings and pathologies, including muscle diseases,

in the preclinical setting, such as therapy of Duchenne

muscular dystrophy (796). AAV-based gene therapy is

now also used clinically, for example, in spinal muscu-

lar atrophy patients (797).Finally,progressisbeing

made in the recognition of our increasingly sedentary

lifestyleasamajorriskfactorforchronicmetabolic

diseases, the prescription of exercise-based interven-

tions in the general population for preventing and/or

treating an ever-increasing number of widespread

conditions, and establishing physical activity as a cor-

nerstone in medical practice and public health (26,

798,799).

In elite sport, world records continue to be broken

across a wide range of events. Performance improve-

ments or declines depend on many factors, including

technology, sports science, support for a particular

sport, talent identiﬁcation, investment of time, and effec-

tiveness of training protocols (800–802). Advances in

elite performance can also vary between individual

events in one sport, as is the case for Olympic swimming

competitions, with strong trends for improvement in

some strokes and a relative plateau in others (803). With

an increasing number of former Olympians and elite ath-

letes now participating in masters competitions, age-

group records are being surpassed and seemingly unat-

tainable performances recorded such as the sub-3 hour

marathon by a 70-yr-old man (804). Although big data

approaches will be facilitated by the rapidly evolving

tracking systems and wearables technologies combined

with machine learning, AI, and other analysis methods

(66,805,806), it is questionable as to what extent train-

ing practices of elite athletes have been facilitated by

any major laboratory-based scientiﬁc breakthroughs to

date. Indeed, despite our greater understanding of

some of the mechanistic underpinnings of muscle plas-

ticity and exercise adaptation, the upper limits of adapta-

tion remain poorly studied (18). Even though numerous

potential regulatory and functional key players have

been identiﬁed, we do not know whether the picture is

complete, how these factors are activated and engaged,

how different pathways are integrated, or how the regu-

latory and functional outcome is speciﬁed, orchestrated,

and coordinated. Moreover, the complexity of the appa-

rent regulatory and functional redundancies, contingen-

cies, alternatives, and adaptive mechanisms that ensure

robust regulation of muscle plasticity as one of the most

fundamental aspects of human life and evolution

remains enigmatic (18). Our insights into the regulation

of muscle plasticity in response to endurance-based

training stimuli far surpasses that of resistance-based

exercise, in part because of the availability of more

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robust or at least more commonly used animal models

and protocols that are more physiological and translat-

able for the former training practice (807,808).

Compared to the muscle and whole body responses to

an acute bout of exercise, the mechanistic aspects of

chronic training-induced plasticity are less well investi-

gated and understood. Similarly, the mechanistic under-

standing of the molecular bases of reduced training

and/or detraining, as well as of retraining and muscle

memory, remains rudimentary (433). Finally, we have lim-

ited knowledge of the dynamic multidirectional cross

talk between muscle and other cell types, within and

beyond muscle tissue, which is instrumental for

adequate muscle function and delays a better delinea-

tion of training adaptation. For example, studies of the

motor unit, the unity of muscle ﬁber and motor neuron,

should include sensory-motor circuits in the spinal cord

and supraspinal systems, brain stem neurons with de-

scending axons, and brain regions that are involved in

locomotor control and integrate sensory feedback, all

important for muscle control, resistance training adapta-

tion, muscle memory, and other processes (329,456,

464,809).

How will we overcome these shortcomings, and what

could the future of muscle research look like? In addition

to new advances in technological possibilities, analysis

methods, and computational modeling approaches, one

aim would be stronger interaction, collaboration, and

networking between basic science, sports sciences, and

coaches as well as athletes (FIGURE 21). All these ﬁelds,

when optimally synergized, may help to obtain a better

understanding of muscle plasticity from the inactive to

the extreme (810,811). Currently, training paradigms pio-

neered by athletes tend to inform and guide research,

as was the case for interval training practiced by Paavo

Nurmi in the 1920s and Emil Zátopek in the 1950s for

middle- and long-distance running disciplines (812).

Such innovative methods are currently enjoying intense

scientiﬁc scrutiny in the reﬁned form of HIIT, for both ath-

letic endeavors and the ﬁtness and well-being of the

general population (100). Athlete feedback is central to

understanding individualized training response, fatigue

recovery, or concurrent training design and helps to study

the mechanistic aspects that underlie these processes

for iterative optimization of training and competition

(71). Importantly, sports psychology and neurobiology

should integrate morphological, cellular, and mecha-

nistic aspects to identify the relevant circuitries,

regions, and signals involved in the control of these

factors, including the cross talk between muscle and

brain (494,813,814).

Bypassing this chain of research by jumping directly

from basic science to athletes often leads to a mismatch

between preclinical data and “real-world”performance.

For example, based on mechanistic insights and mouse

experiments with so-called “exercise mimetics,”some

coaches and athletes experimented with performance-

enhancing compounds, most recently AMPK and PPARb/

dactivators, without waiting for robust scientiﬁc validation

from human trials (45,46). Not only is there no evidence

for performance enhancement in humans (815), but in

somecases(e.g.,metformin,resveratrol,andrapamycin),

there may be a reduction of training adaptation (45,46).

