Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing

Abstract

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage.

Full text

1 3
Eur J Appl Physiol (2016) 116:1595–1625
DOI 10.1007/s00421-016-3411-1
INVITED REVIEW
Genetic variation and exercise‑induced muscle damage:
implications for athletic performance, injury and ageing
Philipp Baumert1 · Mark J. Lake1 · Claire E. Stewart1 · Barry Drust1 ·
Robert M. Erskine1
Received: 22 December 2015 / Accepted: 3 June 2016 / Published online: 13 June 2016
© The Author(s) 2016. This article is published with open access at Springerlink.com
particular type of exercise could help coaches/practition-
ers individualise the exercise training of their athletes/
patients, thus maximising recovery and adaptation, while
reducing overload-associated injury risk. The purpose
of this review is to provide a critical analysis of the lit-
erature concerning gene polymorphisms associated with
exercise-induced muscle damage, both in young and
older individuals, and to highlight the potential mecha-
nisms underpinning these associations, thus providing a
better understanding of exercise-induced muscle damage.
Keywords Exercise-induced muscle damage · Delayed
onset muscle soreness · Single nucleotide polymorphism ·
Creatine kinase · Elderly
Abbreviations
ACE Angiotensin-I converting enzyme
ACTN3 Gene that encodes the α-actinin-3 protein
CCL2 Chemokine (C–C motif) ligand-2
CCR2 Chemokine (C–C motif) receptor type-2
CK Creatine kinase
COL Gene that encodes the collagen protein
IGF Insulin-like growth factor
IL Interleukin
mRNA Messenger ribonucleic acid
MyoD Myogenic differentiation factor
NF-κB Nuclear factor kappa-light-chain-enhancer of
activated B cells
Pax7 Paired box protein-7
ROS Reactive oxygen species
SLC30A8 Gene that encodes the solute carrier family 30
(zinc transporter) member eight protein
SNP Single nucleotide polymorphism
TNF Tumour necrosis factor
Abstract Prolonged unaccustomed exercise involv-
ing muscle lengthening (eccentric) actions can result in
ultrastructural muscle disruption, impaired excitation–
contraction coupling, inflammation and muscle protein
degradation. This process is associated with delayed
onset muscle soreness and is referred to as exercise-
induced muscle damage. Although a certain amount
of muscle damage may be necessary for adaptation to
occur, excessive damage or inadequate recovery from
exercise-induced muscle damage can increase injury
risk, particularly in older individuals, who experience
more damage and require longer to recover from muscle
damaging exercise than younger adults. Furthermore, it
is apparent that inter-individual variation exists in the
response to exercise-induced muscle damage, and there
is evidence that genetic variability may play a key role.
Although this area of research is in its infancy, certain
gene variations, or polymorphisms have been associated
with exercise-induced muscle damage (i.e. individu-
als with certain genotypes experience greater muscle
damage, and require longer recovery, following strenu-
ous exercise). These polymorphisms include ACTN3
(R577X, rs1815739), TNF (−308 G>A, rs1800629), IL6
(−174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A,
rs680). Knowing how someone is likely to respond to a
Communicated by Nigel A. S. Taylor.
* Robert M. Erskine
r.m.erskine@ljmu.ac.uk
1 Research Institute for Sport and Exercise Sciences, Liverpool
John Moores University, Liverpool L3 3AF, UK
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1596 Eur J Appl Physiol (2016) 116:1595–1625
1 3
Introduction
People who engage in unaccustomed, strenuous physical
exercise can experience stiff or sore muscles, a feeling that
is usually apparent for 24–72 h after exercise. This phe-
nomenon is known as delayed onset muscle soreness. Sev-
eral investigations have revealed that these unaccustomed
eccentric actions, during which the muscle is lengthened
while it is active, provoke stiffer and more tender muscles
compared to concentric or isometric contractions (Arm-
strong 1984; Armstrong et al. 1991). These contractions are
strongly associated with damage to skeletal muscle consist-
ing of structural disruption of sarcomeres, disturbed excita-
tion–contraction coupling and calcium signalling, leading
to an inflammatory response and the activation of several
muscle protein degradation pathways. This process has
been referred to as exercise-induced muscle damage (Hyl-
dahl and Hubal 2014; Peake et al. 2005) and is normally
accompanied by swelling, and a temporary reduction in
both maximum strength and range of motion (Baird et al.
2012; Brown et al. 1999; Clarkson et al. 1992). Circulating
muscle-specific proteins [e.g., creatine kinase (CK), myo-
globin and α-actin] are commonly used to indicate exer-
cise-induced muscle damage (Huerta-Alardín et al. 2005;
Martinez Amat et al. 2007), whereas tenascin-C is thought
to be an indicator for disruption of the overlying connective
tissue and the extracellular matrix (Flück et al. 2003).
Exercise-induced muscle damage can be divided into
the initial damage phase, which occurs during the exercise
bout, and the secondary damage phase, which is linked
with the delayed inflammatory response (Kuipers 1994;
Howatson and Van Someren 2008). These phases are even-
tually followed by muscle remodelling (Flann et al. 2011;
Thiebaud 2012; Tidball 2005). Although there is evidence
to suggest that a certain amount of muscle damage is a
positive stimulus for muscle restructuring, hypertrophy
and strength gains (Roig et al. 2008), in rare cases, strenu-
ous unaccustomed exercise can lead to exertional rhabdo-
myolysis, which is characterised by muscle fibre necrosis
(Warren et al. 2002b). Intracellular muscle contents leak
into the circulation and extracellular fluid, which can lead
to kidney failure or even to death (Knochel 1990; Clarkson
et al. 2005b). Furthermore, the response to muscle damage
seems to be age-dependent. There is evidence to suggest
that older people are more susceptible to muscle damage
compared to young adults, which is reflected by impaired
muscle regeneration and hampered remodelling (Conceição
et al. 2012; Peake et al. 2010; Snijders et al. 2009).
From the plethora of studies that have investigated exer-
cise-induced muscle damage, it is apparent that variability
in the response to muscle damaging exercise exists between
(Vincent et al. 2010; Clarkson et al. 2005b) and within
studies (Nosaka and Clarkson 1996). Variations between
studies can occur due to different study population, age,
gender and a small sample size (Eynon et al. 2013; Toft
et al. 2002). However, intra-study variation within a
homogenous cohort warrants further consideration, with
evidence to suggest that genetic variability may play a role.
Some genes have common variations in sequence, known
as polymorphisms, which, depending on where this poly-
morphism occurs within the gene, can directly affect gene
expression and ultimately the amount of protein produced.
The most common type of sequence variation is a single
nucleotide polymorphism (SNP), where one nucleotide
substitutes another. Another type of common sequence
variation is the insertion/deletion (indel) polymorphism,
in which a specific nucleotide sequence is present (inser-
tion) or absent (deletion) from the allele. Some polymor-
phisms can modify the protein product, thus potentially
altering function. It follows, therefore, that polymorphisms
of genes encoding key proteins in the muscle–tendon unit
(such as the ACTN3 R577X SNP) have implications for the
ability to recover from strenuous exercise, thus influencing
the risk of injury. This may be particularly relevant in elite
athlete groups, who are known to have different genetic
profiles compared to the general population (Yang et al.
2003; Myerson et al. 1999). Moreover, specific gene poly-
morphisms (e.g. COL1A1 rs1800012, COL5A1 rs12722,
rs3196378, MMP3 rs679620, rs591058 and rs650108) have
been associated with tendon/ligament injury prevalence
(e.g., Achilles tendinopathy/rupture and anterior cruciate
ligament rupture) (Bell et al. 2012; Laguette et al. 2011;
Collins and Raleigh 2009). However, very little is known
about the potential genetic association with muscle damage
and muscle regeneration in response to muscle damaging
exercise, either in young or older people, or the mecha-
nisms that underpin that association.
As older people appear to be more susceptible to exer-
cise-induced muscle damage than younger adults (Jiménez-
Jiménez et al. 2008; Manfredi et al. 1991; Fielding et al.
1991; Roth et al. 2000), older people with a genetic predis-
position to greater muscle damage, may be at a greater risk
of developing muscle–tendon unit injury (Laguette et al.
2011; September et al. 2007). As a result, these individuals
may experience prolonged disuse and therefore increased
ageing-associated muscle atrophy (i.e., sarcopaenia), which
is associated with reductions in strength and quality of life.
Knowing who requires longer to recover from a bout of
strenuous exercise, may help practitioners prescribe per-
sonalised exercise medicine to their patients, thus optimis-
ing health and reducing the risk of injury and further mus-
cle wasting. One of the greatest challenges facing exercise
genetic research is the investigation of functionally relevant
genetic variation and of their mechanisms of action. The
aims of this review are to (1) provide a critical review of
the current literature on exercise-induced muscle damage
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1597Eur J Appl Physiol (2016) 116:1595–1625
1 3
and, therefore, to improve our understanding of the differ-
ent phases of the responses to muscle damaging exercise;
(2) emphasise those studies that have investigated the asso-
ciation between genetic variation and muscle damage, both
in young and older people; and (3) propose mechanistic
explanations that may underpin these associations.
Genetic variation and the initial phase
of exercise‑induced muscle damage
Exercise-induced muscle damage can result in damage
to the ultrastructure of the muscle fibre (including Z-line
streaming), to the extracellular matrix, and to overextended
sarcomeres and t-tubules of skeletal muscle tissue (Brown
et al. 1997b; Kjær 2004; Friden and Lieber 1992, 2001;
Friden et al. 1981). Structural disruption of sarcomeres is
thought to be caused by the heterogeneity of sarcomere
length (Morgan 1990) and, consequently, some sarcom-
eres resist eccentric actions more than others (Allen et al.
2005; Friden et al. 1981). Prolonged strain causes weaker
sarcomeres to be stretched beyond the optimum overlap of
actin and myosin filaments (Fig. 1). This results in popped
sarcomeres and appears as a broadening, smearing or even
disruption of the Z-lines. Interestingly, the thinnest Z-lines
are detected in the faster (type II) muscle fibres, which
generate the highest shortening velocities, and the widest
Z-lines are found in slow (type I) muscle fibres (Knoll et al.
2011). Consequently, fast-twitch fibres are more sensitive
than slow twitch fibres to Z-disk streaming (Proske and
Morgan 2001; Appell et al. 1992). This mechanical damage
is one mechanism by which a prolonged loss of strength
occurs immediately after excessive strain (Cheung et al.
2003; Hyldahl and Hubal 2014; Friden and Lieber 1992).
The transmission of muscle fibre force to the tendon
(leading to joint movement) occurs not only in the longi-
tudinal direction in line with the direction of pull of the
tendon, but also in the lateral direction (between adjacent
fibres to the overlying connective tissue and extracellular
matrix) (Kjær 2004; Hughes et al. 2015). The extracellular
matrix in skeletal muscle provides structural and biochemi-
cal support to the contractile tissue, and is associated with
the inflammatory response and satellite cell activation (see
“Skeletal muscle remodelling following exercise-induced
Fig. 1 Initial phase of exercise-induced muscle damage. Due to dif-
ferent abilities of each sarcomere to resist eccentric actions, some
of the sarcomeres will be stretched beyond the optimum overlap of
actin and myosin filaments, resulting in Z-line streaming (Morgan,
1990) (1). This is accompanied by increased permeability of the
sarcolemma (2). Extracellular Ca2+ influx into the muscle fibre acti-
vates different Ca2+-sensitive proteases (calpains). Calpain activation
leads to proteolysis of cytoskeletal and costameric proteins (Thiebaud
2012) (3). However, a failure of excitation–contraction coupling also
seems to play an important role in strength loss following strenuous
exercise, as murine muscle exposed to caffeine revealed an attenuated
loss of muscle strength (Warren et al. 1993) (4). Figure adapted from
Hyldahl and Hubal (2014)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1598 Eur J Appl Physiol (2016) 116:1595–1625
1 3
muscle damage”) (Hyldahl and Hubal 2014; Kjær 2004).
The relative proportion of different collagen subtypes in
the extracellular matrix of skeletal muscle and tendon var-
ies depending on the position and function of the connect-
ing tissues (Kjær 2004; Duance et al. 1977; Davis et al.
2013). The contractile apparatus is connected to the extra-
cellular matrix by costameres (structural complexes com-
prising proteins such as dystrophin, focal adhesion kinase
and integrins) and by intermediate filament proteins, such
as desmin (Hughes et al. 2015). According to Ramaswamy
et al. (2011), more than 80 % of muscle force is transferred
via this lateral pathway. Thus, costameres, intermediate fil-
ament proteins and the extracellular matrix are considered
essential for the integrity of skeletal muscle and the main-
tenance of lateral force transmission. Furthermore, they
are thought to play an important role in injury prevention
by stabilising the myofilaments (Lovering and De Deyne
2004; Stauber et al. 1990; Hughes et al. 2015). The degra-
dation of cytoskeletal, costameric and extracellular matrix
proteins could negatively influence the lateral transmis-
sion of force between adjacent muscle fibres, which could,
at least in part, be the source of the prolonged decrease
of maximum strength seen following strenuous exercise
(Raastad et al. 2010).
Activation of Ca2+ proteases (calpains) appears to play
an important part in the muscle damage–repair process.
Damage to the sarcolemma results in the accumulation of
excess intracellular Ca2+, which activates different calcium-
sensitive proteases, localised predominantly at the I band
and Z disk regions of myofibrils (Belcastro et al. 1998). The
activation results in proteolysis within minutes of cytoskel-
etal and costameric proteins (Thiebaud 2012; Lovering and
De Deyne 2004; Boppart et al. 2008; Zhang et al. 2008;
Allen et al. 2005), and calpain activity is still measurable
three days after exercise-induced muscle damage (Raastad
et al. 2010). This intra- and extracellular damage requires
the removal and repair of the damaged proteins, and is there-
fore followed by an inflammatory response and by activa-
tion of the ubiquitin–proteasome pathway (see “Genetic var-
iation and the secondary phase of exercise-induced muscle
damage”) (Wei et al. 2005; Tidball 2005). However, the loss
of strength after eccentric muscle contractions was reversed
by exposing murine muscle to caffeine (Balnave and Allen
1995; Warren et al. 1993). Caffeine facilitates the influx of
free intracellular Ca2+ from sarcoplasmic reticulum into the
cytosol of the muscle (Warren et al. 1993; Proske and Mor-
gan 2001). This phenomenon cannot be explained by dam-
age to the sarcomere, so it can be concluded that sarcomere
damage is not the only cause of strength loss, as impaired
ECC also appears to play a role (Cheung et al. 2003; Hyl-
dahl and Hubal 2014). Increased permeability of the sarco-
lemma, due to damaged muscle fibre structure, metabolic
disturbance, and fibre remodelling, is likely to be the main
reason for elevated plasma CK and myoglobin (Kjær 2004;
Baird et al. 2012).
A repeated bout of the same eccentric exercise causes
significantly fewer symptoms, such as a lower sensation
of pain and almost no increase in serum CK activity plus
faster recovery of muscle function (Brown et al. 1997a).
This well-established phenomenon is referred to as the
repeated bout effect and can last up to six months (Nosaka
et al. 2001). A repeated bout of strength training results
in a different expression of genes, which are involved in
pro- and anti-inflammatory responses, leading to reduced
inflammation (Gordon et al. 2012). There is also evidence
that the repeated bout effect, at least in part, is based on
restructuring of the muscle after damage (McHugh 2003).
Likewise, extracellular matrix remodelling is believed to be
associated with protection of skeletal muscle against future
damage, which is indicated by an increase in gene expres-
sion of collagen types I and III and laminin-β2 (Mackey
et al. 2011). This is thought to occur in line with muscle
remodelling of intermediate filaments and the addition of
sarcomeres in series (leading to longer fibres) (Friden et al.
1984; Armstrong 1990; Hyldahl and Hubal 2014).
Considering all of the above, candidate SNPs influenc-
ing the initial phase of contraction-induced damage are
likely to be functional SNPs of genes encoding key struc-
tural proteins within the sarcomere, the extracellular matrix
and the costameric protein complexes linking the two. The
following sections will highlight the evidence to support
this hypothesis. Table 1 summarises every candidate SNP
that has been discussed in this review.