Moreover, such compounds may have a signiﬁcant risk of

severeadverseeffectsthatmightnotberelevantinthe

time frame of application and life expectancy in rodents

but could have detrimental long-term effects in humans

(45,46). For example, prolonged, sustained activation of

AMPK could lead to a catabolic state, lactic acidosis, car-

diac hypertrophy, brain inﬂammation, and reduced cogni-

tive abilities (45,46,816). PPARb/dligands increase the

risk of tumors in rodents when given at high doses over a

prolonged period of time, and even AMPK’sactioncan

switch from tumor suppressor to tumor promoter once

cancer develops (45,46,817). It is encouraging to see

that integrative approaches are increasingly pursued at

different centers and organizations in which elite athlete

training and health management is under the same roof

as integrative research. Thus, collectively, mechanistic

understanding, implementation in training design, techno-

logical innovations, and other advances, cross-fertilized

with data from psychology, nutrition, and sleep research,

will help to further optimize athletic performance in a

safe, personalized, and evidence-based approach (818,

819). Thereby, pseudoscience, baseless claims, “quick

ﬁxes,”and other potentially detrimental interventions can

be minimized and information separated from misinfor-

mation (820). Finally, integrative research in exercise

should be combined with exercise medicine to further our

understanding of the immense potential of exercise-

based interventions to prevent and treat many chronic

diseases in the general population (821), along with

the use of training for injury rehabilitation in physical ther-

apy. A better understanding in the athletic setting thus

could and should inform interventions in the general popu-

lation and in patients (822). For example, studies of resil-

ience and motivation might also help to design approaches

to facilitate and improve adherence and compliance to exer-

cise training (823–825). Such an approach could leverage

novel avenues such as virtual reality exergames (826,827).

Insights into exercise physiology are leveraged in disease

diagnostic, prevention, treatment, and rehabilitation, e.g.,

the use of blood pressure measurements during exercise

(exercise hypertension) to reveal undiagnosed or masked

hypertension and predict cardiovascular disease risks

(828,829). Many more areas exist in which concepts

derived from elite sports will beneﬁt non-athletes and

patients (822). In this context, exercise sociology

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could contribute to overcome existing individual

and societal challenges (830). Hopefully, exercise

will ﬁrmly be recognized and accepted in all aspects

of clinical practice and the political and societal

framework established to facilitate and promote an

active lifestyle.

Finally, an issue that will have to be addressed in the

ﬁeld of biological/sports science is the formulation of

hypotheses and interpretation of data and results. Too

often, papers claim to have solved an open question in

an absolute manner, even though in many cases seem-

ingly conﬂicting, contradictory, or non-overlapping alter-

native studies exist. Often, such studies depend on

relatively small subject numbers and might have to be

interpreted in light of age, sex, training protocol, sam-

pling time, and other parameters (diet, sleep, comorbid-

ities, ﬁtness level, chronotype, and time of day of the

study) (831). Human and animal studies are guilty of this

alike. Studies in model organisms have a limited predic-

tive power for human exercise physiology but enable

Large cohort data, wearables

Individual athletes

Model organisms

Molecular biology

Prevention and treatment

Mechanisms,

Causality

Human relevance

(descriptive, correlative)

Athlete/coach

feedback

Sports psychology

Nutritional sciences

Chronobiology and sleep research

Basic muscle

science

Human exercise

physiology

Exercise is

medicine

Cell culture models,

organoids

Computational biology,

modeling

FIGURE 21. The future of exercise science for safe, evidence-based, and personalized approaches. To overcome existing hurdles and efﬁciently

leverage the power of novel techniques and approaches, a close interaction between basic muscle research, applied human exercise physiol-

ogy, as well as athletes and coaches should be aimed for. Model organisms, cell culture, and molecular and computational biology might provide

insights into cause-effect relationships, epistasis, etiologies, and mechanisms complementing the descriptive and correlative studies in human

volunteers. Inversely, data from large cohorts that will become available because of widespread use of wearables and trackers as well as those

obtained in and based on feedback from athletes and coaches will reveal processes and pathways to be explored in mechanistic detail. The mo-

lecular athlete should furthermore be informed by sports psychology, e.g., in regard to motivation, perseverance, compliance and adherence,

nutritional sciences, chronobiology, sleep research, and other ﬁelds of relevance to training. Finally, a mutual exchange between the observa-

tions in training and those in various pathologies associated with an inactive lifestyle or inadequate muscle functionality will help to push the

boundaries of physical activity interventions in the prevention and treatment of numerous diseases. Image created with BioRender.com, with

permission.

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causative and mechanistic insights, which are difﬁcult to

conduct in human trials that rely mainly on descriptive or

correlative data. Moreover, while model organisms pro-

vide access to all different types of muscle beds and

allow the analysis of whole muscles, human studies are

in most cases limited to small, single biopsies of one

muscle (typically the vastus lateralis), taken at different

times before, during, or after exercise, with considerable

variability in outcomes and hence interpretation of

results (388,446,832). It might be advisable to be aware

of possible limitations and keep an open mind vis-à-vis

alternative interpretations, study-speciﬁc bias, and sys-

tem complexity surpassing simplistic explanations. For

example, there most likely is more than one cause for

muscle fatigue (833); satellite cell recruitment might be

important for hypertrophy in some but not all cases

(658); the relative contribution of training intensity and

volume on mitochondrial function in muscle might be

very context-dependent (104,105) as is the relative con-

tribution of muscle hypertrophy to gains in strength

(834,835); and polarized or pyramidal intensity distribu-

tions might be optimal for performance enhancement

(116,132–134). Even “established principles,”“dogmas,”

and “laws”should constantly be questioned, validated,

and reﬁned. Unfortunately, more often than not, litera-

ture searches for such ﬁndings disappear into a trail of

never-ending, consecutive citations. In addition, data

and the arising hypotheses must be examined under

consideration of the technical and conceptual possibil-

ities of the respective historical time period. For exam-

ple, Henneman’s size principle of motor unit recruitment

(836) certainly holds up under the laboratory conditions

using the exact preparations and the methods that were

used in the 1950s to 1970s. However, the rigid view of

this principle has since been reﬁned and modiﬁed with

novel approaches (i.e., using more complex musculoten-

don-skeletal systems, physiologically relevant range of

forces, physiological and neural stimulation as opposed

to electromyography and -physiology, or consideration

of neural drive, cortical and afferent input to each indi-

vidual motor neuron) (319,321,330,625). Moreover, it is

not clear how the size principle can accommodate mus-

cle ﬁber type shifts in exercise (624), and recent scRNA-

seq and snRNA-seq approaches revealed a greater di-

versity in motor neuron populations than the classically

deﬁned types based on transcriptional proﬁles (326,

837). Thus, even though probably correct at its core, the

size principle might be oversimpliﬁed, and motor unit

recruitment and plasticity certainly warrant further study.

Similarly, even though Nobel prize worthy, August

Krogh’s ideas on oxygen delivery and muscle microvas-

culature have, for some aspects, not withstood the test

of time or have been reﬁned and altered by more mod-

ern and comprehensive methods (595). The myonuclear

domain hypothesis was postulated to account for the

syncytial nature of myoﬁbers, implying that a nucleus is

needed for adequate support for transcription and trans-

lation within a speciﬁccellvolume,henceaﬁxed myonu-

clear domain, in these extraordinarily large cells (838).

Accordingly, satellite cell recruitment would be needed

to provide additional nuclei in ﬁber hypertrophy (839).

However, the myonuclear domain hypothesis fails to

provide an adequate and complete explanation for sev-

eral observations. First, removal of myonuclei in atro-

phy is controversial and not observed consistently

(839–843). Second, the myonuclear domain has high

ﬂexibility and scales with body size, ﬁber type, mito-

chondrial activity, ﬁber hypertrophy, and other param-

eters (838,844–846). Third, even though the spacing

between most myonuclei is roughly even, regional

differences exist, most notably in the tight clusters of

three to ﬁve subsynaptic myonuclei at the NMJ and

similar clusters at the myotendinous junction, for both

of which one nucleus should theoretically be sufﬁ-

cient to serve the respective cytoplasmic domain

(468). Ample evidence exists of intracellular move-

ment of myonuclei (847), as in postexercise ﬁber

repair (649), exchange of proteins between nuclei

(650), and microtubule-mediated transport of ribonu-

cleoproteins and RNAs within the myoﬁber (651), all of

which imply a highly plastic system transcending a

more rigid deﬁnition of myonuclear domains. Finally,

in cells that rival myoﬁbers in terms of size or length,

such as certain motor neurons with an axonal length

of >1m(848) compared with some of the longest

muscle ﬁbers in the human musculus sartorius reach-

ing the length of 60 cm (849), one nucleus, located

asymmetrically in the cell body in the spinal cord,

seems sufﬁcient to provide transcripts for the whole

cell. Thus, the evolutionary pressure for and physio-

logical function of the syncytial nature of myoﬁbers

remain largely mysterious.

These are just a few examples to illustrate that in exer-

cise biology and sport science, as in any place of scien-

tiﬁc and social discourse (850–852), we should have

passionate arguments but remain fair, civil, agnostic,

and open minded, carefully consider alternative results

and hypotheses, and constantly challenge, validate, and

reﬁne (or refute!) seemingly “established”principles. In

the ﬁnal analyses, modern sports science and exercise

biology offer numerous opportunities to assist elite ath-

letes to reﬁne training methods, optimize adaptation,

stay healthy and injury free, achieve their desired phy-

sique, and ﬁght against fatigue factors that limit success-

ful performance. The accomplishments of elite athletes

will continue to entertain and amaze us, as science

attempts to catch up and explain the biological bases of

such feats.