Alpha‑actinin‑3 R577X polymorphism and the initial
phase of exercise‑induced muscle damage
Of all the polymorphisms that have been associated with
exercise-induced muscle damage, the most investigated is
the ACTN3 R577X SNP (Clarkson et al. 2005b; Deuster
et al. 2013; Pimenta et al. 2012; Seto et al. 2011; Venckunas
et al. 2012; Vincent et al. 2010) (Table 1). The protein iso-
forms, α-actinin-2 and α-actinin-3, are crucial components
of the Z-line in mammalian skeletal muscle and anchor
actin filaments to the Z-lines, cross-linking the thin fila-
ments to the adjacent sarcomeres (Mills et al. 2001; North
et al. 1999; Blanchard et al. 1989). Whilst α-actinin-2 is
ubiquitously expressed in skeletal muscle, α-actinin-3 is
only expressed in fast-twitch fibres of human skeletal mus-
cle (North and Beggs 1996; North et al. 1999). A functional
SNP (rs1815739; substitution of a C with a T nucleotide)
results in an abortive stop codon (X-allele) rather than the
expression of the amino acid arginine (R-allele) at amino
acid 577 of exon 16 on chromosome 11, resulting in an
individual being either RR, RX or XX genotype. As a con-
sequence, XX homozygotes are not able to express the
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1599Eur J Appl Physiol (2016) 116:1595–1625
1 3
Table 1 Gene polymorphisms associated with exercise-induced muscle damage
Gene polymorphism Subjects Exercise performed ‘Protective’ allele References
ACE (I/D) (rs4646994) Moderately active young men and women 50 unilateral eccentric elbow flexion contractions D Yamin et al. (2007)
Physically active young men and women Step up exercise for 5 min followed by 15 knee
bends with a backpack weighted at 30 % of their
body weight
– Heled et al. 2007
ACTN3 R577X (rs1815739) Untrained healthy young men and women 50 unilateral eccentric elbow flexion contractions – Clarkson et al. (2005b)
Untrained healthy young men 4 series of 20 bilateral maximal eccentric knee
extensions
R Vincent et al. (2010)
Wild type and Actn3 knockout mice Eccentric contractions on isolated extensor digito-
rum longus muscles at 30 % stretch
R Seto et al. (2011)
Professional male soccer athletes Plyometric leg exercise R Pimenta et al. (2012)
Moderately active young men Two bouts of 50 drop jumps separated by two weeks X Venckunas et al. (2012)
Male and female patients Retrospective cohort study for risk of exertional
rhabdomyolysis
R Deuster et al. (2013)
Female athletes Retrospective cohort study for risk of muscle injury X Iwao-Koizumi et al. (2014)
CCL2 −3441(C>T) (rs3917878) Untrained healthy young males and females 50 unilateral eccentric elbow flexion contractions C Hubal et al. (2010)
CCL2 −289 (G>C) (rs2857656) Elite soccer players Retrospective cohort study for risk of non-contact
musculoskeletal soft tissue injuries
C Pruna et al. (2013)
CCR2 −941(A>C) (rs3918358) Healthy untrained men and women 50 unilateral eccentric elbow flexion contractions A Hubal et al. (2010)
CCR2 4439 (T>C) (rs1799865) Healthy untrained men and women 50 unilateral eccentric elbow flexion contractions T Hubal et al. (2010)
CKM Ncol (A>G) (rs1803285) Moderately active young men and women Step up exercise for 5 min followed by 15 knee
bends with a backpack weighted at 30 % of their
body weight
G Heled et al. (2007)
Moderately active young men and women 50 unilateral eccentric elbow flexion contractions – Yamin et al. (2010)
Healthy men and women of different ages 4–21 km running race – Miranda-Vilela et al. (2012)
Male and female patients Retrospective cohort study for risk of exertional
rhabdomyolysis
A Deuster et al. (2013)
IGF2 13790 (C>G) (rs3213221) Healthy untrained men and women 50 unilateral eccentric elbow flexion contractions C Devaney et al. (2007)
IGF2 17200 (G>A) (rs680) Healthy untrained men and women 50 unilateral eccentric elbow flexion contractions G Devaney et al. (2007)
IGF2AS 1364 (A>C) (rs4244808) Healthy untrained men and women 50 unilateral eccentric elbow flexion contractions C Devaney et al. (2007)
IGF2AS 11711 (G>T) (rs7924316) Healthy untrained men and women 50 unilateral eccentric elbow flexion contractions G Devaney et al. (2007)
IL1B −3737 (C>T) (rs4848306) Healthy untrained men 3 sets of 8 contractions at 80 % of the subject’s
maximal voluntary contraction followed by a 4th
set to voluntary failure for leg press, leg curl, and
leg extension, respectively
C Dennis et al. (2004)
IL1B −511 (C>T) (rs16944) Healthy untrained men 3 sets of 8 contractions at 80 % of the subject’s
maximal voluntary contraction followed by a 4th
set to voluntary failure for leg press, leg curl, and
leg extension, respectively
– Dennis et al. (2004)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1600 Eur J Appl Physiol (2016) 116:1595–1625
1 3
Table 1 continued
Gene polymorphism Subjects Exercise performed ‘Protective’ allele References
(Non-) professional athletes versus control Cross-sectional study – Cauci et al. (2010)
IL1B 3954 (C>T) (rs1143634) Healthy untrained men 3 sets of 8 contractions at 80 % of the subject’s
maximal voluntary contraction followed by a 4th
set to voluntary failure for leg press, leg curl, and
leg extension, respectively
T Dennis et al. (2004)
(Non-) Professional athletes versus control Cross-sectional study – Cauci et al. (2010)
IL6 −174 (G>C) (rs1800795) Moderately active young men and women 50 unilateral eccentric elbow flexion contractions G Yamin et al. (2008)
Male and female patients Retrospective cohort study for risk of exertional
rhabdomyolysis
– Deuster et al. (2013)
Older obese women 7 sets of 10 bilateral eccentric knee extensions with
a load corresponding to 110 % of 10-repetition
maximum.
C Funghetto et al. (2013)
INS 1045 (C>G) (rs3842748) Healthy untrained men and women 50 unilateral eccentric elbow flexion contractions C Devaney et al. (2007)
MLCK 49 (C>T) (rs2700352) Untrained healthy young men and women 50 unilateral eccentric elbow flexion contractions C Clarkson et al. (2005b)
MLCK 37885 (C>A) (rs28497577) Untrained healthy young men and women 50 unilateral eccentric elbow flexion contractions C Clarkson et al. (2005b)
Male and female patients Retrospective cohort study for risk of exertional
rhabdomyolysis
C Deuster et al. (2013)
OPN −66 (T>G) (rs28357094) Healthy untrained men and women 24 unilateral eccentric elbow flexion contractions T Barfield et al. (2014)
SLC30A8 (C>T) (rs13266634) Untrained healthy young men and women 50 unilateral eccentric elbow flexion contractions T Sprouse et al. (2014)
SOD2 (C>T) (rs4880) Healthy male and female volunteers of different
ages
4–21 km running race C Akimoto et al. (2010)
TNF −308 (G>A) (rs1800629) Moderately active young men and women 50 unilateral eccentric elbow flexion contractions A Yamin et al. (2008)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1601Eur J Appl Physiol (2016) 116:1595–1625
1 3
protein α-actinin-3 (MacArthur and North 2004; North
and Beggs 1996; North et al. 1999). A sub-section of the
population is XX homozygous, ranging from less than 1 %
in African Bantus to 18 % in Europeans, to 25 % in Asian
populations (Mills et al. 2001). Absence of α-actinin-3 does
not result in a disease phenotype due to compensatory up-
regulation of α-actinin-2 (North et al. 1999) but there is evi-
dence that this nonsense SNP affects physical performance
(Erskine et al. 2014; Niemi and Majamaa 2005; Clarkson
et al. 2005a; Moran et al. 2007).
The ACTN3 XX genotype has been associated with
smaller muscle volume (Erskine et al. 2014), slower base-
line sprint times (Niemi and Majamaa 2005; Moran et al.
2007), lower strength (Erskine et al. 2014; Clarkson et al.
2005a), and lower muscle power (Clarkson et al. 2005a;
Seto et al. 2011; Walsh et al. 2008; Moran et al. 2007;
Erskine et al. 2014). These findings are supported by Actn3
knock-out mouse models, demonstrating a shift in the
properties of fast muscle fibres towards a more oxidative
fast fibre profile, lower muscle strength, reduced mass and
decreased diameter of IIb fibres (Chan et al. 2011; MacAr-
thur et al. 2007, 2008). Strong evidence has been presented
that, as a consequence of the up-regulation of α-actinin-2 in
XX homozygotes, more calsarcin-2 is bound to α-actinin-2
and less to calcineurin (Seto et al. 2013). The binding affin-
ity of calsarcin-2, which functions as an inhibitor of cal-
cineurin activation, is greater for α-actinin-2 compared to
α-actinin-3. Consequently, a higher level of free calcineu-
rin is able to activate the downstream signalling of the
slow myogenic programme. Given the larger size, higher
force and power generating capacity, and lower fatigue
resistance of type II fibres compared to type I fibres (Bot-
tinelli et al. 1996), the evidence presented by Seto et al.
(2013) provides a mechanistic explanation for the associa-
tions between ACTN3 genotype and muscle size, strength,
power, and endurance phenotypes.
Recent investigations have suggested that α-actinin-3
may be evolutionarily optimised for the minimization of
muscle damage (Yang et al. 2003). The majority of the
human studies support the hypothesis that XX homozy-
gotes are more susceptible to strenuous exercise com-
pared to their RR or RX counterparts (Pimenta et al. 2012;
Vincent et al. 2010; Deuster et al. 2013). For instance,
ACTN3 XX homozygotes are approximately three times
more likely to develop exertional rhabdomyolysis com-
pared to people of RR or RX genotypes (Deuster et al.
2013). However, other studies have revealed no differences
between ACTN3 genotypes regarding markers of muscle
damage (Clarkson et al. 2005b), or have shown contrary
effects post-exercise (Venckunas et al. 2012) or in muscle
injury risk (Iwao-Koizumi et al. 2014). The cross-sectional
study of Clarkson et al. (2005b) revealed no differences in
strength loss but a lower baseline CK activity in the blood
in ACTN3 XX homozygotes compared to carriers of the
ACTN3 R-allele. These baseline differences in CK activity
may have been due to ACTN3 genotype-dependent differ-
ences in muscle mass (i.e., smaller muscle volume in XX
homozygotes versus R-allele carriers) (Erskine et al. 2014).
Movements with repeated stretch–shortening cycles,
eccentric followed by immediate concentric muscle con-
traction) (Venckunas et al. 2012) seem to have a different
demand profile for the muscle–tendon unit compared to
purely eccentric actions (Fig. 2) (Seto et al. 2011; Vincent
et al. 2010). Due to the fact that α-actinin is linked to both
the longitudinal and lateral transmission of force (Hughes
et al. 2015; Yang and Xu 2012), we propose that α-actinin-3
deficiency (XX genotype) with a more elastic Z-line (Broos
et al. 2012) might result in benefits to stretch–shortening
cycle movements compared to R-allele carriers. Although
stretch–shortening cycle includes an eccentric element,
contrary to the type of maximal eccentric contractions typi-
cally used in exercise-induced muscle damage studies, the
force and the eccentric phase involved in the active braking
phase of stretch–shortening cycles are generally fast and
of short duration (Nicol et al. 2006). Interestingly, muscle
activation decreases with increasing velocity in the eccen-
tric phase under the stretch–shortening cycle conditions
(Benoit and Dowling 2006), which indicates that other
non-contractile (elastic) structures, such as the extracellu-
lar matrix/tendon, might provide important contribution to
the power output by storing energy (Kjær 2004; Yang and
Xu 2012). Indeed, a highly compliant elastic musculoten-
dinous system is thought to elevate the use of elastic strain
energy in stretch–shortening cycle movements (Wilson
et al. 1991). Thus, individually performed eccentric actions
with greater longitudinal force transmission might damage
the link between the contractile structure and the Z-line,
which might activate the calpain system to a greater extent.
The transmission of muscle fibre force to the ten-
don may occur faster by the stiffer Z-line including
α-actinin-3 in the longitudinal direction (Hughes et al.
2015; Broos et al. 2012) and, also, might reduce muscle
damage in eccentric actions performed without a stretch–
shortening cycle compared to the α-actinin-3 deficient
fibres (Seto et al. 2011; Vincent et al. 2010). Head et al.
(2015) revealed a significantly increased sarcoplasmic
reticulum Ca2+ pumping and leakage in ACTN3 XX
homozygotes, which was probably due to a higher expres-
sion of the specific Ca2+ channel sarco(endo)plasmic
reticulum calcium-adenosine-triphosphatase-1 gene, and
of the Ca2+ binding proteins, calsequestrin and sarcalu-
menin, in the sarcoplasmic reticulum (Head et al. 2015).
Increased dynamics with elevated intracellular Ca2+ lev-
els during and after exertional muscle damage may lead
to increased cytoskeletal damage and membrane disrup-
tion (Zhang et al. 2008; Head et al. 2015; Quinlan et al.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1602 Eur J Appl Physiol (2016) 116:1595–1625
1 3
2010). Muscle damage induced by exclusively performed
eccentric actions might lead to increased desmin deg-
radation (Yu 2013), which results in fewer connections
with the extracellular matrix and adjacent myofibrils,
and could be an explanation for the higher susceptibil-
ity of XX homozygotes in this mode of exercise. Taken
together, the different effect of the ACTN3 R577X SNP
in diverse mode of exercises could explain the fact that
studies show mixed results. This may be why there are
differences in ACTN3 genotype frequency in short and
long distance athletes of stretch–shortening cycle-related
sports (e.g., running) (Yang et al. 2003), whereas both
short and long distance athletes in power sports, com-
monly carried out without stretch–shortening cycles
(e.g., swimming), show no difference in genotype/allele
frequency distribution (Ben-Zaken et al. 2015). This
demonstrates why future studies should not only distin-
guish between power and endurance athletes, but should
focus on sport-specific movements when investigating
the association with genetic variation.
Fig. 2 Proposed changes in sarcomere structure during stretch–
shortening cycle movements and purely eccentric actions, focus-
sing on α-actinin (highlighted in red and underlined). The left-hand
side shows the sarcomere longitudinally in a quasi-3D model at
rest, and the α-actinin elongation during purely eccentric actions,
and stretch–shortening cycle movements (1). The right-hand side
illustrates the sarcomere cross-section at the level of the Z-line (2).
At rest, α-actinin is set to roughly 90° between the antiparallel actin
filaments, while under active tension, the space between the antipar-
allel actin filaments increases and α-actinin is stretched to a basket-
weave lattice (Gautel 2011). Alpha-actinin is thought to play a key
role in the longitudinal (via the anchoring of actin filaments to the
Z-line) and lateral (via costamere fibre-to-fibre interaction) transmis-
sion of muscle fibre force (Hughes et al. 2015; Yang and Xu 2012).
Moreover, human type II muscle fibres from ACTN3 XX homozy-
gotes (where α-actinin-3 deficiency is compensated by the presence
of α-actinin-2) are less stiff than type II muscle fibres from ACTN3
R-allele carriers (Broos et al. 2012). Thus, it is likely that α-actinin-2
is able to store more energy than α-actinin-3 during the active stretch
phase of the stretch–shortening cycle, which is released during the
shortening phase (Kjær 2004; Yang and Xu 2012). We propose that
stretch–shortening cycle movements increase the actin filament spac-
ing to a greater extent compared to purely eccentric actions, thus
elongating α-actinin to become almost completely straight at peak
eccentric force. Individuals with α-actinin-3 deficiency (ACTN3 XX
homozygotes) might, therefore, benefit from having a more elas-
tic Z-line during stretch–shortening cycle movements compared to
R-allele carriers (Broos et al. 2012), resulting in a reduced damage
response to stretch–shortening movements (Venckunas et al. 2012).
Figure adapted from Gautel (2011) (color figure online)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1603Eur J Appl Physiol (2016) 116:1595–1625
1 3
Myosin light chain kinase polymorphisms and the
initial phase of exercise‑induced muscle damage
Every myosin head is connected with two light chains on
the long lever arm, which are known as the essential and
the regulatory light chains. In skeletal and cardiac mus-
cles of mammals, troponin and tropomyosin have the role
of triggering the contraction following the increase in free
cytosolic Ca2+, while the regulatory light chain modulates
Ca2+ activation (Sweeney et al. 1993; Cheung et al. 2003;
Lossie et al. 2014). Repeated Ca2+ influx due to muscu-
lar contraction activates myosin light chain kinase, and
this enzyme phosphorylates the regulatory light chains. It
has been shown that regulatory light chain phosphoryla-
tion results in increased Ca2+ sensitivity (Szczesna et al.
2002), which increases the rate of force development pre-
dominantly in type II muscle fibres (Childers and McDon-
ald 2004). This might be the result of an increased number
of force-generating cross-bridges. However, the increased
force output by light chain phosphorylation might also
result in elevated muscle damage, which has been shown in
skinned fast-twitch fibres (Childers and McDonald 2004).
Two different SNPs of the myosin light chain
kinase gene [49 (C>T) (rs2700352) and 37885 (C>A)
(rs28497577)] have been investigated concerning exercise-
induced muscle damage (Clarkson et al. 2005b). T-allele
carriers of the 49 (C>T) SNP have shown increased base-
line strength in comparison to CC carriers but TT homozy-
gotes revealed increased circulatory levels of the muscle
damage biomarkers (CK and myoglobin) following eccen-
tric exercise. Furthermore, A-allele carriers of the 37885
(C>A) SNP have revealed greater muscle strength loss and
increased plasma CK following strenuous exercise. This
is in line with the findings of Deuster et al. (2013), who
showed that exertional rhabdomyolysis cases are about five
times more likely for the A-allele of the 37885 (C>A) SNP
of the myosin light chain kinase gene compared to carri-
ers of the C-allele. The mechanisms, however, are unclear.
Clarkson et al. (2005b) suggested that these SNPs may
alter regulatory light chain phosphorylation, thus leading to
higher muscle strain and subsequently greater muscle dam-
age following strenuous exercise.
Muscle‑specific creatine kinase polymorphisms and the
initial phase of exercise‑induced muscle damage
The creatine kinase enzyme is expressed in the cytosol
and mitochondria of tissues with high energy consump-
tion (e.g., skeletal muscle fibres). The cytosolic enzyme is
composed of the two subunits muscle type (M) and brain
type (B), which provide three different combination pos-
sibilities: CK-BB (predominantly in brain), CK-MB (in
cardiac muscle) and CK-MM (in skeletal muscle). Skeletal
muscle-specific CK is bound to the M-line structure and to
the sarcoplasmic reticulum of myofibrils (Wallimann et al.
1992; Brancaccio et al. 2007). In healthy individuals, most
serum CK consists of skeletal muscle CK (Brancaccio et al.
2007). Creatine kinase can leak from muscle fibres into the
circulation following the mechanical tearing of the sarco-
lemma and opening of stretch-activated channels following
contraction-induced damage, although the exact mecha-
nism is still unclear (Allen et al. 2005).
The skeletal muscle CK-encoding gene is located at the
19q13.2–13.3 region of the chromosome 19 (Nigro et al.
1987). The Ncol (A>G) SNP (rs1803285) of the mus-
cle creatine kinase gene, is mapped to the 3′ untranslated
region, which means it could affect the localization, trans-
lation efficiency and stability of the mRNA, which might
mediate the location and function of the protein (Wilson
et al. 1995). Interestingly, the genes for the ryanodine
receptor 1 (Robinson et al. 2006) and myotonic dystrophy
protein kinase (Brunner et al. 1989), which are associated
with muscle function and specific myopathies, are mapped
to the same area of chromosome 19. According to Deuster
et al. (2013), Ncol GG homozygotes are present in 28.1 %
of African Americans, in 14.2 % of Caucasians, 0 % of His-
panic and 8.3 % of Asian individuals. Investigations of the
Ncol SNP of the muscle creatine kinase gene have revealed
different outcomes. In the study of Deuster et al. (2013),
GG homozygotes were reportedly 3.1 times more likely to
experience exertional rhabdomyolysis than carriers of the
A-allele. However, Heled et al. (2007) revealed that NcoI
AA homozygotes had a sixfold higher risk of being a high
responder of circulating CK to eccentric exercise than GG
or AG genotypes. Other studies do not support a role for the
Ncol SNP of the muscle creatine kinase gene in explain-
ing the CK variability between individuals (Miranda-Vilela
et al. 2012; Yamin et al. 2010). However, the mechanism
remains poorly understood and is confounded by the dif-
ferent methodological designs implemented by researchers.
Furthermore, Heled et al. (2007) and Yamin et al. (2010)
have only investigated CK response as a marker for muscle
damage. Further studies with several other muscle damage
markers such as muscle strength loss and soreness could
provide a better physiological/systems-based understand-
ing of the influence of this NcoI SNP on exertional muscle
damage. An additional restriction fragment length polymor-
phism, the TaqI SNP of the muscle creatine kinase gene,
has been shown to be in strong linkage disequilibrium with
the NcoI SNP (Miranda-Vilela et al. 2012). The TaqI 1-2
genotype has indicated a lower risk for inflammation after a
track event between 4 and 21 km, whereby the participants
could choose their preferential distance. However, no fur-
ther studies have been undertaken towards understanding a
potential role for this SNP in association with muscle dam-
age. It is possible that these SNPs change the half-life of
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1604 Eur J Appl Physiol (2016) 116:1595–1625
1 3
the CK enzyme and the intracellular concentration of CK
(Heled et al. 2007). Elevated intracellular CK concentration
might increase calpain activation, thus resulting in greater
protein degradation.
Genetic variation and the secondary phase
of exercise‑induced muscle damage
The secondary phase of muscle damage is a complex event
that has been linked to inflammation (Schoenfeld 2010),
where leucocytes infiltrate muscles with damaged fibres
and remain there for days or even weeks (Tidball 2005).
Although the results of published studies are inconsistent
(Schneider and Tiidus 2007), in vitro (Kanda et al. 2013;
Suzuki and Ford 1999) and in vivo studies (Paulsen et al.
2010) support a role for neutrophils in muscle damage. It
is assumed that neutrophils (Suzuki et al. 1996) migrate to
the region of injury in the early stage of muscle damage
(Fig. 3). Neutrophils contribute to the degradation of dam-
aged muscle tissue by producing reactive oxygen species
(ROS), which are reported to attract macrophages to the
area of trauma (McGinley et al. 2009; Nguyen and Tidball
2003).
Reactive oxygen species can directly and indirectly mod-
ulate muscle damage through several mechanisms (Toumi
et al. 2006). A potential mechanism to link oxidative stress
with calpain-mediated proteases is via ROS decreasing
plasma membrane Ca2+-adenosine-triphosphatase activity
(Siems et al. 2003), which might encourage Ca2+ accumu-
lation within the cell (Powers and Jackson 2008). Although
ROS is toxic, it may also play an important role as a sec-
ondary messenger in cell signalling and in the regulation
of gene expression resulting in ROS-mediated adaptation to
exercise (Schoenfeld 2012; Hornberger et al. 2003; Crane
et al. 2013).
In contrast to neutrophils, there is strong evidence that
macrophages and monocytes infiltrate the endomysium and
especially the perimysium of the injured area of the mus-
cle (Hubal et al. 2008; Paulsen et al. 2010). Macrophages
replace neutrophils within 24 h and remain present for up
to 14 days after exercise (Malm et al. 2000). During the
early stages of muscle damage, there is an increase of M1
macrophages (which express CD68 surface marker but not
CD163), supporting the removal of cellular debris by pro-
ducing cytotoxic levels of nitric oxide. This is followed by
a shift from M1 to M2 macrophages (CD68−/CD163+),
which promote the activation of satellite cells and the
Fig. 3 The secondary phase of muscle damage. Leucocytes infiltrate
the site of myotrauma (Tidball 2005). Firstly, neutrophils migrate to
damaged muscle fibres and produce reactive oxygen species (ROS)
to degrade cellular debris (Suzuki et al. 1996) (1). Neutrophils are
substituted by macrophages within 24 h (Malm et al. 2000), with M1
macrophages removing cellular debris by producing cytotoxic levels
of nitric oxide (NO) (2). In the latter stage of muscle damage, a shift
from M1 to M2 macrophages is associated with the activation of sat-
ellite cells and the subsequent regeneration of muscle fibres (Tidball
2011) (3). Neutrophils and macrophages also express tumour necro-
sis factor (TNF), which activates the ubiquitin–proteasome pathway
(Tidball and Villalta 2010) (4). This pathway regulates proteolysis by
attaching ubiquitin polymers (Ub) to cellular debris via three different
types of enzymes (E1–E3 ligases). As a result, these ubiquitin-marked
proteins will be degraded by the 26S-proteasome complex (Reid
2005)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1605Eur J Appl Physiol (2016) 116:1595–1625
1 3
subsequent regeneration of muscle fibres (see “Skeletal
muscle remodelling following exercise-induced muscle
damage”) (Mahoney et al. 2008; Kanda et al. 2013; Tidball
and Villalta 2010; Philippou et al. 2012; Zanou and Gailly
2013).
Leucocyte accumulation and the following remodelling
appear to be gradual processes regulated by the extent of
damage (Paulsen et al. 2010, 2012). In an extreme case
of muscle damage, remodelling may become maladaptive
characterised by necrosis, incomplete healing, and fibrotic
scar tissue formation (Butterfield 2010). Cytokines play
particularly well-characterised roles in an orchestrated
regulated fashion of the activation and modulation of the
inflammatory response (Paulsen et al. 2012). Recent inves-
tigations revealed that some cytokines are also expressed
by skeletal muscle, and are therefore named myokines
(Pedersen et al. 2003). The role of cytokines in the phase
of inflammation following exercise-induced muscle dam-
age is explained in the comprehensive review of Paulsen
et al. (2012). Cytokines are classified as (1) pro-inflam-
matory cytokines [promoting inflammation, e.g. inter-
leukin (IL)-1α, IL-1β and tumour necrosis factor (TNF)];
(2) anti-inflammatory cytokines (inhibiting inflammation,
e.g. IL-10, IL-4 and IL-13) and chemokines (abbreviated
from chemotactic cytokines), which attract leucocytes and
other cells to migrate from the blood to the region of injury
[e.g., chemokine (C–C motif) ligand 2 (CCL2)] (Paulsen
et al. 2012; Peake et al. 2005; Suzuki et al. 2002). Muscle
cytokine expression after strenuous exercise is predomi-
nantly pro-inflammatory (Peake et al. 2005).
In addition, some cytokines such as IL-6 can act either
as a pro- or an anti-inflammatory agent, depending on the
environment (Pedersen and Febbraio 2008). The majority
of cytokines are released from several cell types including
muscle fibres, fibroblasts, neutrophils, and macrophages,
and the expression of cytokines is determined by the mode,
intensity and duration of exercise (Peake et al. 2015). Fur-
thermore, the action patterns of some of these cytokines
change during the inflammatory response. These find-
ings make it difficult to identify the specific roles of each
cytokine after exercise-induced muscle damage (Smith
et al. 2008). However, the invading neutrophils and mac-
rophages express TNF at the early phase of inflammatory
response (Philippou et al. 2012; Tidball and Villalta 2010;
Warren et al. 2002a). Tumour necrosis factor is able to acti-
vate the ubiquitin–proteasome pathway, which is one of the
main mechanisms for the cellular protein degradation in
eukaryotic cells (Murton et al. 2008; Li et al. 2005). The
ubiquitin–proteasome pathway regulates proteolysis by
attaching ubiquitin polymers to damaged proteins via three
distinct types of enzymes (known as E1–E3 ligases). Sub-
sequently, the 26S-proteasome complex degrades the ubiq-
uitin-marked protein (Reid 2005). Tumour necrosis factor
increases the gene expression of the E3 ligases, muscle ring
finger 1 (MuRF1) and muscle atrophy F-box (MAFbx; also
referred to as Atrogin1) (Li et al. 2003, 2005; Murton et al.
2008; Bodine et al. 2001). Thus, it is thought that TNF is an
important factor in the instigation of the remodelling pro-
cess after exertional muscle damage (Murton et al. 2008).
There is evidence to suggest that muscles of older indi-
viduals exhibit higher levels of damage following strenu-
ous exercise than of younger individuals (Jiménez-Jiménez
et al. 2008; Manfredi et al. 1991; Fielding et al. 1991;
Roth et al. 2000). Biopsies from the vastus lateralis muscle
revealed greater muscle damage in older men in compari-
son to younger subjects immediately after eccentric exer-
cise (Manfredi et al. 1991; Roth et al. 2000). Furthermore,
older women demonstrated a threefold greater percentage
reduction in strength 24 h after unaccustomed eccentric
exercise than younger women (Roth et al. 2000). In addi-
tion, the recovery time to baseline strength was prolonged
(up to 7 days) compared with the young sedentary sub-
jects (4 days) (Ploutz-Snyder et al. 2001). Other studies
support the finding that the secondary phase of exercise-
induced muscle damage appears to differ between older
and younger adults (Thalacker-Mercer et al. 2010; Jimé-
nez-Jiménez et al. 2008). On closer examination, neutro-
phil (Cannon et al. 1994) and both M1 and M2 macrophage
(Przybyla et al. 2006; Hamada et al. 2005) recruitment is
impaired in muscle from older individuals in the second-
ary phase of muscle damage following strenuous exer-
cise. The increase in plasma IL-6 concentration following
eccentric exercise also tends to be blunted in older versus
younger adults (Toft et al. 2002; Conceição et al. 2012).
This is further supported by findings of blunted increases
in muscle TNF and transforming growth factor-β1 (TGF-
β1) and larger increase of IL-1β messenger ribonucleic
acid (mRNA) expression within older muscle after eccen-
tric exercise (Przybyla et al. 2006; Hamada et al. 2005).
These findings could simply be due to the difficulty in rais-
ing levels pro-inflammatory cytokine levels over and above
the chronically elevated levels found in older people (see
“Skeletal muscle remodelling following exercise-induced
muscle damage”). Alternatively, as macrophages are the
major source of TNF and TGF-β1 within the muscle fol-
lowing exercise-induced muscle damage (Tidball 2011;
Fadok et al. 1998), it is possible that lower macrophage
recruitment in older individuals would lead to lower TNF
and TGF-β1 expression and production (Hamada et al.
2005). Unaccustomed high-intensity resistance exercise
(sufficient to cause moderate muscle damage) has been
shown to induce greater nuclear factor kappa-light-chain-
enhancer of activated B (NF-κB) and heat shock protein
70 protein expression in older versus younger human
adult muscle (Thalacker-Mercer et al. 2010). Nuclear fac-
tor kappa-light-chain-enhancer of activated B is activated
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1606 Eur J Appl Physiol (2016) 116:1595–1625
1 3
by pathways associated with muscle protein degradation
(Roubenoff et al. 2003): its activation up-regulates the
expression of muscle-specific ubiquitin ligases MAFbx and
MuRF1 (Gumucio and Mendias 2013; Patel et al. 2014).
Heat shock proteins mediate the correct folding of dena-
tured proteins which would explain the increased expres-
sion of heat shock protein 70 in accordance with increased
NF-κB activation following muscle damage (Thalacker-
Mercer et al. 2010; Morton et al. 2009) (see “Genetic vari-
ation and the initial phase of exercise-induced muscle dam-
age”). Given these compelling studies, the question arises
as to whether cytokine SNPs also play a role in muscle
damage induction or repair or both.
Interleukin‑1 polymorphisms and the secondary phase
of exercise‑induced muscle damage
The interleukin-1 (IL1) family of cytokine genes is located
together on chromosome 2, and includes IL-1α (IL1A),
IL-1β (IL1B) and IL-1 receptor antagonist (IL-1Ra; IL1RN)
(Dennis et al. 2004). Interleukin-1α and IL-1β are agonists
of the IL-1 receptor type I (IL-1R1) and promote inflam-
mation. In general, IL-1β acts synergistically with TNF
and induces the expression of several other pro-inflamma-
tory genes (Dinarello 2009). Following eccentric exercise
in humans, systemic levels of IL-1β increase marginally
(Peake et al. 2005), but there is an increase of local IL-1β
levels within skeletal muscle up to five days post exer-
cise (Fielding et al. 1993). In contrast, IL-1Ra acts as an
antagonist of IL-1R1, preventing the binding of IL-1α and
IL-1β with IL-1R1, respectively. Instead of IL-1β, IL-1Ra
is highly concentrated in plasma following intense physi-
cal exercise (Paulsen et al. 2012). In the absence of IL-1Ra,
the activity of IL-1 is unrestricted and leads to increased
inflammatory response (Dinarello 2009).
Different SNPs of the IL1B gene have been investigated
in relation to the response to exercise and exercise-induced
muscle damage: (1) at position −511 (C>T) (rs16944) in
the promoter region (di Giovine et al. 1992); (2) at posi-
tion +3954 (C>T) (rs1143634) in exon 5 (TaqI restriction
site polymorphism) (Bioque et al. 1995); and (3) at position
−3737 (C>T) (Dennis et al. 2004; Vangsted et al. 2011).
Dennis et al. (2004) investigated the associations of selected
IL1 SNPs with the inflammatory response following a sin-
gle bout of resistance exercise. Twenty-four sedentary Cau-
casian males were recruited based on specific clusters of
IL1 SNPs (haplotypes) (+4845 IL1A, +3954 IL1B, −511
IL1B, and −3737 IL1B polymorphisms). Only participants
with the IL1B C/C (+3954) or with the T/T (−3737) geno-
type showed an increased inflammatory response (changes
in inflammatory associated cytokines and M1 macrophages
number) in skeletal muscle. However, the concentration of
macrophages did not change. This leads to the assumption
that the cytokine release by each macrophage is elevated or
local production by the skeletal muscle itself is increased.
Individuals with the above-mentioned genotypes, who also
carried the C-allele of the IL1RN +2018 (T>C) SNP, dem-
onstrated a further increase of inflammatory response fol-
lowing resistance exercise.
Cauci et al. (2010) found that the IL1B +3954 (C>T)
SNP, together with the −511 (C>T), have no influence on
athletic phenotype, which is in accordance with the findings
that neither plasma IL-1β nor IL1B mRNA is influenced by
physical activity (Petersen and Pedersen 2005; Mahoney
et al. 2008). In addition, a multi-allelic insertion polymor-
phism in intron 2 of the IL-1RN gene (rs380092) contains a
variable number tandem repeat of an 86-bp length of DNA
(Mansfield et al. 1994). Allele 2 (two repeats of the 86 bp
region) of the IL1RN intron 2 variable number tandem
repeat was significantly more frequent in athletes compared
to non-athletes. In addition, there was a higher frequency
distribution of the 1/2 (allele 1 with four repeats and allele
2 with two repeats of the 86 bp region) genotype variable
number tandem repeat IL1RN in high-grade professional
athletes than in non-professional athletes. In contrast, the
frequency of IL1RN allele 2 homozygotes did not differ
between athletes and non-athletes. Unfortunately, this study
has only distinguished between professional (high-grade),
non-professional (medium-grade) athletes, and non-ath-
letes. Athlete status was not discriminated within the differ-
ent types of sport, which is necessary, as different mode of
exercises require different physical traits. However, in vitro
investigations showed that the IL1RN allele 2 has been
associated with a lower expression of IL-1Ra (Dewberry
et al. 2000), but increased production of the pro-inflam-
matory cytokine IL-1β (Santtila et al. 1998). Cauci et al.
(2010) suggested that carriers of IL1RN allele-2 displayed a
moderate increase of IL-1-dependent inflammation, which
results in benefits to athletic performance. IL1RN allele 2
might support the removal of cellular debris, promoting a
faster recovery. However, IL1RN allele 2 homozygotes may
lead to a sharp increase of inflammation, which negatively
influences the recovery or remodelling. Further investiga-
tion is necessary to confirm these findings.
Tumour necrosis factor −308 G>A polymorphism
and the secondary phase of exercise‑induced muscle
damage
Tumour necrosis factor (formerly known as tumour necro-
sis factor-α) is a pro-inflammatory cytokine with short half-
life and low circulating levels (Reid and Li 2001; Pedersen
2011) and is associated with the occurrence of metabolic
disorders (Borst 2004). Plomgaard et al. (2005) have shown
that TNF infusion in healthy individuals alters insulin sig-
nalling transduction and subsequently induces insulin
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1607Eur J Appl Physiol (2016) 116:1595–1625
1 3
resistance in skeletal muscle. Like IL-1β, systemic TNF
concentration does not change or is only slightly increased
after intense exercise (Peake et al. 2015). However, local
expression of TNF within the skeletal muscle is signifi-
cantly elevated after exercise (Peake et al. 2015). Tumour
necrosis factor is associated with up-regulation of catabolic
pathways and suppression of protein synthesis in skeletal
muscle (Ling et al. 1997), mediated by NF-κB, which
stimulates the ubiquitin–proteasome pathway (Reid and Li
2001). This is in line with Tiainen et al. (2012), who have
shown that high plasma levels of TNF are associated with
reduced physical performance in men. Furthermore, intra-
venous infusion of TNF in rats led to a significant drop in
systemic IGF-I and IGF-binding proteins 3 levels, suggest-
ing a negative influence of TNF on the IGF system (Llo-
vera et al. 1998).
The minor A-allele of the rare TNF −308 (rs1800629)
SNP is associated with increased plasma TNF concentra-
tion (Karimi et al. 2009) and with impaired improvement
of physical performance in older women following physi-
cal activity (Pereira et al. 2013). Presumably, the A-allele is
a stronger activator of TNF transcription than the G-allele
(Wilson et al. 1997). To the best of our knowledge, only
one study has investigated an association between the
TNF −308 (G>A) SNP and its association with exercise-
induced muscle damage. Interestingly, carriers of the
A-allele showed a non-significant (P = 0.06) blunting of
elevated plasma CK following eccentric exercise (Yamin
2009; Yamin et al. 2008). However, no AA homozygotes
were included in this investigation. The TNF −308 A-allele
was associated with higher plasma TNF concentration
and impaired improvements in physical fitness follow-
ing chronic exercise in older populations, while in young,
healthy individuals, A-allele carriers demonstrated blunted
CK activity in the blood after eccentric exercise. However,
CK activity was measured at the peak activity 96 h post-
exercise in Yamin et al. (2008). The blunted CK activ-
ity of TNF −308 A-allele carriers in the study by Yamin
et al. (2008) might not be attributed to the muscle damage
itself but may be caused by attenuated remodelling, such
as myoblast fusion which is accompanied by CK activ-
ity (Zalin 1972). Due to the fact that membrane damage
might be repaired in a short time (Bansal et al. 2003), other
mechanisms should be considered for the prolonged leak-
age of CK. Elevated TNF attenuates myoblast fusion and
differentiation which might impair the regeneration of the
muscle (Stewart et al. 2004). Subsequently, carriers of the
TNF −308 A-allele might have a higher susceptibility to
muscle atrophy and sarcopenia due to the impaired ability
of muscle remodelling. However, Lappalainen (2009) has
indicated some technical limitations of the assay which
might have influenced the data interpretation of Yamin
et al. (2008). Further studies are needed, which investigate
a potential association between the TNF −308 SNP and
other muscle damage markers.