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GLOSSARY

AMPK AMP-dependent protein kinase

ATP Adenosine triphosphate

CSA Cross-sectional area

DOMS Delayed-onset muscle soreness

ECM Extracellular matrix

EPO Erythropoietin

Hb Hemoglobin

HIF-1aHypoxia-inducible factor 1a

HIIT High-intensity interval training

IL Interleukin

MPS Muscle protein synthesis

mTOR Mammalian target of rapamycin

mTORC1 mTOR complex 1

NMJ Neuromuscular junction

OXPHOS Oxidative phosphorylation

PGC-1aPeroxisome proliferator-activated receptor ccoac-

tivator 1a(gene name PPARGC1A)

1RM One-repetition maximum

RYR Ryanodine receptor

SERCA Sarcoplasmic/endoplasmic reticulum Ca2

ATPase

SNP Single-nucleotide polymorphism

SR Sarcoplasmic reticulum

VEGF Vascular epithelial growth factor

VO2max Maximal oxygen uptake

CORRESPONDENCE

C. Handschin (christoph.handschin@unibas.ch); R. Furrer

(regula.furrer@unibas.ch); J. A. Hawley ( john.hawley@acu.

edu.au).

ACKNOWLEDGMENTS

The authors thank the members of their research groups for

helpful discussions and comments regarding this manuscript.

We also thank the coaches and athletes for sharing training

plans. Because of space limitations, we have been unable to

include all of the pertinent and original work by some of our

peers, for which we apologize in advance. The ﬁgures were

created with BioRender.com. Images were obtained from pub-

lic repositories and acknowledged in the respective ﬁgure

legends.

GRANTS

Work in the laboratory of R.F. and C.H. related to this article

was supported by the Swiss National Science Foundation

(310030_184832), the European Research Council (616830-

MUSCLE_NET), Innosuisse (44112.1 IP-LS), the Swiss Society

for Research on Muscle Diseases, the Jain Foundation, the

Biozentrum, and the University of Basel.

DISCLOSURES

C.H. is an associate editor of Physiological Reviews and was

not involved in and did not have access to information regard-

ing the peer-review process or ﬁnal disposition of this article.

An alternate editor oversaw the peer-review and decision-

making process for this article. None of the other authors has

any conﬂicts of interest, ﬁnancial or otherwise, to disclose.

AUTHOR CONTRIBUTIONS

R.F., J.A.H., and C.H. prepared ﬁgures; drafted manuscript;

edited and revised manuscript; and approved the ﬁnal version

of the manuscript.

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Progressive overload in cardiorespiratory exercise training for young and old: Is increasing duration or intensity of exercise more important?

Article

May 2024
MED HYPOTHESES

Preparing for 2024 Sydney Marathon

Thesis

Full-text available

Apr 2024

Csaba Tarnai

Amateur marathon runners desire to excel at their chosen sport and to use the correct and latest research on how to optimise training and competition outcomes. Yet they do not have access to professional team of sport scientists, nutritionists, psychologists, and a well-equipped sports lab. This paper intends to review from the perspective of a self-coached 50year old sub-3 marathon runner for the marathon world championships in Sydney what is the latest research, what tools and technologies are available and how can they be integrated into the training of such amateur athletes. We will construct an Annual Training Plan; our starting point is the current level within a multi-year plan, the race ambitions for current year, and overall longer-term athletic goals. With an amateur runner, five years of experience, and a desire to diversify into middle-distance triathlon for current athletic year we will use a traditional training plan with a single peak for Sydney. We now need to assess the athletes fitness, based on VO2max , LT, and RE. Based on this, the desired race outcomes, and the training phase we construct the weekly running workouts. Generally speaking VO 2max is best supported by HIIT, LT by long-runs, and RE by running volume and strength workouts. The initial stages focus on volume which is gradually replaced by intensity. To help recovery within the week we need to vary training intensity and include lower-intensity weeks. To reduce injury risk from high running mileage we will focus only on four high quality run workouts and enhance the overall aerobic system with cross-training (cycling and swimming) and strength training. Training intensity needs to be distributed in a polarised way with 80% of volume in moderate aerobic zones and upto 20% in severe zones. Strength training is 3 session in the general stages, becoming 2 in competitive stage and completely removed in final pre-race weeks. To “Dose & Response” running intensity we will use critical power as measured by Stryd and benchmark against gold-standard laboratory tests. Other measures we will track with TrainingPeaks and WKO5 are key internal and external load for stress management (CTL, RHR, HRV), recovery management (sleep duration, time awake, and sleep quality), injury prevention (weekly running mileage and perceived injury for injury prevention), body composition (caloric expenditure, BMR, BM, and skinfold measurement), and polarised weekly running volume (hours of run training by intensity domain). Nutrition needs to be aligned to daily workloads mostly by varying levels of CHO, while guaranteeing a steady and well-distributed level of protein, mostly in the form of EAA. Nutritional needs are aligned with phases in the training plan, most notably in later precompetition stages where glycogen stores need to be topped-up while keeping body mass as low as possible. This is also supported by 1-2 LSD in fasted state to help use fat as substrate. In addition to physiologic adaptations, training also needs to hone psychological skills. Mental fatigue can be detrimental to competition as central and peripheral muscle fatigue. We will train the psychology by focusing on setting goals, dissociation from fatigue, association with the flow of the exercise, attentional focus which we will also train through yoga, visualisation of the event, positive self-talk, and flow & prayer. With 12 time zone difference and 24-hour long flight we must minimise travel fatigue and jet lag with melatonin, nutrition, recovery, easy workouts, and pre-taper psychology. Moreover we need gut training to assume 90 g/CHO/hour with 40mg caffeine. If all this is executed well we anticipate a sub-3, fastest Hungarian running outcome for Sydney 2024 world championships.

Ketogenic Diet plus Resistance Training Applied to Physio-Pathological Conditions: A Brief Review

Article

Full-text available

Jun 2024

The ketogenic diet (KD) is a nutritional strategy characterized by a reduced intake of carbohydrates (between 30 and 45 g per day or ≈5% of one's total calories from this macronutrient). The regimen induces physiological ketosis in which serum levels of ketone bodies increase from 0.5 to 3.0 mM, becoming an essential contributor to energy production. The popularity of using the KD to lose weight and its application in specific physio-pathological conditions, such as epilepsy, lipedema, and polycystic ovary syndrome, which is maintained over extended periods, gave us the impulse to write this brief review. In these types of physio-pathological conditions, subjects can achieve favorable training outcomes even if adhering to a KD. Therefore, performing resistance training under the KD to enhance muscle status and quality of life could be possible. It is important to note that, while some statements here suggest potential future directions, they are hypotheses that require experimental validation, even if they are supported by the independent benefits reported from the KD and resistance training and represent a promising area for future research.

Adaptogenic Herbs as Natural Sources of Sports Performance Enhancers

Article

Full-text available

Jun 2024
Open Med Chem J

Different parts of many plants, including seeds, bark, leaves, roots, fruit, stems, or flowers with known or suspected therapeutic properties are used to make herbal medications. In the past ten years, the number of athletes using herbal supplements has increased dramatically. Herbal remedies are becoming more and more popular among athletes and non-athletes as a way of improving their endurance and strength. Several diseases and impairments related to body stress are managed using herbal adaptogens; these adaptogens are also used to enhance focus, boost endurance during fatigue moments, improve physical strength/stamina, enhance energy levels, restore stress-affected cognitive function, improve sexual dysfunction, and maintain the level of cortisol. This study employed a research approach that requires the use of terms like “Herbal adaptogens, ashwagandha, endurance, athletes, turmeric, muscle strength” during a preliminary search of some of the popular databases such as Google, PubMed, Embase, ScienceDirect, OVID Medline, Google Scholar, and Web of Science. The leading herbal adaptogens on the global market (such as ashwagandha , Rhodiola roseas , astragalus, holy basil, cordyceps, and turmeric) were examined in this article based on their source. Also covered in this work are the potential negative effects of these adaptogens and how they can help athletes perform better by increasing their muscle mass, recovery, and endurance.

Influence of voluntary isocapnic hyperpnoea on recovery after high-intensity exercise in elite short-track speedskaters – randomized controlled trial

Article

Full-text available

Jun 2024

Respiratory muscle training plays a significant role in reducing blood lactate concentration (bLa) and attenuating negative physiological stress reactions. Therefore, we investigated if voluntary isocapnic hyperpnoea (VIH) performed after a maximum anaerobic effort influences bLa and perceived fatigue level in well-trained speedskaters. 39 elite short-track speedskaters participated in a trial with two parallel groups: experimental and control. All the participants performed the Wingate Anaerobic Test (WAnT). The experimental group performed a VIH-based recovery protocol 20 min after exercise, the control group used passive recovery only. Blood samples were taken 3 and 30 min after the WAnT to measure bLa. Fatigue was self-appraised on a 0–10 perceived rating-of-fatigue (ROF) scale 3 and 30 min after the WAnT. Noteworthy, but not statistically significant changes between the experimental and control groups were observed for changes in bLa (p = 0.101). However, statistically significant changes between the groups were found for ROF (p = 0.003, ηp² = 0.211, ω² = 0.106). Moreover, statistically significant interactions between post-exercise bLa clearance and VO2max (p = 0.028) and inspiratory muscle strength (p = 0.040) were observed. Our findings provided preliminary insight that VIH may be an efficient recovery protocol after anaerobic exercise performed by elite athletes. The association between VO2max and post-exercise bLa clearance indicates the vital role of aerobic fitness in repeated-efforts ability in short-track speedskaters. The study was registered at ClinicalTrials.gov as NCT05994092 on 15th August 2023.