Interleukin‑6 −174 G>C polymorphism and the
secondary phase of exercise‑induced muscle damage
Interleukin-6 (IL-6) modulates the release of differ-
ent cytokines, such as of TNF and IL-1Ra (Steensberg
et al. 2003; Starkie et al. 2003). The human IL6 gene is
mapped to chromosome 7p21–24 with a 303 bp upstream
promoter (Fishman et al. 1998). Interleukin-6 plasma
concentration is affected by exercise duration and inten-
sity (Fischer et al. 2004), and the amount of muscle
mass involved (Ostrowski et al. 2000), particularly dur-
ing weight-bearing exercise (Catoire and Kersten 2015).
Eccentric exercise induces a delayed peak and a slower
decrease of plasma IL-6 after exercise in comparison to
other modes of exercise, such as running (Fischer 2006;
Pedersen and Fischer 2007). According to McKay et al.
(2009), IL-6 may play a role as an important signalling
molecule associated with satellite cell proliferation after
strenuous exercise. Furthermore, damaged extracellular
matrix might have an effect on IL-6 expression, as IL-6
is involved in collagen synthesis (Andersen et al. 2011).
These findings suggest that the different circulating IL-6
timescale of prolonged but non-damaging exercise and
of eccentric exercise occurs due to a different source
and function of IL-6 expression. Whilst muscle fibres,
peritendinous connective tissue (Langberg et al. 2002)
and adipose tissue (Holmes et al. 2004) all express and
release IL-6 into the circulation without activating pro-
inflammatory pathways (Pedersen 2011), eccentric exer-
cise might induce more local IL-6 expression within the
skeletal muscle with pro-inflammatory properties (Nie-
man et al. 1998, 2000). The delayed peak of plasma
IL-6 concentration after strenuous eccentric exercise
might occur due to release into the circulation follow-
ing the mechanical tearing of the sarcolemma and open-
ing of stretch-activated channels due to exertional muscle
damage.
A functional −174 G>C SNP (rs1800795) has been
detected in the promoter region of the IL6 gene. The fre-
quency distribution of the G-allele ranges between 45 and
100 % in the worldwide population (Borinskaya et al.
2013) and it is associated with an increased plasma IL-6
response in healthy people (Bennermo et al. 2004; Fishman
et al. 1998; Pereira et al. 2011). The −174 G-allele might
affect the glucocorticoid receptor and elevate the transcrip-
tional activation due to its close positioning with the recep-
tor (Yamin et al. 2008; Rein et al. 1995). This IL6 SNP
shows a somewhat ambiguous picture: according to Ruiz
et al. (2010), both GG and GC genotypes are more frequent
in elite power athletes compared to endurance athletes and
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1608 Eur J Appl Physiol (2016) 116:1595–1625
1 3
to non-athletes. There was no difference between endur-
ance athletes and the control group, which is in the line
with the findings of Yamin et al. (2008). In young individu-
als, C-allele carriers of the IL6 SNP presented higher CK
values following eccentric exercise compared with GG
homozygotes (Yamin et al. 2008; Yamin 2009). In power-
orientated sports, which are associated with muscle dam-
age during training or competition, GG homozygotes might
have benefits with faster recovery and elevated satellite
cell proliferation in the long term. However, Deuster et al.
(2013), who did not observe any association between this
IL6 SNP and exertional rhabdomyolysis, challenge this
conclusion.
Ageing-related declines in physical function are asso-
ciated with chronically elevated systemic IL-6 concentra-
tion (Ershler and Keller 2000; da Cunha Nascimento et al.
2015). However, Walston et al. (2005) could not confirm
any association between IL6 genotypes and serum IL-6 in
older women. Furthermore, in the study of Funghetto et al.
(2013), in older obese women, plasma CK integral (area
under the curve of CK between the different time points)
values were lower and IL-6 integral values were higher for
carriers of the C-allele after eccentric exercise. However,
there was only a moderate increase in plasma CK con-
centration and no change in IL-6 concentration, probably
resulting from the relatively low intensity of the eccentric
exercise protocol used. Of note, the interaction between
the −174 G>C SNP and obesity seems to be a complex
one (Joffe et al. 2013). Linkage disequilibrium of this
−174 G>C SNP with several other SNPs on the IL6 gene
cannot be excluded (Qi et al. 2007). In diseased, obese and
older populations with chronically elevated circulating
IL-6, an increased IL-6 response might be harmful after
eccentric exercise (Funghetto et al. 2013; Bennermo et al.
2004).
In summary, the pattern of circulatory IL-6 and CK lev-
els in association with the IL6 −174 G>C SNP appears
to be diametrically opposed. It might be that an elevated
IL-6 response and lower CK levels associated with the
G-allele are beneficial due to increased IL-6 production of
macrophages (Patel et al. 2010) and satellite cell prolifera-
tion (McKay et al. 2009) in a healthy population follow-
ing eccentric exercise (Yamin et al. 2008). However, the
G-allele might have a negative effect in those presenting
with chronic low-grade systemic inflammation. Without
knowing the actual source of IL-6 expression and its subse-
quent pro- or anti-inflammatory effect, cumulative plasma
IL-6 concentration is probably an inaccurate biomarker of
muscle damage (Pedersen and Febbraio 2008). The influ-
ence of the IL6 −174 G>C SNP is not fully clear and
needs further investigation, particularly in conjunction with
both local and circulatory measures of IL-6 expression/
concentration.
Chemokine ligand 2 and chemokine receptor
type 2 polymorphisms and the secondary phase
of exercise‑induced muscle damage
Like interleukin-6, the chemokine (C–C motif) ligand-2
(CCL2), also known as monocyte chemoattractant pro-
tein 1 (MCP1), can be classified as an exercise factor, as
it mediates systemic changes induced by chronic exercise
training (Catoire and Kersten 2015). Monocyte chem-
oattractant protein 1 receptor (CCR2) is one of the major
receptors, which binds CCL2, beside CCL7 and CCL13
(Harmon et al. 2010). CCL2 is mainly expressed within
the interstitial space between myofibres following muscle
damaging exercise, and is co-localised with macrophages
and satellite cells in the muscle (Hubal et al. 2008). Con-
centric exercise does not influence local CCL2 expression
(Hubal et al. 2008). However, in line with the findings of
Warren et al. (2005), that Ccr2-knockout mice have shown
impaired regeneration, inflammation, and fibrotic response
following freeze injury, a strong interaction between
CCL2/CCR2 and the immune response after muscle dam-
age is suggested (Hubal et al. 2008; Yahiaoui et al. 2008).
Interestingly, whilst local CCL2 mRNA expression fur-
ther increased after a second bout of eccentric exercise in
comparison to the first bout (Hubal et al. 2008), systemic
response of CCL2 decreased after repeated downhill run-
ning (Smith et al. 2007).
Hubal et al. (2010) investigated several CCL2/CCR2
SNPs in association with exercise-induced muscle damage
in the elbow flexor muscles. Following strenuous exercise,
the T-allele of the CCL2 rs3917878 (C>T) SNP was associ-
ated with a delayed recovery of maximum strength in men
and a higher CK response in women (Hubal et al. 2010).
C-allele carriers of the CCR2 (rs3918358) SNP showed a
delayed recovery of strength in females, and the C-allele
of the CCR2 (rs1799865) SNP increased soreness in both
genders (Hubal et al. 2010). The significant differences
between the alleles of these three SNPs occurred 4–10 days
following exertional muscle damage, confirming the action
pattern of CCL2/CCR2 in muscle repair/regeneration.
Furthermore, the GG genotype of the CCL2 gene variant
(rs2857656), for which significant differences were found
in pre-exercise maximum strength compared to the major
C-allele (Harmon et al. 2010), was associated with the
magnitude of muscle injury in professional soccer players
(Pruna et al. 2013). According to Hubal et al. (2010), there
were moderate associations between CCL2/CCR2 geno-
types and baseline CCL2 activity (as a product of CCL2
expression and the availability of CCR2). Higher CCL2
activity might be an advantage in the recovery period fol-
lowing muscle damage in healthy individuals due to its
ability to serve as a chemoattractant to macrophages and its
possible activation of satellite cell proliferation (Yahiaoui
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1609Eur J Appl Physiol (2016) 116:1595–1625
1 3
et al. 2008). However, further investigation is needed to
identify the potential molecular mechanisms underpinning
the influence of each of these SNPs in changing CCL2
activity in response to muscle damaging exercise in elderly
and obese people, in whom chronic systemic inflammation
is already an issue.
Osteopontin −66 T>G polymorphism and the
secondary phase of exercise‑induced muscle damage
The extracellular matrix protein and pro-inflammatory
cytokine osteopontin (also known as secreted phosphopro-
tein 1) is expressed in numerous cell types including skele-
tal muscle (Kahles et al. 2014; Zanotti et al. 2011; Giachelli
et al. 1998). Whereas the earliest studies suggested that it
had a central role in bone remodelling (Rodan 1995), sub-
sequent studies suggest that osteopontin has also a role as
a chemoattractant for macrophages (Hirata et al. 2003),
and possibly neutrophils (Yang et al. 2014). Osteopontin is
virtually undetectable in resting skeletal muscle but, after
induced muscle damage in mice, osteopontin expression is
elevated 100-times compared to baseline transcription lev-
els (Hoffman et al. 2013; Hirata et al. 2003).
A common SNP in the transcriptional promoter of the
osteopontin gene (−66 T>G, rs28357094), which over-
laps a specificity protein-1 transcription factor-binding
site, results in different phenotypic characteristics (Barfield
et al. 2014). The minor G-allele is associated with an 80 %
reduction in osteopontin gene expression in vitro (Gia-
copelli et al. 2004; Barfield et al. 2014) and with a 17 %
increase in baseline upper arm muscle volume in women
(Hoffman et al. 2013). Surprisingly, this increased muscle
volume did not influence muscle strength (Hoffman et al.
2013). After exercise-induced muscle damage, women car-
rying the G-allele revealed significantly elevated muscle
swelling, increased loss of muscle strength (Barfield et al.
2014) and CK values were elevated in two women with the
rare GG genotype (Hoffman et al. 2013). In contrast, the
G-allele was linked with less grip strength and with more
rapid progression in patients with Duchenne muscular
dystrophy (Pegoraro et al. 2011). Further investigations of
Barfield et al. (2014) revealed several enhancer sequences
on the osteopontin gene promoter for multiple steroid hor-
mone-binding sites (i.e. oestrogen receptor, glucocorticoid
receptor, vitamin D receptor and a potential NF-κB bind-
ing site). Oestrogen hormone treatment of modified human
myoblasts with the allele-specific osteopontin promoters
has shown that the human myoblasts with the transfected
G-allele promoter revealed a threefold increase in osteo-
pontin gene expression, whereas the T-allele construct was
unaffected by oestrogen treatment. From this, we can infer
that there may be an allele-specific interaction between
the oestrogen enhancer and the more proximal specificity
protein-1 transcription factor site leading to a hypothetical
model for sexual dimorphism (Barfield et al. 2014). Thus,
women with the G-allele seem to be more susceptible to
muscle damage. Likewise, a similar allele-specific inter-
action between the NF-κB or glucocorticoid binding site
and the specificity protein-1 transcription factor site might
explain the association between the G-allele and Duch-
enne muscular dystrophy. Barfield et al. (2014) suggest that
chronic inflammation might lead to an augmentation of the
pro-inflammatory response, which accelerates the progress
of the disease. However, the study of Barfield et al. (2014)
has several limitations. TT genotype has shown a similar
loss of force over time in both the exercised and non-exer-
cised arm following exertional muscle damage. In addition,
due to the low number of volunteers (n = 6) who com-
pleted the eccentric exercise intervention, further investiga-
tions are needed to replicate and verify these findings.
Skeletal muscle remodelling
following exercise‑induced muscle damage
Skeletal muscle regeneration is a complex process that is
mediated by satellite cells, and in which several factors are
activated to regulate muscle remodelling (Kurosaka and
Machida 2012). Satellite cells are mononucleated muscle
stem cells and are located on the outer surface of the mus-
cle fibre, between the basal lamina and sarcolemma (Hawke
and Garry 2001). Usually, satellite cells remain quiescent
but are activated following damage (Fig. 4) (Chambers and
McDermott 1996; Grobler et al. 2004). They proliferate
24–48 h later and then do one of three things: (1) return
to quiescence and restore the population of satellite cells;
(2) migrate to the site of injury and support the repair pro-
cess by increasing the nuclei-to-cytoplasm ratio; (3) fuse
with other myogenic cells to form myotubes, thus generat-
ing new fibres to replace damaged myofibres (Hawke and
Garry 2001; Grobler et al. 2004; Tidball and Villalta 2010;
Sharples and Stewart 2011).
Macrophages are essential, not only for removing tis-
sue debris, but also in the activation of satellite cells. M1
macrophages provoke myoblast proliferation (Arnold et al.
2007; Cantini et al. 2002) and, together with neutrophils,
they attract satellite cells to the site of injury by releasing
TNF (Torrente et al. 2003). M2 macrophages stimulate
the differentiation of satellite cells into mature myofibres
(Arnold et al. 2007), and in vitro studies indicate that mac-
rophages support differentiation through ultimate increases
in myogenin expression (Cantini et al. 2002). Activated
satellite cells initially up-regulate two different myogenic
regulatory factors, MyoD and myogenic factor-5 (Smith
et al. 1994). In the period of proliferation, the satellite
cells express paired box protein 7 (Pax7) and MyoD but
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1610 Eur J Appl Physiol (2016) 116:1595–1625
1 3
those that return to quiescence to maintain the satellite cell
pool only express Pax7 (Tedesco et al. 2010; Al-Shanti
and Stewart 2009). However, subsequent down-regulation
of Pax7/3 induces cell differentiation. The satellite cells
exit the cell cycle and enter the early differentiation stage
where myogenic factor 6 (herculin) and myogenin are up-
regulated (Zammit 2008; Wahl et al. 2008; Le Grand and
Rudnicki 2007). Myoblasts differentiate into myocytes
and then eventually fuse and form multinucleated myofi-
bres (Le Grand and Rudnicki 2007). Recent investigations
revealed that MyoD and myogenin induce myomaker gene
transcription (Millay et al. 2013, 2014). The absence of
myomaker, which is expressed on the cell surface of myo-
blasts, leads to inhibition of myoblast fusion in mice (Mil-
lay et al. 2013). However, more information is required to
explain the roles of myomaker in muscle regeneration and
recovery following muscle damaging exercise.
The extracellular matrix provides structural and bio-
chemical support to contractile tissue and it is associated
with the inflammatory response and satellite cell activa-
tion (Hyldahl and Hubal 2014; Kjær 2004). Activated
satellite cells migrate to the site of injury along the basal
lamina (Hughes and Blau 1990), a process that is facili-
tated by the basal lamina components (i.e. collagen IV,
laminin-2 and nidogens) (Goetsch and Niesler 2011).
Components of the extracellular matrix (collagen I and
III, fibronectin and other extracellular matrix molecules)
provide a temporary scaffold to support the migration of
the activated progenitor cells (Goetsch et al. 2013). Dif-
ferent chemotactic gradients, including a large num-
ber of chemokines, also support the migration from the
niche towards the site of myotrauma, and some of these
chemokines are released from the extracellular matrix
itself (Griffin et al. 2010; Goetsch et al. 2013). Further-
more, there is evidence that synthesis of type I, III and
probably IV collagen within the endomysium and the
perimysium increase after contraction-induced damage
(Mackey et al. 2004; Koskinen et al. 2001).
Fig. 4 The cycle of skeletal muscle fibre regeneration following
exercise-induced muscle damage. This cycle is mediated by satellite
cells, which are activated following stressful physiological conditions
such as exercise-induced muscle damage (Grobler et al. 2004). Acti-
vated satellite cells initially up-regulate two different myogenic regu-
latory factors, MyoD and myogenic factor-5 and, during the prolifera-
tion, paired box protein 7 (Pax7). If satellite cells return to quiescence
and restore the population of satellite cells, MyoD will be down-reg-
ulated (i). However, subsequent cell differentiation is accompanied
with down-regulation of Pax7/3. During this early differentiation
stage, herculin and myogenin are up-regulated. Myoblasts differen-
tiate into myocytes and then eventually migrate to the site of injury
and support the repair process by increasing the nuclei-to-cytoplasm
ratio (ii). Different chemotactic gradients, including a large number
of chemokines, support the migration to the region of injury. A recent
investigation in mice revealed that the absence of myomaker, which
is expressed on the cell surface of myoblasts, leads to inhibition of
myoblast fusion (Millay et al. 2013). Alternatively, the myocytes fuse
with other myogenic cells to form myotubes, thus generating new
fibres to replace damaged myofibres (iii). Figure adapted from Tidball
(2011) and Al-Shanti and Stewart (2009)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1611Eur J Appl Physiol (2016) 116:1595–1625
1 3
Chronic low-grade systemic inflammation (i.e. elevated
levels of circulating pro-inflammatory cytokines), is a com-
mon observation in older people (Conceição et al. 2012;
Franceschi et al. 2007). In this context, basal circulating
cytokines (e.g. TNF and IL-6) and myostatin were found
to correlate inversely with grip strength of older men (Patel
et al. 2014). Although the mechanism for this inverse rela-
tionship is still unclear, it is possible that pro-inflammatory
cytokines interfere with satellite cell differentiation, accel-
erate muscle protein degradation and inhibit muscle protein
synthesis, leading to reduced muscle mass and strength.
This would also result in slower repair and reduced adapta-
tion of older skeletal muscle to resistance exercise (Peake
et al. 2010). Indeed, Dreyer et al. (2006) have counted
the numbers of satellite cells per muscle fibre 24 h after a
single bout of maximal eccentric exercise. Although both
young and older men demonstrated an increase in satellite
cell numbers, the response was significantly blunted in the
older population. However, it is still a matter of debate, if
the number of satellite cells changes during the ageing pro-
cess, and whether this is the main cause for what has been
coined anabolic resistance in the elderly.
Gene polymorphisms of the insulin‑like growth factor
family and the remodelling fsignificant gain in muscle
cross‑sectional areaollowing exercise‑induced muscle
damage
The complex process of remodelling is influenced by growth
factors including insulin-like growth factor-I (IGF-I) and
IGF-II (Duan et al. 2010). In addition to IGF-I (IGF1) and
IGF-II (IGF2), the IGF system consists of several IGF-bind-
ing proteins, the insulin receptor, and cell surface receptors
such as the IGF-I receptor and the IGF-II receptor (Wang
et al. 2015). This system promotes satellite cell differentia-
tion and proliferation (O’Dell and Day 1998; Florini et al.
1996; Stewart and Rotwein 1996a, b; Stewart et al. 1996) and
is thought to play an important role during exercise-induced
muscle hypertrophy (Sharples and Stewart 2011; Matheny
et al. 2009). For example, transgenic mice overexpressing
Igf-I in skeletal muscle revealed a significant gain in muscle
cross-sectional area in comparison with wild type mice fol-
lowing chronic muscle overload (Paul and Rosenthal 2002).
Inactivation of the type 1 Igf receptor inhibits the presence of
newly formed nuclei in exercised transgenic mice (Fernán-
dez et al. 2002; Jiao et al. 2013; Wilson et al. 2003), while
maintaining local IGF-I concentration is considered crucial
for maintaining muscle mass and strength with advancing
age (Barton-Davis et al. 1998; Musarò et al. 2001).
Besides their role in hypertrophy, IGFs are crucial in
muscle regeneration following exercise or muscle injury
(Jiao et al. 2013; Mackey et al. 2011). Insulin-like growth
factor-I acts mainly in an autocrine and paracrine manner
to stimulate satellite cells to proliferate and differentiate.
Different isoforms [IGF-IEa, IGF-IEb (in rat) and IGF-IEc
(in human)] of IGF-I are associated with muscle damage
and regeneration. Insulin-like growth factor-IEb and IGF-
IEc are also known as mechano-growth factor, because the
mRNA is expressed in response to overload or damage in
skeletal muscle. The expression of mechano-growth fac-
tor is enhanced shortly after muscle damage, which sub-
sequently promotes satellite cell activation (Hill and Gold-
spink 2003). Afterwards, increased expression of IGF-IEa
elevates myoblast fusion (Yang and Goldspink 2002; Jiao
et al. 2013). Mechano-growth factor also promotes the
activity of cytoplasmic superoxide dismutase, thus pro-
tecting against ROS during the inflammatory response to
muscle damaging exercise (Dobrowolny et al. 2005). Both
IGF-I and IGF-II mRNA increase during myoblast dif-
ferentiation, but presumably autocrine IGF-II is the pre-
dominant myogenic factor during differentiation due to its
enhanced expression, whilst IGF-II is probably elevated
to suppress IGF-I gene expression via the mTOR pathway
(Jiao et al. 2013; Wilson et al. 2003). Marsh et al. (1997)
have also shown an age-dependent decline of IGF2 gene
expression following muscle damage in rats.
As far as we are aware, only Devaney et al. (2007) have
tested the association between IGF SNPs and exercise-
induced muscle damage. Several different SNPs were
investigated, as the IGF2 gene region consists of three
genes: IGF2, IGF2 anti sense (IGF2AS), and the insulin
gene (Lee et al. 2005). The following SNPs: IGF2 (17200
G>A, rs680); IGF2 (13790 C>G, rs3213221); IGF2AS
(1364 A>C, rs4244808); IGF2AS (11711 G>T, rs7924316),
were significantly associated with exercise-induced muscle
damage. Besides an association between the IGF2 17200
(G>A, rs680) and IGF2 13790 (C>G, rs3213221) SNPs
and soreness (after 3 and 4 days), and CK activity in the
blood (both after 7 days) following muscle damaging exer-
cise, every IGF2 SNP investigated was associated with
strenuous exercise-induced muscle strength loss in men.
Only the IGF2AS 1364 (A>C, rs4244808) SNP was associ-
ated with strength loss immediately after exertional muscle
damage in both men and women. In contrast, carriers of the
insulin gene 1045 (C>G, rs3842748) SNP have shown an
increased CK activity 10 days after exercise-induced mus-
cle damage only in women.
Varying IGF-I or IGF-II levels potentially caused by
these SNPs could modulate satellite cell activation and dif-
ferentiation. For instance, the IGF1 cytosine adenine-repeat
SNP located in the promoter region of the IGF-I gene is
believed to change circulating IGF-I levels but the evi-
dence is equivocal (Vaessen et al. 2001; Rosen et al. 1998;
DeLellis et al. 2003; Allen et al. 2002). While Vaessen et al.
(2001) suggest IGF-I levels are increased by these SNPs,
other investigations found a decrease (Rosen et al. 1998)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1612 Eur J Appl Physiol (2016) 116:1595–1625
1 3
or no difference in IGF-I levels (Allen et al. 2002; DeLellis
et al. 2003).
It is remarkable that several SNPs of IGF2 were associ-
ated with a loss of muscle strength directly after exertional
muscle damage, in particular in men. It seems there must
be another process, whereby the IGF2 gene is involved in
the response to muscle damaging exercise separately from
regeneration and differentiation. Here, we would like to
highlight a new hypothesis. Insulin-like growth factor I also
plays an important role in the regulation of protein synthe-
sis, including collagen and myofibrillar protein. Local IGF-
IEa and IGF-IEc mRNA expression is positively correlated
with musculotendinous mRNA expression of COL1A1/3A1
(Boesen et al. 2013; Doessing et al. 2010) and may sub-
sequently increase collagen synthesis in the extracellular
matrix (Hansen et al. 2013). Lower circulating IGF-I lev-
els induced by IGF SNPs may negatively influence the sta-
bility of the extracellular matrix. Therefore, a subsequent
loss in the lateral transmission of force between adjacent
muscle fibres might occur, which could be the source of the
decrease in maximum strength observed immediately after
strenuous exercise. Although, to the best of our knowledge,
no direct effect of IGF-II concentration on human extracel-
lular matrix protein synthesis is known, Keller et al. (1999)
has shown that local Igf-II expression increases after injury
in murine muscle. It is therefore possible that IGF-II is
linked with exercise-induced muscle damage in human
muscle, and possibly with extracellular matrix integrity. A
direct or indirect influence of IGF-II level on extracellular
matrix integrity would, at least in part, explain the signifi-
cant strength loss after muscle damaging exercise and the
association of the IGF2 13790 (C>G, rs3213221) SNP with
the degree of injury in soccer players (Pruna et al. 2013).
Additional gene polymorphisms associated
with exercise‑induced muscle damage
The following gene polymorphisms have been associated
with exercise-induced muscle damage. However, further
investigation is necessary to attribute these polymorphisms
to a specific phase of exercise-induced muscle damage.
Angiotensin‑I converting enzyme insertion/deletion
polymorphism
Angiotensin-I converting enzyme (ACE) has a key role in
the interaction between the kallikrein-kinin and the renin-
angiotensin systems (Schmaier 2003). Angiotensinogen,
which is a precursor protein in the renin-angiotensin sys-
tem, is produced constitutively and released into the circu-
lation mainly by the liver (Deschepper 1994), and can be
cleaved by the protease renin, resulting in the decapeptide
angiotensin-I. The dipeptidase ACE converts angiotensin-
I to the octapeptide hormone angiotensin-II, which acts as
a vasoconstrictor (Munzenmaier and Greene 1996), and
induces skeletal muscle hypertrophy in response to mechan-
ical loading (Gordon et al. 2001). Angiotensin-I converting
enzyme also cleaves the vasodilator bradykinin (Dendorfer
et al. 2001), which supports the increase of arterial blood
pressure (Murphey et al. 2000), as well as Substance P, a
protein from the tachykinin family that functions as a neu-
rotransmitter (released by group III and IV afferent fibres)
(Harrison and Geppetti 2001; Inoue et al. 1998).
The ACE insertion/deletion (I/D) polymorphism
(rs4646994) was the first gene variation to be investigated
in the context of human physical performance-related
traits, and is the most investigated in the renin–angio-
tensin system (Gayagay et al. 1998; Montgomery et al.
1998). The insertion (I) allele of a 287 bp Alu sequence
within intron 16 on chromosome 17 is linked to lower ACE
activity in serum (Rigat et al. 1990) and in cardiac mus-
cle (Phillips et al. 1993; Danser et al. 1995), and reduced
bradykinin degradation (Murphey et al. 2000) compared to
carriers of the D-allele. Carriers of the I-allele are associ-
ated with greater endurance capacity (Montgomery et al.
1998; Ma et al. 2013), whereas the D-allele is associated
with greater muscular strength (Williams et al. 2005), and
elite power athlete status (Costa et al. 2009; Nazarov et al.
2001; Woods et al. 2001). However, recent investigations
have observed that this distinction is not considered suffi-
ciently specific to detect all the phenotypic effects (Lucia
et al. 2005; Rankinen et al. 2000; Thompson and Binder-
Macleod 2006).
The association between the ACE I/D polymorphism and
elite athlete status might be explained by a genotype link
with the susceptibility to exertional muscle damage and
injury. To the best of our knowledge, only two studies have
investigated the influence of the ACE I/D polymorphism on
contraction-induced damage in humans (Heled et al. 2007;
Yamin et al. 2007). Yamin et al. (2007) observed differ-
ent concentrations of circulatory CK between ACE geno-
types after eccentric exercise: II homozygotes elicited the
highest CK response, whilst DD homozygotes elicited the
lowest plasma CK activity after strenuous exercise. This
suggests that the I-allele is associated with a greater sus-
ceptibility to muscle damage, and the potential mechanism
is explained below. However, Heled et al. (2007) could not
find any association between ACE I/D polymorphism and
CK response. The different outcome is probably attributed
to the moderate-intensity exercise test and higher activ-
ity level and different ethnicities of the participants in the
study of Heled et al. (2007). It should be noted that only
CK level was investigated in both studies, which is only
one of several indirect biomarkers of exercise-induced
muscle damage.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1613Eur J Appl Physiol (2016) 116:1595–1625
1 3
In rabbit studies, inhibition of ACE revealed [in combi-
nation with neutral endopeptidase inhibitor] elevated mus-
cle damage in a muscle overuse model induced by electri-
cal stimulation every second day with four sessions in total
(Song et al. 2014), which is in line with the human findings
of Yamin et al. (2007). The muscle damage was accompa-
nied by increased tachykinin, substance P and its preferred
receptor neurokinin-1 receptor expression, which suggests
that the tachykinin family may play a role in the inflam-
matory processes and pain (Song et al. 2014; Dousset et al.
2007). Substance P is widely expressed in human cells and
tissues of the peripheral and central nervous systems but it
is also found in extra neuronal cells and innervated tissues.
Substance P and neurokinin-1 receptor have been associ-
ated with the inflammatory response in smooth muscle
cells and dermal tissues but not in skeletal muscle (Renzi
et al. 2000; Luger 2002). However, elevated substance P
might result in improved remodelling, as demonstrated in
the healing of a rat Achilles tendon (Bring et al. 2012; Stey-
aert et al. 2010).
In contrast, angiotensin-II is known to be involved in
inflammatory process following muscle damage. Block-
ing of the angiotensin-II receptor type 1 improves regen-
eration of injured skeletal muscle (Bedair et al. 2008) and
suppresses ROS production following strenuous exercise in
mice (Sim et al. 2014). Furthermore, nerve growth factor
up-regulation through activation of B2 bradykinin recep-
tors is strongly associated with increased pain sensitivity
(hyperalgesia) (Murase et al. 2010; Babenko et al. 1999).
Angiotensin-I converting enzyme D-allele carriers, which
have a decreased bradykinin half-life, might have attenu-
ated nerve growth factor expression following exertional
muscle damage and therefore a decreased pain sensitivity.
Attenuated substance P and bradykinin in the inflammatory
process may explain the high frequency of D-allele carri-
ers among elite strength/power athletes (Costa et al. 2009).
Athletes with the D-allele might feel less pain and there-
fore might be able to (1) sustain high-intensity training
for longer, (2) reach the limits of their capacity in power/
strength related competition (3) or enable them to practise
more often due to a decreased sensitivity to pain. In other
sport-specific movements, such as short distance swimming
(<200 m), it is crucial to sustain a high level of intensity
accompanied with exercise-induced muscle burning (Costa
et al. 2009; Woods et al. 2001).
Another possibility might be that angiotensin-II indi-
rectly mediates skeletal muscle damage by influencing
angiogenesis in response to exercise (Vaughan et al. 2013).
It is well known that, in a damaged muscle in the days fol-
lowing eccentric exercise, resting capillary blood flow is
elevated and vasodilatation occurs (Rubinstein et al. 1998).
According to Vaughan et al. (2013), the capillary density
of skeletal muscle is lower in untrained carriers of the ACE
I-allele compared to DD homozygotes. Lower capillary
density might impair the migration of neutrophils and mac-
rophages as well as of the removal of cellular debris, which
could negatively affect the extent of muscle damage and
possibly muscle remodelling.
Mitochondrial superoxide dismutase 2 Ala16Val
polymorphism
Strenuous exercise results in oxidative stress, which causes
structural damage to muscle fibres and stimulates an
inflammatory response (Gomez-Cabrera et al. 2008), as
discussed in “Genetic variation and the secondary phase
of exercise-induced muscle damage”. A higher intracel-
lular concentration of antioxidants within a muscle fibre
is thought to protect against the negative impact of ROS
(Schoenfeld 2012; Peake and Suzuki 2004). Superoxide
dismutase is an antioxidant that protects cells and mito-
chondria from free radical damage by converting the anion
superoxide into hydrogen peroxide (Huang et al. 2000).
Inhibition of superoxide dismutase causes the accumula-
tion of superoxide radicals, and can lead to increased dam-
age of mitochondrial membrane and cell apoptosis (Huang
et al. 2000). The Ala16Val (rs4880, C>T) SNP of the super-
oxide dismutase 2, mitochondrial gene (SOD2), has been
associated with muscle damage susceptibility. The T-allele
is associated with reduced mitochondrial superoxide dis-
mutase efficiency against oxidative stress (Shimoda-Mat-
subayashi et al. 1996). Akimoto et al. (2010) demonstrated
that trained runners of TT genotype had an increased
plasma CK concentration after racing 4–21 km. This is in
line with Ahmetov et al. (2014), who revealed that TT car-
riers of the mitochondrial superoxide dismutase gene were
under-represented in power and strength athletes compared
to controls and athletes of low-intensity sports, such as
curling players and shooters. Interestingly, in the study of
Ben-Zaken et al. (2013), the frequency of the C-allele was
significantly higher in both endurance and power athletes
in comparison to the control group. At first glance, these
studies seem to be inconsistent with one another. On closer
inspection, both studies recruited different types of partic-
ipants. In the study of Ahmetov et al. (2014) participants
covered a wide range of different sports, whereas in Ben-
Zaken et al. (2013), only track and field related athletes
participated: 100 and 200 m sprinters and long jumpers
(power athletes); 5000 m and marathon runners (endurance
athletes). These track and field athletes perform sport-spe-
cific movements that is accompanied by stress to the mus-
culoskeletal system through repeated eccentric muscle con-
tractions performed over long periods of time, which leads
to muscle damage. The inflammation accompanying this
damage potentially produces more oxidative stress than the
endurance sports (e.g. swimming) in the study by Ahmetov
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1614 Eur J Appl Physiol (2016) 116:1595–1625
1 3
et al. (2014). Therefore, the T-allele might impair the pro-
tection against oxidative stress due to the lower efficiency
of the mitochondrial superoxide dismutase gene. This may
indicate that there is a relationship between this SNP and
level of athletic performance in sports with a potential risk
of muscle damage. Unfortunately, no study has tested the
effect of the mitochondrial superoxide dismutase SNP on
exercise-induced muscle damage over the course of time.
This could provide insight into the influence of the mito-
chondrial superoxide dismutase C>T SNP on the secondary
phase of muscle damage and the subsequent remodelling.
Solute carrier family 30 member eight C>T
polymorphism
Ageing is often accompanied by insulin resistance due to
reduced habitual physical activity, a reduction in muscle
mass and an increase in adipose tissue (Dela and Kjaer
2006; Dela et al. 1996). Type 2 diabetes mellitus is associ-
ated with disturbed zinc homeostasis and down-regulation
of the solute carrier family 30 (zinc transporter) mem-
ber eight, the product of the SLC30A8 gene (Somboon-
wong et al. 2015). Solute carrier family 30 member eight
is mainly expressed in pancreatic islet beta cells and it
transports zinc from the cytoplasm into intracellular vesi-
cles, which is crucial for insulin crystallisation, storage,
and secretion (Cheng et al. 2015; Lemaire et al. 2009;
Chimienti et al. 2006). The C-allele of the nonsynonymous
SLC30A8 (C>T) SNP (rs13266634) is strongly associated
with type 2 diabetes mellitus risk, in particular in Euro-
pean and Asian populations but not in African populations
(Cheng et al. 2015). This SLC30A8 R325W SNP is associ-
ated with, amongst others, decreased fasting systemic insu-
lin and attenuated insulin secretion in response to glucose
intake (Staiger et al. 2007; Sprouse et al. 2014; Kirchhoff
et al. 2008).
In recent years, there has been an increase in the number
of investigations regarding insulin resistance and muscle
function in people without type 2 diabetes mellitus. Insu-
lin resistance is not only associated with lower force and
muscle mass in young and old individuals with diabetes
(Andreassen et al. 2009; Andersen et al. 2004), but also in
both young (Gysel et al. 2014) and older (Barzilay et al.
2009) healthy people. Insulin signalling increases blood
flow and protein synthesis at rest, and suppresses the break-
down of proteins after resistance exercise, thus improving
net muscle protein balance in particular with amino acid
delivery and availability (Biolo et al. 1999; Fujita et al.