Secular trends and sociodemographic, biological, and behavioural factors associated with handgrip strength in adolescents in southern Brazil: An allometric approach

Article

Full-text available

Jun 2024
J SPORT SCI

More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα

Article

Full-text available

Jun 2024
J PHYSIOL-LONDON

Circadian rhythms, governed by the dominant central clock, in addition to various peripheral clocks, regulate almost all biological processes, including sleep–wake cycles, hormone secretion and metabolism. In certain contexts, the regulation and function of the peripheral oscillations can be decoupled from the central clock. However, the specific mechanisms underlying muscle‐intrinsic clock‐dependent modulation of muscle function and metabolism remain unclear. We investigated the outcome of perturbations of the primary and secondary feedback loops of the molecular clock in skeletal muscle by specific gene ablation of Period circadian regulator 2 (Per2) and RAR‐related orphan receptor alpha (Rorα), respectively. In both models, a dampening of core clock gene oscillation was observed, while the phase was preserved. Moreover, both loops seem to be involved in the homeostasis of amine groups. Highly divergent outcomes were seen for overall muscle gene expression, primarily affecting circadian rhythmicity in the PER2 knockouts and non‐oscillating genes in the RORα knockouts, leading to distinct outcomes in terms of metabolome and phenotype. These results highlight the entanglement of the molecular clock and muscle plasticity and allude to specific functions of different clock components, i.e. the primary and secondary feedback loops, in this context. The reciprocal interaction between muscle contractility and circadian clocks might therefore be instrumental to determining a finely tuned adaptation of muscle tissue to perturbations in health and disease. image Key points Specific perturbations of the primary and secondary feedback loop of the molecular clock result in specific outcomes on muscle metabolism and function. Ablation of Per2 (primary loop) or Rorα (secondary loop) blunts the amplitude of core clock genes, in absence of a shift in phase. Perturbation of the primary feedback loop by deletion of PER2 primarily affects muscle gene oscillation. Knockout of RORα and the ensuing modulation of the secondary loop results in the aberrant expression of a large number of non‐clock genes and proteins. The deletion of PER2 and RORα affects muscle metabolism and contractile function in a circadian manner, highlighting the central role of the molecular clock in modulating muscle plasticity.

Cancer Therapy and Exercise Intolerance: The Heart Is but a Part

Article

Jun 2024

Can stimulants make you smarter, despite stealing your sleep?

Article

May 2024

The Impact of Artificial Intelligence and Machine Learning in Medical Imaging

Chapter

Apr 2024

A significant fundamental change in healthcare can be seen by the integration of artificial intelligence (AI) and machine learning (ML) with medical imaging (MI). This integration holds the potential to improve patient care standards, change clinical procedures, and improve diagnostic accuracy. This chapter presents the possible impact, addressed challenges, opportunities, and impacts on medical diagnosis of recent advancements and growing advances in the application of AI and ML in the field of MI. The rapid development of AI and ML technologies have pushed MI into a new phase of data-driven healthcare and personalized medicine. Furthermore, the applications of AI and ML in MI are a variety of including automated picture analysis and disease identification to prediction, revolutionizing pathology and radiology, and healthcare management. It also suggests a future in which these innovations will work together to improve patient care, improve diagnostic accuracy, and advance healthcare delivery.

Metabolic Signatures of Performance in Elite World Tour Professional Male Cyclists

Article

Full-text available

May 2023
SPORTS MED

Background and Objective Metabolomics studies of recreational and elite athletes have been so far limited to venipuncture-dependent blood sample collection in the setting of controlled training and medical facilities. However, limited to no information is currently available to determine if findings in laboratory settings are translatable to a real-world scenario in elite competitions. The goal of this study was to define molecular signatures of exertion under controlled exercise conditions and use these signatures as a framework for assessing cycling performance in a World Tour competition. Methods To characterize molecular profiles of exertion in elite athletes during cycling, we performed metabolomics analyses on blood isolated from 28 international-level, elite, World Tour professional male athletes from a Union Cycliste Internationale World Team taken before and after a graded exercise test to volitional exhaustion and before and after a long aerobic training session. Moreover, established signatures were then used to characterize the metabolic physiology of five of these cyclists who were selected to represent the same Union Cycliste Internationale World Team during a seven-stage elite World Tour race. Results Using dried blood spot collection to circumvent logistical hurdles associated with field sampling, these studies defined metabolite signatures and fold change ranges of anaerobic or aerobic exertion in elite cyclists, respectively. Blood profiles of lactate, carboxylic acids, fatty acids, and acylcarnitines differed between exercise modes. The graded exercise test elicited significant two- to three-fold accumulations in lactate and succinate, in addition to significant elevations in free fatty acids and acylcarnitines. Conversely, the long aerobic training session elicited a larger magnitude of increase in fatty acids and acylcarnitines without appreciable increases in lactate or succinate. Comparable signatures were revealed after sprinting and climbing stages, respectively, in a World Tour race. In addition, signatures of elevated fatty acid oxidation capacity correlated with competitive performance. Conclusions Collectively, these studies provide a unique view of alterations in the blood metabolome of elite athletes during competition and at the peak of their performance capabilities. Furthermore, they demonstrate the utility of dried blood sampling for omics analysis, thereby enabling molecular monitoring of athletic performance in the field during training and competition.

New horizons in the sociology of sport

Article

Full-text available

Feb 2023

The relevance of a sociological view on the problems of society has never been as important as it is today. To quote the editors of the journal Nature in their editorial, Time for the Social Sciences, from 2015: if you want science to deliver for society, you need to support a capacity to understand that society. In other words, the technological and scientific disciplines cannot simply transfer their findings into everyday life without knowing how society works. But this realisation does not seem to have caught on everywhere. The sociology of sport is entering a critical period that will shape its development and potential transformation over the next decade. In this paper, we review key features and trends within the sociology of sport in recent times, and set out potential future challenges and ways forward for the subdiscipline. Accordingly, our discussion spans a wide range of issues concerning the sociology of sport, including theories and approaches, methods, and substantive research topics. We also discuss the potential contributions of the sociology of sport to addressing key societal challenges. To examine these issues, the paper is organized into three main parts. First, we identify three main concentric challenges, or types of peripheral status, that sociologists of sport must confront: as social scientists, as sociologists, and as sociologists of sport, respectively. Second, we consider various strengths within the positions of sociology and the sociology of sport. Third, in some detail, we set out several ways forward for the sociology of sport with respect to positioning within academe, scaling up research, embracing the glocal and cosmopolitan aspects of sociology, enhancing plurality in theory, improving transnational coordination, promoting horizontal collaborations, and building greater public engagement. The paper is underpinned by over 60 years (combined) of work within the sociology of sport, including extensive international research and teaching.

Look to the stars—Is there anything that public health and rehabilitation can learn from elite sports?

Article

Full-text available

Jan 2023

Determinants of maximal oxygen consumption

Article

Full-text available

Nov 2022
J MUSCLE RES CELL M

Peter D Wagner

This article lays out the determinants of maximal O2 consumption (VO2max) achieved during high intensity endurance exercise. It is not a traditional topical review but rather an educational essay that intertwines chance observations made during an unrelated research project with a subsequent program of stepwise thought, analysis and experimentation to reveal how O2 is delivered to and used by the mitochondria. The centerpiece is the recognition that O2 is delivered by an inter-dependent system of transport components functioning as a “bucket brigade”, made up of the lungs, heart, blood and circulation, and the muscles themselves, each of which affects O2 transport by similar amounts as they change. There is thus no single “limiting factor” to VO2max. Moreover, each component is shown to quantitatively affect the performance of the others. Mitochondrial respiration is integrated into the O2 transport system analysis to reveal its separate contribution to VO2max, and to show that mitochondrial PO2 at VO2max must be extremely low. Clinical application of the O2 transport systems analysis is described to separate central cardiopulmonary from peripheral tissue contributions to exercise limitation, illustrated by a study of patients with COPD. Finally, a short discussion of why muscles operating maximally must endure an almost anoxic state is offered. The hope is that in sum, both the increased understanding of O2 transport and the scientific approach to achieving that understanding described in the review can serve as a model for solving other complex problems going forward.

Common synaptic input, synergies and size principle: Control of spinal motor neurons for movement generation

Article

Full-text available

Nov 2022
J PHYSIOL-LONDON

Understanding how movement is controlled by the CNS remains a major challenge, with ongoing debate about basic features underlying this control. In current established views, the concepts of motor neuron recruitment order, common synaptic input to motor neurons and muscle synergies are usually addressed separately and therefore seen as independent features of motor control. In this review, we analyse the body of literature in a broader perspective and we identify a unified approach to explain apparently divergent observations at different scales of motor control. Specifically, we propose a new conceptual framework of the neural control of movement, which merges the concept of common input to motor neurons and modular control, together with the constraints imposed by recruitment order. This framework is based on the following assumptions: (1) motor neurons are grouped into functional groups (clusters) based on the common inputs they receive; (2) clusters may significantly differ from the classical definition of motor neuron pools, such that they may span across muscles and/or involve only a portion of a muscle; (3) clusters represent functional modules used by the CNS to reduce the dimensionality of the control; and (4) selective volitional control of single motor neurons within a cluster receiving common inputs cannot be achieved. Here, we discuss this framework and its underlying theoretical and experimental evidence. image

Hypertensive Response to Exercise in Athletes: Unremarkable Finding or Relevant Marker for Future Cardiovascular Complications?

Article

Full-text available

Nov 2022

Background: In the general population, hypertensive response to exercise (HRE) predicts new-onset resting hypertension or other cardiovascular diseases. Methods: PubMed was searched for English articles published between January 1st 2000 and April 30th 2020. Additional studies were identified via reference lists of included studies. 92 papers were selected for full text analysis, finally 30 studies were included. Results: The results from 5 follow-up studies suggested an association between HRE and the risk of developing hypertension, while 10 studies reported a link with adverse cardiovascular events in the general population. Another study showed an association between HRE and future hypertension in athletes after a follow-up of 7 years. HRE in athletes was associated with left ventricular hypertrophy in three studies. Two other studies showed a link between HRE and focal myocardial fibrosis in triathletes and myocardial injury, respectively. One study found lower Apoliprotein-1 serum levels in athletes with HRE leading to a higher risk for cardiovascular disease. Only in one study no association with cardiovascular dysfunction in athletes with HRE was found. Conclusions: Based on current evidence, HRE is not a normal finding in athletes. If detected, it should be interpreted as a risk factor for future cardiovascular complications. Future research should address the adequate follow-up and management of athletes with HRE.