2006). Furthermore, exercise-induced muscle damage has
been associated with impaired glycogen synthesis (Cos-
till et al. 1990) and reduced glucose uptake (Nielsen et al.
2015; Asp et al. 1996), probably due to muscle damage
reducing muscle insulin sensitivity (Kirwan et al. 1991).
This could be due to increased TNF expression attenuating
insulin signalling transduction, subsequently inducing insu-
lin resistance in skeletal muscle (Plomgaard et al. 2005)
and suppressing the activation of glucose transporter type 4
in muscle fibres (Asp et al. 1995).
Sprouse et al. (2014) reported that the TT genotype of
the SLC30A8 SNP was associated with lower biomarkers of
muscle damage (reduced soreness, strength loss and plasma
CK and myoglobin levels) following eccentric contrac-
tions of the elbow flexor muscles in men. By increasing the
catabolic pathway, lower insulin levels can lead to a nega-
tive net protein balance (Woolfson et al. 1979; Sacheck
et al. 2007). Therefore, carriers of the SLC30A8 C-allele
might need longer times to recover from strenuous exer-
cise. Further studies should investigate if SLC30A8 geno-
type-dependent insulin production is associated with the
acute and chronic adaptations to resistance exercise, with
regard to muscle protein synthesis and muscle hypertrophy,
respectively.
Discussion
Exercise-induced muscle damage provokes a prolonged
loss of muscle strength, and both elevated soreness and
circulating muscle-specific protein levels. The grade and
actual time-course of strength loss, soreness and of the
inflammation response after exercise is variable. Several
factors that are well documented can influence the response
to muscle damaging exercise, such as exercise mode, inten-
sity or duration (Smith et al. 1989), micro nutrition (Owens
et al. 2014; Bhat and Ismail 2015; Barker et al. 2013)
and muscle (group) intervention (Clarkson and Hubal
2002). Nevertheless, within-study variability is often seen
in response to strenuous exercise (Nosaka and Clarkson
1996).
Several studies have reported differences in SNP-spe-
cific gene activity resulting in different expression of the
coding proteins, which may influence the susceptibly to
exercise-induced muscle damage (Seto et al. 2011). Indi-
viduals, who are high responders to exercise-induced
muscle damage (i.e. demonstrate a greater loss of muscle
strength and higher circulating levels of CK or myoglobin)
might have a higher predisposition to injury (Kibler et al.
1992; Clansey et al. 2012). This is in line with the observa-
tion that history of one type of muscle injury increases the
risk of developing other types of muscle injuries (Orchard
2001; Freckleton and Pizzari 2013). The same principle
may apply to high responders to exercise-induced muscle
damage in a squad of athletes performing the same exer-
cise training together. High responders, who might need a
longer recovery time after a strength training intervention
in comparison to others in the same squad, might have a
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1615Eur J Appl Physiol (2016) 116:1595–1625
1 3
higher potential for musculotendinous injuries due to over-
training. Both presumptions may result in an increased
dropout rate of athletes with specific genotype profiles due
to higher rates of (overtraining) injury extending over sev-
eral years (Kibler et al. 1992). It would be interesting to
investigate if a high responder to exercise-induced mus-
cle damage is a low/high responder to chronic resistance
training.
Eccentric resistance exercise training is a potent method
of inducing muscle hypertrophy (Seynnes et al. 2007;
Norrbrand et al. 2008), and may therefore be prescribed
to older people to counter sarcopenia (Reeves et al. 2004;
Morse et al. 2007). However, the increased susceptibility to
muscle damage following eccentric exercise in older peo-
ple (Ploutz-Snyder et al. 2001) might lead to an increased
risk of over-use injuries and impaired recovery from injury
(Brooks and Faulkner 1990; McArdle et al. 2004). Fur-
thermore, if certain older individuals are genetically pre-
disposed to experience relatively more exercise-induced
muscle damage than age-matched individuals with a pro-
tective genetic profile, these people are at an even greater
risk of injury. Thus, a different form of exercise may be
more appropriate for these individuals. The identification
of both young and older high-risk individuals would, there-
fore, allow more personalised exercise prescriptions to help
reduce the risk of injuries and maintain/improve quality of
life.
Association studies can potentially reveal new mecha-
nisms of genes. For instance, several IGF2 SNPs have been
associated with strength loss immediately after muscle
damaging exercise, which cannot exclusively be explained
by satellite cell differentiation (Devaney et al. 2007). It is
interesting that (1) certain genotypes of several IL6 gene
SNPs appear to be beneficial in healthy individuals regard-
ing muscle damage response, but are disadvantageous
in chronic disease and ageing; (2) sex-specific genotype
associations with exercise-induced muscle damage have
been reported (Devaney et al. 2007; Sprouse et al. 2014).
Further investigations are necessary to uncover genotype–
phenotype interactions and, in particular, the interaction of
specific polymorphisms. A specific polygenic profile might
help to explain the inter-individual variance in the response
to both acute eccentric damaging exercise and chronic
strength training.
Moreover, the ACTN3 R577X SNP has been associ-
ated with different responses to muscle damaging exercise,
according to the mode of damaging exercise. It is likely
that stretch–shortening cycle-related movements place dif-
ferent demands on the musculotendinous system compared
to exercises, which are performed without stretch–short-
ening cycles, thus explaining the equivocal findings con-
cerning the association between this SNP and exercise-
induced muscle damage (see “Alpha-actinin-3 R577X
polymorphism and the initial phase of exercise-induced
muscle damage”). Consequently, we recommend that
future studies distinguish between exercise-induced muscle
damage caused by eccentric contractions with or without
stretch–shortening cycles. Furthermore, real-world modes
of exercise should be incorporated into studies investigat-
ing the genetic association with exertional muscle damage
in both young and older people. Not only will this improve
our understanding of the mechanisms underpinning the
deteriorated response of ageing muscle to exercise, but also
it will help in prescribing more practical exercise therapies
to poor exercise responders, young or old.
Conclusions
Understanding the causes and consequences of these
genetic associations with exercise-induced muscle dam-
age may eventually allow the identification of individu-
als, who are at high-risk of developing specific injuries.
For instance, those who are genetically more predisposed
to muscle damage, and who require longer recover from
strenuous exercise, are at greater risk of developing over-
use injuries. Knowing how someone is likely to respond
to a particular type of exercise would help coaches tailor
the training and nutrition of their athletes (moving from
a one size fits all to an individualised approach), thus
maximising recovery and positive adaptation, and reduc-
ing the risk of injury. It would also help general practi-
tioners prescribe personalised exercise medicine to older
individuals, who may normally be prescribed resistance
type training to counter the effects of sarcopenia, but are
already at a higher risk of suffering from exercise-induced
muscle damage due to chronically elevated systemic
inflammation.
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://crea-
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
References
Ahmetov II, Naumov VA, Donnikov AE, Maciejewska-Karłowska A,
Kostryukova ES, Larin AK, Maykova EV, Alexeev DG, Fedo-
tovskaya ON, Generozov EV (2014) SOD2 gene polymorphism
and muscle damage markers in elite athletes. Free Radical Res
48(8):948–955
Akimoto AK, Miranda-Vilela AL, Alves PC, Pereira LC, Lordelo GS,
Hiragi Cde O, da Silva IC, Grisolia CK, Klautau-Guimaraes
Mde N (2010) Evaluation of gene polymorphisms in exer-
cise-induced oxidative stress and damage. Free Radical Res
44(3):322–331. doi:10.3109/10715760903494176
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1616 Eur J Appl Physiol (2016) 116:1595–1625
1 3
Allen NE, Davey GK, Key TJ, Zhang S, Narod SA (2002) Serum
insulin-like growth factor I (IGF-I) concentration in men
is not associated with the cytosine-adenosine repeat poly-
morphism of the IGF-I gene. Cancer Epidem Biomark
11(3):319–320
Allen DG, Whitehead NP, Yeung EW (2005) Mechanisms of stretch-
induced muscle damage in normal and dystrophic muscle:
role of ionic changes. J Physiol 567(3):723–735. doi:10.1113/
jphysiol.2005.091694
Al-Shanti N, Stewart CE (2009) Ca2+/calmodulin-dependent tran-
scriptional pathways: potential mediators of skeletal mus-
cle growth and development. Biol Rev 84(4):637–652.
doi:10.1111/j.1469-185X.2009.00090.x
Andersen H, Nielsen S, Mogensen CE, Jakobsen J (2004) Muscle
strength in type 2 diabetes. Diabetes 53(6):1543–1548
Andersen MB, Pingel J, Kjaer M, Langberg H (2011) Interleu-
kin-6: a growth factor stimulating collagen synthesis in human
tendon. J Appl Physiol 110(6):1549–1554. doi:10.1152/
japplphysiol.00037.2010
Andreassen CS, Jakobsen J, Ringgaard S, Ejskjaer N, Andersen H
(2009) Accelerated atrophy of lower leg and foot muscles—a
follow-up study of long-term diabetic polyneuropathy using
magnetic resonance imaging (MRI). Diabetologia 52(6):1182–
1191. doi:10.1007/s00125-009-1320-0
Appell H-J, Soares JMC, Duarte JAR (1992) Exercise, mus-
cle damage and fatigue. Sports Med 13(2):108–115.
doi:10.2165/00007256-199213020-00006
Armstrong RB (1984) Mechanisms of exercise-induced delayed
onset muscular soreness: a brief review. Med Sci Sport Exerc
16(6):529–538
Armstrong RB (1990) Initial events in exercise-induced muscular
injury. Med Sci Sport Exerc 22(4):429–435
Armstrong RB, Warren GL, Warren JA (1991) Mechanisms of exer-
cise-induced muscle fibre injury. Sports Med 12(3):184–207
Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plon-
quet A, Gherardi RK, Chazaud B (2007) Inflammatory mono-
cytes recruited after skeletal muscle injury switch into antiin-
flammatory macrophages to support myogenesis. J Exp Med
204(5):1057–1069. doi:10.1084/jem.20070075
Asp S, Daugaard JR, Richter EA (1995) Eccentric exercise decreases
glucose transporter GLUT4 protein in human skeletal muscle. J
Physiol 482(3):705–712
Asp S, Daugaard JR, Kristiansen S, Kiens B, Richter EA (1996)
Eccentric exercise decreases maximal insulin action in humans:
muscle and systemic effects. J Physiol 494(3):891–898
Babenko V, Graven-Nielsen T, Svensson P, Drewes AM, Jensen TS,
Arendt-Nielsen L (1999) Experimental human muscle pain and
muscular hyperalgesia induced by combinations of serotonin
and bradykinin. Pain 82(1):1–8
Baird MF, Graham SM, Baker JS, Bickerstaff GF (2012) Creatine-
kinase-and exercise-related muscle damage implications for
muscle performance and recovery. J Nutr Metab 2012:1–13.
doi:10.1155/2012/960363
Balnave CD, Allen DG (1995) Intracellular calcium and force in sin-
gle mouse muscle fibres following repeated contractions with
stretch. J Physiol 488(1):25–36
Bansal D, Miyake K, Vogel SS, Groh S, Chen C-C, Williamson
R, McNeil PL, Campbell KP (2003) Defective membrane
repair in dysferlin-deficient muscular dystrophy. Nature
423(6936):168–172
Barfield WL, Uaesoontrachoon K, Wu C-S, Lin S, Chen Y, Wang PC,
Kanaan Y, Bond V, Hoffman EP (2014) Eccentric muscle challenge
shows osteopontin polymorphism modulation of muscle damage.
Hum Mol Genet 23(15):4043–4050. doi:10.1093/hmg/ddu118
Barker T, Henriksen VT, Martins TB, Hill HR, Kjeldsberg CR, Sch-
neider ED, Dixon BM, Weaver LK (2013) Higher serum
25-hydroxyvitamin D concentrations associate with a faster
recovery of skeletal muscle strength after muscular injury.
Nutrients 5(4):1253–1275
Barton-Davis ER, Shoturma DI, Musaro A, Rosenthal N, Sweeney
HL (1998) Viral mediated expression of insulin-like growth fac-
tor I blocks the aging-related loss of skeletal muscle function.
Proc Natl Acad Sci USA 95(26):15603–15607
Barzilay JI, Cotsonis GA, Walston J, Schwartz AV, Satterfield S,
Miljkovic I, Harris TB (2009) Insulin resistance is associated
with decreased quadriceps muscle strength in nondiabetic adults
aged ≥70 years. Diabetes Care 32(4):736–738
Bedair HS, Karthikeyan T, Quintero A, Li Y, Huard J (2008) Angio-
tensin II receptor blockade administered after injury improves
muscle regeneration and decreases fibrosis in normal skeletal
muscle. Am J Sports Med 36(8):1548–1554
Belcastro AN, Shewchuk LD, Raj DA (1998) Exercise-induced
muscle injury: a calpain hypothesis. Mol Cell Biochem
179(1–2):135–145
Bell RD, Shultz SJ, Wideman L, Henrich VC (2012) Collagen gene
variants previously associated with anterior cruciate ligament
injury risk are also associated with joint laxity. Sports Health
4(4):312–318
Bennermo M, Held C, Stemme S, Ericsson CG, Silveira A, Green
F, Tornvall P (2004) Genetic predisposition of the interleu-
kin-6 response to inflammation: implications for a variety of
major diseases? Clin Chem 50(11):2136–2140. doi:10.1373/
clinchem.2004.037531
Benoit DL, Dowling JJ (2006) In vivo assessment of elbow flexor
work and activation during stretch–shortening cycle tasks.
J Electromyogr Kinesiol 16(4):352–364. doi:10.1016/j.
jelekin.2004.07.006
Ben-Zaken S, Eliakim A, Nemet D, Kassem E, Meckel Y
(2013) Increased prevalence of MnSOD genetic polymor-
phism in endurance and power athletes. Free Radical Res
47(12):1002–1008
Ben-Zaken S, Eliakim A, Nemet D, Rabinovich M, Kassem E, Meckel
Y (2015) ACTN3 polymorphism: comparison between elite
swimmers and runners. Sports Med Open 1(1):13. doi:10.1186/
s40798-015-0023-y
Bhat M, Ismail A (2015) Vitamin D treatment protects against
and reverses oxidative stress induced muscle proteolysis.
J Steroid Biochem Mol Biol 152:171–179. doi:10.1016/j.
jsbmb.2015.05.012
Biolo G, Williams BD, Fleming RY, Wolfe RR (1999) Insulin action
on muscle protein kinetics and amino acid transport during
recovery after resistance exercise. Diabetes 48(5):949–957.
doi:10.2337/diabetes.48.5.949
Bioque G, Crusius JBA, Koutroubakis I, Bouma G, Kostense PJ,
Meuwissen SGM, Pena AS (1995) Allelic polymorphism
in IL-1 beta and IL-1 receptor antagonist (IL-1Ra) genes in
inflammatory bowel disease. Clin Exp Immunol 102(2):379–
383. doi:10.1111/j.1365-2249.1995.tb03793.x
Blanchard A, Ohanian V, Critchley D (1989) The structure and func-
tion of α-actinin. J Muscle Res Cell Motil 10(4):280–289
Bodine SC, Latres E, Baumhueter S, Lai VK-M, Nunez L, Clarke
BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan
ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD,
Glass DJ (2001) Identification of ubiquitin ligases required
for skeletal muscle atrophy. Science 294(5547):1704–1708.
doi:10.1126/science.1065874
Boesen AP, Dideriksen K, Couppé C, Magnusson SP, Schjerling
P, Boesen M, Kjær M, Langberg H (2013) Tendon and skel-
etal muscle matrix gene expression and functional responses
to immobilisation and rehabilitation in young males: effect of
growth hormone administration. J Physiol 591(23):6039–6052.
doi:10.1113/jphysiol.2013.261263
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1617Eur J Appl Physiol (2016) 116:1595–1625
1 3
Boppart MD, Volker SE, Alexander N, Burkin DJ, Kaufman SJ
(2008) Exercise promotes alpha7 integrin gene transcrip-
tion and protection of skeletal muscle. Am J Physiol Regul
Integr Comp Physiol 295(5):R1623–R1630. doi:10.1152/
ajpregu.00089.2008
Borinskaya SA, Gureev AS, Orlova AA, Sanina ED, Kim AA, Gas-
emianrodsari F, Shirmanov VI, Balanovsky OP, Rebrikov DV,
Koshechkin AV, Yankovsky NK (2013) Allele frequency dis-
tributions of −174G/C polymorphism in regulatory region of
interleukin 6 gene (IL6) in Russian and worldwide populations.
Genetika 49(1):113–124
Borst SE (2004) The role of TNF-α in insulin resistance. Endocrine
23(2–3):177–182
Bottinelli R, Canepari M, Pellegrino MA, Reggiani C (1996) Force-
velocity properties of human skeletal muscle fibres: myosin
heavy chain isoform and temperature dependence. J Physiol
495(2):573-586
Brancaccio P, Maffulli N, Limongelli FM (2007) Creatine kinase
monitoring in sport medicine. Brit Med Bull 81(1):209–230
Bring DKI, Paulson K, Renstrom P, Salo P, Hart DA, Ackermann PW
(2012) Residual substance P levels after capsaicin treatment
correlate with tendon repair. Wound Repair Regen 20(1):50–60
Broos S, Malisoux L, Theisen D, Francaux M, Deldicque L, Thomis
MA (2012) Role of alpha-actinin-3 in contractile properties of
human single muscle fibers: a case series study in paraplegics.