Flexible neural control of motor units

Article

Full-text available

Oct 2022
NAT NEUROSCI

Voluntary movement requires communication from cortex to the spinal cord, where a dedicated pool of motor units (MUs) activates each muscle. The canonical description of MU function rests upon two foundational tenets. First, cortex cannot control MUs independently but supplies each pool with a common drive. Second, MUs are recruited in a rigid fashion that largely accords with Henneman’s size principle. Although this paradigm has considerable empirical support, a direct test requires simultaneous observations of many MUs across diverse force profiles. In this study, we developed an isometric task that allowed stable MU recordings, in a rhesus macaque, even during rapidly changing forces. Patterns of MU activity were surprisingly behavior-dependent and could be accurately described only by assuming multiple drives. Consistent with flexible descending control, microstimulation of neighboring cortical sites recruited different MUs. Furthermore, the cortical population response displayed sufficient degrees of freedom to potentially exert fine-grained control. Thus, MU activity is flexibly controlled to meet task demands, and cortex may contribute to this ability.

Temporal dynamics of the multi-omic response to endurance exercise training across tissues

Preprint

Full-text available

Oct 2022

Regular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues in Rattus norvegicus over 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex-specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of the Mef2 family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and are provided in an easily accessible public repository ( https://motrpac-data.org/ ). Highlights Multi-tissue resource identifies 35,439 analytes regulated by endurance exercise training at 5% FDR across 211 combinations of tissues and molecular platforms. Interpretation of systemic and tissue-specific molecular adaptations produced hypotheses to help describe the health benefits induced by exercise. Robust sex-specific responses to endurance exercise training are observed across multiple organs at the molecular level. Deep multi-omic profiling of six tissues defines regulatory signals for tissue adaptation to endurance exercise training. All data are available in a public repository, and processed data, analysis results, and code to reproduce major analyses are additionally available in convenient R packages.

Narrative Review of Sex Differences in Muscle Strength, Endurance, Activation, Size, Fiber Type, and Strength Training Participation Rates, Preferences, Motivations, Injuries, and Neuromuscular Adaptations

Article

Nov 2022
J STRENGTH COND RES

James L. Nuzzo

Nuzzo, JL. Narrative review of sex differences in muscle strength, endurance, activation, size, fiber type, and strength training participation rates, preferences, motivations, injuries, and neuromuscular adaptations. J Strength Cond Res 37(2): 494-536, 2023-Biological sex and its relation with exercise participation and sports performance continue to be discussed. Here, the purpose was to inform such discussions by summarizing the literature on sex differences in numerous strength training-related variables and outcomes-muscle strength and endurance, muscle mass and size, muscle fiber type, muscle twitch forces, and voluntary activation; strength training participation rates, motivations, preferences, and practices; and injuries and changes in muscle size and strength with strength training. Male subjects become notably stronger than female subjects around age 15 years. In adults, sex differences in strength are more pronounced in upper-body than lower-body muscles and in concentric than eccentric contractions. Greater male than female strength is not because of higher voluntary activation but to greater muscle mass and type II fiber areas. Men participate in strength training more frequently than women. Men are motivated more by challenge, competition, social recognition, and a desire to increase muscle size and strength. Men also have greater preference for competitive, high-intensity, and upper-body exercise. Women are motivated more by improved attractiveness, muscle "toning," and body mass management. Women have greater preference for supervised and lower-body exercise. Intrasexual competition, mate selection, and the drive for muscularity are likely fundamental causes of exercise behaviors in men and women. Men and women increase muscle size and strength after weeks of strength training, but women experience greater relative strength improvements depending on age and muscle group. Men exhibit higher strength training injury rates. No sex difference exists in strength loss and muscle soreness after muscle-damaging exercise.

Molecular Responses to Acute Exercise and Their Relevance for Adaptations in Skeletal Muscle to Exercise Training

Article

Jul 2023
PHYSIOL REV

Repeated, episodic bouts of skeletal muscle contraction undertaken frequently as structured exercise training is a potent stimulus for physiological adaptation in many organs. Specifically in skeletal muscle, remarkable plasticity is demonstrated by the remodeling of muscle structure and function in terms of muscular size, force, endurance, and contractile velocity as a result of the functional demands induced by various types of exercise training. This plasticity, and the mechanistic basis for adaptations to skeletal muscle in response to exercise training, is underpinned by activation and/or repression of molecular pathways and processes induced in response to each individual acute exercise session. These pathways include the transduction of signals arising from neuronal, mechanical, metabolic, and hormonal stimuli through complex signal transduction networks, which are linked to a myriad of effector proteins involved in the regulation of pre- and post-transcriptional processes, and protein translation and degradation processes. This review therefore describes acute exercise-induced signal transduction and the molecular responses to acute exercise in skeletal muscle including emerging concepts such as epigenetic pre- and post-transcriptional regulation, and the regulation of protein translation and degradation. A critical appraisal of methodological approaches and the current state of knowledge informs a series of recommendations offered as future directions in the field.

The molecular athlete: Exercise physiology from mechanisms to medals

Abstract and Figures

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