PLoS One 7(11):1–6
Brooks SV, Faulkner JA (1990) Contraction-induced injury: recovery
of skeletal muscles in young and old mice. Am J Physiol - Cell
Physiology 258(3):C436–C442
Brown SJ, Child RB, Day SH, Donnelly AE (1997a) Exercise-
induced skeletal muscle damage and adaptation following
repeated bouts of eccentric muscle contractions. J Sport Sci
15(2):215–222
Brown SJ, Child RB, Day SH, Donnelly AE (1997b) Indices of skel-
etal muscle damage and connective tissue breakdown following
eccentric muscle contractions. Eur J Appl Physiol Occup Phys-
iol 75(4):369–374. doi:10.1007/s004210050174
Brown S, Day S, Donnelly A (1999) Indirect evidence of human skel-
etal muscle damage and collagen breakdown after eccentric
muscle actions. J Sport Sci 17(5):397–402
Brunner HG, Korneluk RG, Coerwinkel-Driessen M, MacKenzie A,
Smeets H, Lambermon HMM, Van Oost BA, Wieringa B, Rop-
ers H-H (1989) Myotonic dystrophy is closely linked to the
gene for muscle-type creatine kinase (CKMM). Hum Genet
81(4):308–310
Butterfield TA (2010) Eccentric exercise in vivo: strain-induced mus-
cle damage and adaptation in a stable system. Exerc Sport Sci
Rev 38(2):51–60
Cannon JG, Fiatarone MA, Fielding RA, Evans WJ (1994) Aging and
stress-induced changes in complement activation and neutrophil
mobilization. J Appl Physiol 76(6):2616–2620
Cantini M, Giurisato E, Radu C, Tiozzo S, Pampinella F, Senigaglia
D, Zaniolo G, Mazzoleni F, Vitiello L (2002) Macrophage-
secreted myogenic factors: a promising tool for greatly enhanc-
ing the proliferative capacity of myoblasts in vitro and in vivo.
Neurol Sci 23(4):189–194. doi:10.1007/s100720200060
Catoire M, Kersten S (2015) The search for exercise factors in
humans. FASEB J 29(5):1615–1628. doi:10.1096/fj.14-263699
Cauci S, Di Santolo M, Ryckman KK, Williams SM, Banfi G (2010)
Variable number of tandem repeat polymorphisms of the inter-
leukin-1 receptor antagonist gene IL-1RN: a novel association
with the athlete status. BMC Med Genet 11(1):29
Chambers RL, McDermott JC (1996) Molecular basis of skeletal
muscle regeneration. Can J Appl Physiol 21(3):155–184
Chan S, Seto JT, Houweling PJ, Yang N, North KN, Head SI (2011)
Properties of extensor digitorum longus muscle and skinned
fibers from adult and aged male and female Actn3 knockout
mice. Muscle Nerve 43(1):37–48. doi:10.1002/mus.21778
Cheng L, Zhang D, Zhou L, Zhao J, Chen B (2015) Association
between SLC30A8 rs13266634 polymorphism and type 2 dia-
betes risk: a meta-analysis. Med Sci Monit 21:2178–2189
Cheung K, Hume PA, Maxwell L (2003) Delayed onset muscle sore-
ness. Sports Med 33(2):145–164
Childers MK, McDonald KS (2004) Regulatory light chain phos-
phorylation increases eccentric contraction-induced injury in
skinned fast-twitch fibers. Muscle Nerve 29(2):313–317
Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Van-
dewalle B, Kerr-Conte J, Van Lommel L, Grunwald D, Favier
A, Seve M (2006) In vivo expression and functional charac-
terization of the zinc transporter ZnT8 in glucose-induced insu-
lin secretion. J Cell Sci 119(Pt 20):4199–4206. doi:10.1242/
jcs.03164
Clansey AC, Hanlon M, Wallace ES, Lake MJ (2012) Effects of
fatigue on running mechanics associated with tibial stress frac-
ture risk. Med Sci Sport Exerc 44(10):1917–1923
Clarkson PM, Hubal MJ (2002) Exercise-induced muscle damage in
humans. Am J Phys Med Rehabil 81(11):S52–S69
Clarkson PM, Nosaka K, Braun B (1992) Muscle function after exer-
cise-induced muscle damage and rapid adaptation. Med Sci
Sport Exerc 24(5):512–520
Clarkson PM, Devaney JM, Gordish-Dressman H, Thompson PD,
Hubal MJ, Urso M, Price TB, Angelopoulos TJ, Gordon PM,
Moyna NM (2005a) ACTN3 genotype is associated with
increases in muscle strength in response to resistance training in
women. J Appl Physiol 99(1):154–163
Clarkson PM, Hoffman EP, Zambraski E, Gordish-Dressman H,
Kearns A, Hubal M, Harmon B, Devaney JM (2005b) ACTN3
and MLCK genotype associations with exertional muscle
damage. J Appl Physiol (1985) 99(2):564–569. doi:10.1152/
japplphysiol.00130.2005
Collins M, Raleigh SM (2009) Genetic risk factors for musculoskel-
etal soft tissue injuries. Med Sport Sci 54:136–149
Conceição MS, Libardi CA, Nogueira FRD, Bonganha V, Gáspari
AF, Chacon-Mikahil MPT, Cavaglieri CR, Madruga VA (2012)
Effects of eccentric exercise on systemic concentrations of pro-
and anti-inflammatory cytokines and prostaglandin (E2): com-
parison between young and postmenopausal women. Eur J Appl
Physiol 112(9):3205–3213
Costa AM, Silva AJ, Garrido ND, Louro H, de Oliveira RJ, Bre-
itenfeld L (2009) Association between ACE D allele and elite
short distance swimming. Eur J Appl Physiol 106(6):785–790.
doi:10.1007/s00421-009-1080-z
Costill DL, Pascoe DD, Fink WJ, Robergs RA, Barr SI, Pearson D
(1990) Impaired muscle glycogen resynthesis after eccentric
exercise. J Appl Physiol 69(1):46–50
Crane JD, Abadi A, Hettinga BP, Ogborn DI, MacNeil LG, Steinberg
GR, Tarnopolsky MA (2013) Elevated mitochondrial oxidative
stress impairs metabolic adaptations to exercise in skeletal mus-
cle. PLoS One 8(12):e81879
da Cunha Nascimento D, de Sousa NMF, de Sousa Neto IV, Tibana
RA, de Souza VC, Vieira DCL, Camarço NF, de Oliveira S, de
Almeida JA, Navalta J (2015) Classification of pro-inflamma-
tory status for interleukin-6 affects relative muscle strength in
obese elderly women. Aging Clin Exp Res 27(6):791–797
Danser AJ, Schalekamp MA, Bax WA, van den Brink AM, Saxena
PR, Riegger GA, Schunkert H (1995) Angiotensin-converting
enzyme in the human heart effect of the deletion/insertion poly-
morphism. Circulation 92(6):1387–1388
Davis ME, Gumucio JP, Sugg KB, Bedi A, Mendias CL (2013) MMP
inhibition as a potential method to augment the healing of skel-
etal muscle and tendon extracellular matrix. J Appl Physiol
115(6):884–891
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1618 Eur J Appl Physiol (2016) 116:1595–1625
1 3
Dela F, Kjaer M (2006) Resistance training, insulin sensitivity and
muscle function in the elderly. Essays Biochem 42:75–88
Dela F, Mikines KJ, Larsen JJ, Galbo H (1996) Training-induced
enhancement of insulin action in human skeletal muscle: the
influence of aging. J Gerontol A Biol 51(4):B247–B252
DeLellis K, Ingles S, Kolonel L, McKean-Cowdin R, Henderson B,
Stanczyk F, Probst-Hensch NM (2003) IGF1 genotype, mean
plasma level and breast cancer risk in the Hawaii/Los Angeles
multiethnic cohort. Br J Cancer 88(2):277–282
Dendorfer A, Wolfrum S, Wagemann M, Qadri F, Dominiak P (2001)
Pathways of bradykinin degradation in blood and plasma of
normotensive and hypertensive rats. Am J Physiol Heart Circ
Physiol 280(5):H2182–H2188
Dennis RA, Trappe TA, Simpson P, Carroll C, Huang BE, Nagara-
jan R, Bearden E, Gurley C, Duff GW, Evans WJ (2004) Inter-
leukin-1 polymorphisms are associated with the inflammatory
response in human muscle to acute resistance exercise. J Phys-
iol 560(3):617–626
Deschepper CF (1994) Angiotensinogen: hormonal regulation and
relative importance in the generation of angiotensin II. Kidney
Int 46(6):1561–1563
Deuster PA, Contreras-Sesvold CL, O’Connor FG, Campbell WW,
Kenney K, Capacchione JF, Landau ME, Muldoon SM, Rush-
ing EJ, Heled Y (2013) Genetic polymorphisms associated with
exertional rhabdomyolysis. Eur J Appl Physiol 113(8):1997–
2004. doi:10.1007/s00421-013-2622-y
Devaney JM, Hoffman EP, Gordish-Dressman H, Kearns A, Zam-
braski E, Clarkson PM (2007) IGF-II gene region polymor-
phisms related to exertional muscle damage. J Appl Physiol
102(5):1815–1823
Dewberry R, Holden H, Crossman D, Francis S (2000) Interleu-
kin-1 receptor antagonist expression in human endothelial
cells and atherosclerosis. Arterioscler Thromb Vasc Biol
20(11):2394–2400
di Giovine FS, Takhsh E, Blakemore AIF, Duff GW (1992) Single
base polymorphism at −511 in the human interleukin-1 beta
gene (IL1 beta). Hum Mol Genet 1(6):450
Dinarello CA (2009) Immunological and inflammatory functions
of the interleukin-1 family. Annu Rev Immunol 27:519–550.
doi:10.1146/annurev.immunol.021908.132612
Dobrowolny G, Giacinti C, Pelosi L, Nicoletti C, Winn N, Barberi L,
Molinaro M, Rosenthal N, Musarò A (2005) Muscle expres-
sion of a local Igf-1 isoform protects motor neurons in an ALS
mouse model. J Cell Biol 168(2):193–199
Doessing S, Holm L, Heinemeier KM, Feldt-Rasmussen U, Schjerling
P, Qvortrup K, Larsen JO, Nielsen RH, Flyvbjerg A, Kjaer M
(2010) GH and IGF1 levels are positively associated with mus-
culotendinous collagen expression: experiments in acromegalic
and GH deficiency patients. Eur J Endocrinol 163(6):853–862
Dousset E, Avela J, Ishikawa M, Kallio J, Kuitunen S, Kyrolainen
H, Linnamo V, Komi PV (2007) Bimodal recovery pattern in
human skeletal muscle induced by exhaustive stretch–shorten-
ing cycle exercise. Med Sci Sport Exerc 39(3):453–460
Dreyer HC, Blanco CE, Sattler FR, Schroeder ET, Wiswell RA (2006)
Satellite cell numbers in young and older men 24 hours after
eccentric exercise. Muscle Nerve 33(2):242–253
Duan C, Ren H, Gao S (2010) Insulin-like growth factors (IGFs), IGF
receptors, and IGF-binding proteins: roles in skeletal muscle
growth and differentiation. Gen Comp Endocrinol 167(3):344–
351. doi:10.1016/j.ygcen.2010.04.009
Duance VC, Restall DJ, Beard H, Bourne FJ, Bailey AJ (1977) The
location of three collagen types in skeletal muscle. FEBS Lett
79(2):248–252
Ershler WB, Keller ET (2000) Age-associated increased interleukin-6
gene expression, late-life diseases, and frailty. Annu Rev Med
51(1):245–270
Erskine RM, Williams AG, Jones DA, Stewart CE, Degens H (2014)
The individual and combined influence of ACE and ACTN3
genotypes on muscle phenotypes before and after strength train-
ing. Scand J Med Sci Sports 24(4):642–648
Eynon N, Hanson ED, Lucia A, Houweling PJ, Garton F, North KN,
Bishop DJ (2013) Genes for elite power and sprint perfor-
mance: ACTN3 leads the way. Sports Med 43(9):803–817
Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson
PM (1998) Macrophages that have ingested apoptotic cells
in vitro inhibit proinflammatory cytokine production through
autocrine/paracrine mechanisms involving TGF-beta, PGE2,
and PAF. J Clin Invest 101(4):890
Fernández AM, Dupont J, Farrar RP, Lee S, Stannard B, Le Roith
D (2002) Muscle-specific inactivation of the IGF-I receptor
induces compensatory hyperplasia in skeletal muscle. J Clin
Invest 109(3):347–355
Fielding RA, Meredith CN, O’Reilly KP, Frontera WR, Cannon JG,
Evans WJ (1991) Enhanced protein breakdown after eccentric
exercise in young and older men. J Appl Physiol 71(2):674–679
Fielding RA, Manfredi TJ, Ding W, Fiatarone MA, Evans WJ, Can-
non JG (1993) Acute phase response in exercise. III. Neutrophil
and IL-1 beta accumulation in skeletal muscle. Am J Physiol
Reg I 265(1):R166–R172
Fischer CP (2006) Interleukin-6 in acute exercise and training: what is
the biological relevance? Exerc Immunol Rev 12:6–33
Fischer CP, Hiscock NJ, Penkowa M, Basu S, Vessby B, Kallner A,
Sjöberg LB, Pedersen BK (2004) Supplementation with vita-
mins C and E inhibits the release of interleukin-6 from contract-
ing human skeletal muscle. J Physiol 558(2):633–645
Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Hum-
phries S, Woo P (1998) The effect of novel polymorphisms in
the interleukin-6 (IL-6) gene on IL-6 transcription and plasma
IL-6 levels, and an association with systemic-onset juvenile
chronic arthritis. J Clin Invest 102(7):1369–1376. doi:10.1172/
JCI2629
Flann KL, LaStayo PC, McClain DA, Hazel M, Lindstedt SL (2011)
Muscle damage and muscle remodeling: no pain, no gain? J
Exp Biol 214(4):674–679
Florini JR, Ewton DZ, Coolican SA (1996) Growth hormone and the
insulin-like growth factor system in myogenesis. Endocr Rev
17(5):481–517. doi:10.1210/edrv-17-5-481
Flück M, Chiquet M, Schmutz S, Mayet-Sornay M-H, Desplanches D
(2003) Reloading of atrophied rat soleus muscle induces tenas-
cin-C expression around damaged muscle fibers. Am J Physiol
Reg I 284(3):R792–R801
Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Pan-
ourgia MP, Invidia L, Celani L, Scurti M (2007) Inflammaging
and anti-inflammaging: a systemic perspective on aging and
longevity emerged from studies in humans. Mech Ageing Dev
128(1):92–105
Freckleton G, Pizzari T (2013) Risk factors for hamstring muscle
strain injury in sport: a systematic review and meta-analysis. Br
J Sports Med 47(6):351–358
Friden J, Lieber RL (1992) Structural and mechanical basis of
exercise-induced muscle injury. Med Sci Sports Exerc
24(5):521–530
Friden J, Lieber RL (2001) Eccentric exercise-induced injuries to con-
tractile and cytoskeletal muscle fibre components. Acta Physiol
Scand 171(3):321–326
Friden J, Sjöström M, Ekblom B (1981) A morphological study of
delayed muscle soreness. Experientia 37(5):506–507
Friden J, Kjörell U, Thornell L-E (1984) Delayed muscle soreness
and cytoskeletal alterations: an immunocytological study in
man. Int J Sports Med 5(01):15–18
Fujita S, Rasmussen BB, Cadenas JG, Grady JJ, Volpi E (2006)
Effect of insulin on human skeletal muscle protein synthesis
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1619Eur J Appl Physiol (2016) 116:1595–1625
1 3
is modulated by insulin-induced changes in muscle blood flow
and amino acid availability. Am J Physiol Endocrinol Metab
291(4):E745–E754
Funghetto SS, Prestes J, Silva Ade O, Farias DL, Teixeira TG, Vieira
DC, Souza VC, Sousa NM, Navalta JW, Melo GF, Karnikowski
MG (2013) Interleukin-6 −174G/C gene polymorphism affects
muscle damage response to acute eccentric resistance exercise
in elderly obese women. Exp Gerontol 48(11):1255–1259.
doi:10.1016/j.exger.2013.08.009
Gautel M (2011) The sarcomeric cytoskeleton: who picks up the
strain? Curr Opin Cell Biol 23(1):39–46
Gayagay G, Yu B, Hambly B, Boston T, Hahn A, Celermajer DS,
Trent RJ (1998) Elite endurance athletes and the ACE I
allele–the role of genes in athletic performance. Hum Genet
103(1):48–50
Giachelli CM, Lombardi D, Johnson RJ, Murry CE, Almeida M
(1998) Evidence for a role of osteopontin in macrophage infil-
tration in response to pathological stimuli in vivo. Am J Pathol
152(2):353–358
Giacopelli F, Marciano R, Pistorio A, Catarsi P, Canini S, Karsenty
G, Ravazzolo R (2004) Polymorphisms in the osteopontin
promoter affect its transcriptional activity. Physiol Genomics
20(1):87–96. doi:10.1152/physiolgenomics.00138.2004
Goetsch KP, Niesler CU (2011) Optimization of the scratch assay for
in vitro skeletal muscle wound healing analysis. Anal Biochem
411(1):158–160
Goetsch KP, Myburgh KH, Niesler CU (2013) In vitro myoblast
motility models: investigating migration dynamics for the
study of skeletal muscle repair. J Muscle Res Cell Motil
34(5–6):333–347
Gomez-Cabrera M-C, Domenech E, Viña J (2008) Moderate exercise
is an antioxidant: upregulation of antioxidant genes by training.
Free Radic Biol Med 44(2):126–131
Gordon SE, Davis BS, Carlson CJ, Booth FW (2001) ANG II is
required for optimal overload-induced skeletal muscle hypertro-
phy. Am J Physiol Endocrinol Metab 280(1):E150–E159
Gordon PM, Liu D, Sartor MA, IglayReger HB, Pistilli EE, Gutmann
L, Nader GA, Hoffman EP (2012) Resistance exercise train-
ing influences skeletal muscle immune activation: a microarray
analysis. J Appl Physiol 112(3):443–453
Griffin CA, Apponi LH, Long KK, Pavlath GK (2010) Chemokine
expression and control of muscle cell migration during myo-
genesis. J Cell Sci 123(18):3052–3060
Grobler L, Collins M, Lambert MI (2004) Remodelling of skeletal
muscle following exercise-induced muscle damage: review arti-
cle. Int Sportmed J 5(2):67–83
Gumucio JP, Mendias CL (2013) Atrogin-1, MuRF-1, and sarcopenia.
Endocrine 43(1):12–21
Gysel T, Calders P, Cambier D, Roman de Mettelinge T, Kaufman
J, Taes Y, Zmierczak H-G, Goemaere S (2014) Association
between insulin resistance, lean mass and muscle torque/force
in proximal versus distal body parts in healthy young men. J
Musculoskelet Neuron Interact 14(1):41–49
Hamada K, Vannier E, Sacheck JM, Witsell AL, Roubenoff R (2005)
Senescence of human skeletal muscle impairs the local inflam-
matory cytokine response to acute eccentric exercise. FASEB
J 19(2):264–266. doi:10.1096/fj.03-1286fje
Hansen M, Boesen A, Holm L, Flyvbjerg A, Langberg H, Kjær M
(2013) Local administration of insulin-like growth factor-I
(IGF-I) stimulates tendon collagen synthesis in humans. Scand
J Med Sci Sports 23(5):614–619
Harmon BT, Orkunoglu-Suer EF, Adham K, Larkin JS, Gordish-
Dressman H, Clarkson PM, Thompson PD, Angelopoulos TJ,
Gordon PM, Moyna NM (2010) CCL2 and CCR2 variants are
associated with skeletal muscle strength and change in strength
with resistance training. J Appl Physiol 109(6):1779–1785
Harrison S, Geppetti P (2001) Substance p. Int J Biochem Cell Biol
33(6):555–576
Hawke TJ, Garry DJ (2001) Myogenic satellite cells: physiology to
molecular biology. J Appl Physiol (1985) 91(2):534–551
Head SI, Chan S, Houweling PJ, Quinlan KGR, Murphy R, Wagner
S, Friedrich O, North KN (2015) Altered Ca2+ kinetics asso-
ciated with α-actinin-3 deficiency may explain positive selec-
tion for ACTN3 null allele in human evolution. PLoS Genet
11(1):e1004862
Heled Y, Bloom MS, Wu TJ, Stephens Q, Deuster PA (2007) CM-MM
and ACE genotypes and physiological prediction of the creatine
kinase response to exercise. J Appl Physiol 103(2):504–510
Hill M, Goldspink G (2003) Expression and splicing of the insulin-
like growth factor gene in rodent muscle is associated with mus-
cle satellite (stem) cell activation following local tissue damage.
J Physiol 549(2):409–418
Hirata A, Masuda S, Tamura T, Kai K, Ojima K, Fukase A, Motoy-
oshi K, Kamakura K, Miyagoe-Suzuki Y, Takeda S (2003)
Expression profiling of cytokines and related genes in regen-
erating skeletal muscle after cardiotoxin injection: a role
for osteopontin. Am J Pathol 163(1):203–215. doi:10.1016/
S0002-9440(10)63644-9
Hoffman EP, Gordish-Dressman H, McLane VD, Devaney JM,
Thompson PD, Visich P, Gordon PM, Pescatello LS, Zoeller
RF, Moyna NM (2013) Alterations in osteopontin modify mus-
cle size in females in both humans and mice. Med Sci Sport
Exerc 45(6):1060
Holmes AG, Watt MJ, Febbraio MA (2004) Suppressing lipolysis
increases interleukin-6 at rest and during prolonged moderate-
intensity exercise in humans. J Appl Physiol 97(2):689–696
Hornberger TA, McLoughlin TJ, Leszczynski JK, Armstrong DD,
Jameson RR, Bowen PE, Hwang ES, Hou H, Moustafa ME,
Carlson BA, Hatfield DL, Diamond AM, Esser KA (2003) Sele-
noprotein-deficient transgenic mice exhibit enhanced exercise-
induced muscle growth. J Nutr 133(10):3091–3097
Howatson G, Van Someren KA (2008) The prevention and treat-
ment of exercise-induced muscle damage. Sports Med
38(6):483–503
Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W (2000) Super-
oxide dismutase as a target for the selective killing of cancer
cells. Nature 407(6802):390–395. doi:10.1038/35030140
Hubal MJ, Chen TC, Thompson PD, Clarkson PM (2008) Inflamma-
tory gene changes associated with the repeated-bout effect. Am
J Physiol Reg I 294(5):R1628–R1637
Hubal MJ, Devaney JM, Hoffman EP, Zambraski EJ, Gordish-Dress-
man H, Kearns AK, Larkin JS, Adham K, Patel RR, Clarkson
PM (2010) CCL2 and CCR2 polymorphisms are associated
with markers of exercise-induced skeletal muscle damage. J
Appl Physiol 108(6):1651–1658
Huerta-Alardín AL, Varon J, Marik PE (2005) Bench-to-bedside
review: rhabdomyolysis—an overview for clinicians. Crit Care
9(2):158–169
Hughes SM, Blau HM (1990) Migration of myoblasts across
basal lamina during skeletal muscle development. Nature
345(6273):350–353
Hughes DC, Wallace MA, Baar K (2015) Effects of aging, exer-
cise and disease on force transfer in skeletal muscle. Am
J Physiol Endocrinol Metab 309(1):E1–E10. doi:10.1152/
ajpendo.00095.2015
Hyldahl RD, Hubal MJ (2014) Lengthening our perspective: morpho-
logical, cellular and molecular respones to eccentric exercise.
Muscle Nerve 49(2):155–170. doi:10.1002/mus.24077
Inoue M, Tokuyama S, Nakayamada H, Ueda H (1998) In vivo signal
transduction of tetrodotoxin-sensitive nociceptive responses by
substance P given into the planta of the mouse hind limb. Cell
Mol Neurobiol 18(5):555–561
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1620 Eur J Appl Physiol (2016) 116:1595–1625
1 3
Iwao-Koizumi K, Ota T, Hayashida M, Yonetani Y, Nakata K (2014)
The ACTN3 gene is a potential biomarker for the risk of non-
contact sports injury in female athletes. J Mol Biomark Diagn
S6:2
Jiao S, Ren H, Li Y, Zhou J, Duan C, Lu L (2013) Differential regu-
lation of IGF-I and IGF-II gene expression in skeletal muscle
cells. Mol Cell Biochem 373(1–2):107–113
Jiménez-Jiménez R, Cuevas MJ, Almar M, Lima E, García-López
D, De Paz JA, González-Gallego J (2008) Eccentric training
impairs NF-κB activation and over-expression of inflammation-
related genes induced by acute eccentric exercise in the elderly.
Mech Ageing Dev 129(6):313–321
Joffe YT, Collins M, Goedecke JH (2013) The relationship between
dietary fatty acids and inflammatory genes on the obese pheno-
type and serum lipids. Nutrients 5(5):1672–1705
Kahles F, Findeisen HM, Bruemmer D (2014) Osteopontin: a novel
regulator at the cross roads of inflammation, obesity and diabe-
tes. Mol Metab 3(4):384–393
Kanda K, Sugama K, Hayashida H, Sakuma J, Kawakami Y, Miura
S, Yoshioka H, Mori Y, Suzuki K (2013) Eccentric exercise-
induced delayed-onset muscle soreness and changes in mark-
ers of muscle damage and inflammation. Exerc Immunol Rev
19:72–85
Karimi M, Goldie LC, Cruickshank MN, Moses EK, Abraham LJ
(2009) A critical assessment of the factors affecting reporter
gene assays for promoter SNP function: a reassessment of
−308 TNF polymorphism function using a novel integrated
reporter system. Eur J Hum Genet 17(11):1454–1462
Keller HL, St Pierre Schneider B, Eppihimer LA, Cannon JG (1999)
Association of IGF-I and IGF-II with myofiber regeneration
in vivo. Muscle Nerve 22(3):347–354
Kibler WB, Chandler TJ, Stracener ES (1992) 4: musculoskeletal
adaptations and injuries due to overtraining. Exerc Sport Sci
Rev 20(1):99–126
Kirchhoff K, Machicao F, Haupt A, Schafer SA, Tschritter O, Staiger
H, Stefan N, Haring HU, Fritsche A (2008) Polymorphisms
in the TCF7L2, CDKAL1 and SLC30A8 genes are associated
with impaired proinsulin conversion. Diabetologia 51(4):597–
601. doi:10.1007/s00125-008-0926-y
Kirwan JP, Bourey RE, Kohrt WM, Staten MA, Holloszy JO (1991)
Effects of treadmill exercise to exhaustion on the insulin
response to hyperglycemia in untrained men. J Appl Physiol
70(1):246–250
Kjær M (2004) Role of extracellular matrix in adaptation of ten-
don and skeletal muscle to mechanical loading. Physiol Rev
84(2):649–698
Knochel JP (1990) Catastrophic medical events with exhaustive exer-
cise: “white collar rhabdomyolysis”. Kidney Int 38(4):709–719
Knoll R, Buyandelger B, Lab M (2011) The sarcomeric Z-disc
and Z-discopathies. J Biomed Biotechnol 2011:1–12.
doi:10.1155/2011/569628
Koskinen SOA, Wang W, Ahtikoski AM, Kjaer M, Han XY, Komu-
lainen J, Kovanen V, Takala TES (2001) Acute exercise
induced changes in rat skeletal muscle mRNAs and pro-
teins regulating type IV collagen content. Am J Physiol Reg I
280(5):R1292–R1300
Kuipers H (1994) Exercise-induced muscle damage. Int J Sports Med
15(03):132–135
Kurosaka M, Machida S (2012) Exercise and skeletal muscle regen-
eration. J Phys Fitness Sports Med 1(3):537–540
Laguette M-J, Abrahams Y, Prince S, Collins M (2011) Sequence
variants within the 3′-UTR of the COL5A1 gene alters mRNA
stability: implications for musculoskeletal soft tissue injuries.
Matrix Biol 30(5):338–345
Langberg H, Olesen JL, Gemmer C, Kjær M (2002) Substantial eleva-
tion of interleukin-6 concentration in peritendinous tissue, in
contrast to muscle, following prolonged exercise in humans. J
Physiol 542(3):985–990
Lappalainen J (2009) IL6 genotype and creatine kinase response to
exercise. Eur J Appl Physiol 106(2):315
Le Grand F, Rudnicki MA (2007) Skeletal muscle satellite cells and
adult myogenesis. Curr Opin Cell Biol 19(6):628–633
Lee HJ, Kim KJ, Park MH, Kimm K, Park C, Oh B, Lee JY (2005)
Single-nucleotide polymorphisms and haplotype LD analysis of
the 29-kb IGF2 region on chromosome 11p15.5 in the Korean
population. Hum Hered 60(2):73–80. doi:10.1159/000088269
Lemaire K, Ravier MA, Schraenen A, Creemers JW, Van de Plas R,
Granvik M, Van Lommel L, Waelkens E, Chimienti F, Rut-
ter GA, Gilon P, in’t Veld PA, Schuit FC (2009) Insulin crys-
tallization depends on zinc transporter ZnT8 expression, but
is not required for normal glucose homeostasis in mice. Proc
Natl Acad Sci USA 106(35):14872–14877. doi:10.1073/
pnas.0906587106
Li YP, Lecker SH, Chen Y, Waddell ID, Goldberg AL, Reid MB
(2003) TNF-alpha increases ubiquitin-conjugating activity
in skeletal muscle by up-regulating UbcH2/E220k. FASEB J
17(9):1048–1057. doi:10.1096/fj.02-0759com
Li YP, Chen Y, John J, Moylan J, Jin B, Mann DL, Reid MB (2005)
TNF-alpha acts via p38 MAPK to stimulate expression of the
ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB J
19(3):362–370. doi:10.1096/fj.04-2364com
Ling PR, Schwartz JH, Bistrian BR (1997) Mechanisms of host wast-
ing induced by administration of cytokines in rats. Am J Physiol
Endocrinol Metab 272(3):E333–E339
Llovera M, Garcia-Martinez C, Lopez-Soriano J, Carbo N, Agell N,
Lopez-Soriano FJ, Argiles JM (1998) Role of TNF receptor 1
in protein turnover during cancer cachexia using gene knockout
mice. Mol Cell Endocrinol 142(1–2):183–189
Lossie J, Köhncke C, Mahmoodzadeh S, Steffen W, Canepari M, Maf-
fei M, Taube M, Larchevêque O, Baumert P, Haase H (2014)
Molecular mechanism regulating myosin and cardiac functions
by ELC. Biochem Biophys Res Commun 450(1):464–469
Lovering RM, De Deyne PG (2004) Contractile function, sarco-
lemma integrity, and the loss of dystrophin after skeletal muscle
eccentric contraction-induced injury. Am J Physiol Cell Physiol
286(2):C230–C238
Lucia A, Gomez-Gallego F, Chicharro JL, Hoyos J, Celaya K, Cor-
dova A, Villa G, Alonso JM, Barriopedro M, Perez M, Ear-
nest CP (2005) Is there an association between ACE and
CKMM polymorphisms and cycling performance status dur-
ing 3-week races? Int Sportmed J 26(6):442–447. doi:10.105
5/s-2004-821108
Luger TA (2002) Neuromediators—a crucial component of the skin
immune system. J Dermatol Sci 30(2):87–93
Ma F, Yang Y, Li X, Zhou F, Gao C, Li M, Gao L (2013) The associa-
tion of sport performance with ACE and ACTN3 genetic poly-
morphisms: a systematic review and meta-analysis. PLoS One
8(1):e54685
MacArthur DG, North KN (2004) A gene for speed? The evolution
and function of α-actinin-3. Bioessays 26(7):786–795
MacArthur DG, Seto JT, Raftery JM, Quinlan KG, Huttley GA, Hook
JW, Lemckert FA, Kee AJ, Edwards MR, Berman Y (2007)
Loss of ACTN3 gene function alters mouse muscle metabolism
and shows evidence of positive selection in humans. Nat Genet
39(10):1261–1265
MacArthur DG, Seto JT, Chan S, Quinlan KG, Raftery JM, Turner N,
Nicholson MD, Kee AJ, Hardeman EC, Gunning PW, Cooney
GJ, Head SI, Yang N, North KN (2008) An Actn3 knock-
out mouse provides mechanistic insights into the association
between alpha-actinin-3 deficiency and human athletic perfor-
mance. Hum Mol Genet 17(8):1076–1086. doi:10.1093/hmg/
ddm380
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1621Eur J Appl Physiol (2016) 116:1595–1625
1 3
Mackey AL, Donnelly AE, Turpeenniemi-Hujanen T, Roper HP
(2004) Skeletal muscle collagen content in humans after high-
force eccentric contractions. J Appl Physiol 97(1):197–203
Mackey AL, Brandstetter S, Schjerling P, Bojsen-Moller J, Qvortrup
K, Pedersen MM, Doessing S, Kjaer M, Magnusson SP, Lang-
berg H (2011) Sequenced response of extracellular matrix dead-
hesion and fibrotic regulators after muscle damage is involved
in protection against future injury in human skeletal muscle.
FASEB J 25(6):1943–1959
Mahoney DJ, Safdar A, Parise G, Melov S, Fu M, MacNeil L, Kaczor
J, Payne ET, Tarnopolsky MA (2008) Gene expression profiling
in human skeletal muscle during recovery from eccentric exer-
cise. Am J Physiol Reg I 294(6):R1901–R1910
Malm C, Nyberg P, Engström M, Sjödin B, Lenkei R, Ekblom B,
Lundberg I (2000) Immunological changes in human skeletal
muscle and blood after eccentric exercise and multiple biopsies.
J Physiol 529(1):243–262
Manfredi TG, Fielding RA, O’Reilly KP, Meredith CN, Lee HY,
Evans WJ (1991) Plasma creatine kinase activity and exercise-
induced muscle damage in older men. Med Sci Sport Exerc
23(9):1028–1034
Mansfield JC, Holden H, Tarlow JK, Di Giovine FS, McDowell TL,
Wilson AG, Holdsworth CD, Duff GW (1994) Novel genetic
association between ulcerative colitis and the anti-inflammatory
cytokine interleukin-1 receptor antagonist. Gastroenterology
106(3):637–642
Marsh DR, Criswell DS, Hamilton MT, Booth FW (1997) Association
of insulin-like growth factor mRNA expressions with muscle
regeneration in young, adult, and old rats. Am J Physiol Reg I
273(1):R353–R358
Martinez Amat A, Marchal Corrales JA, Rodriguez Serrano F, Bou-
laiz H, Prados Salazar JC, Hita Contreras F, Caba Perez O, Car-
rillo Delgado E, Martin I, Aranega Jimenez A (2007) Role of
alpha-actin in muscle damage of injured athletes in compari-
son with traditional markers. Br J Sports Med 41(7):442–446.
doi:10.1136/bjsm.2006.032730
Matheny W, Merritt E, Zannikos SV, Farrar RP, Adamo ML (2009)
Serum IGF-I-deficiency does not prevent compensatory skel-
etal muscle hypertrophy in resistance exercise. Exp Biol Med
234(2):164–170
McArdle A, Dillmann WH, Mestril R, Faulkner JA, Jackson MJ
(2004) Overexpression of HSP70 in mouse skeletal muscle pro-
tects against muscle damage and age-related muscle dysfunc-
tion. FASEB J 18(2):355–357
McGinley C, Shafat A, Donnelly AE (2009) Does antioxidant vitamin
supplementation protect against muscle damage? Sports Med
39(12):1011–1032
McHugh MP (2003) Recent advances in the understanding of the
repeated bout effect: the protective effect against muscle dam-
age from a single bout of eccentric exercise. Scand J Med Sci
Sports 13(2):88–97
McKay BR, De Lisio M, Johnston A, O’Reilly CE, Phillips SM, Tar-
nopolsky MA, Parise G (2009) Association of interleukin-6 sig-
nalling with the muscle stem cell response following muscle-
lengthening contractions in humans. PLoS One 4(6):e6027
Millay DP, O’Rourke JR, Sutherland LB, Bezprozvannaya S, Shel-
ton JM, Bassel-Duby R, Olson EN (2013) Myomaker is a
membrane activator of myoblast fusion and muscle formation.
Nature 499(7458):301–305
Millay DP, Sutherland LB, Bassel-Duby R, Olson EN (2014) Myomaker
is essential for muscle regeneration. Genes Dev 28(15):1641
Mills M, Yang N, Weinberger R, Vander Woude DL, Beggs AH,
Easteal S, North K (2001) Differential expression of the actin-
binding proteins, α-actinin-2 and -3, in different species: impli-
cations for the evolution of functional redundancy. Hum Mol
Genet 10(13):1335–1346
Miranda-Vilela AL, Akimoto AK, Lordelo GS, Pereira LC, Grisolia
CK, de Nazaré Klautau-Guimarães M (2012) Creatine kinase
MM TaqI and methylenetetrahydrofolate reductase C677T
and A1298C gene polymorphisms influence exercise-induced
C-reactive protein levels. Eur J Appl Physiol 112(1):183–192
Montgomery HE, Marshall R, Hemingway H, Myerson S, Clark-
son P, Dollery C, Hayward M, Holliman DE, Jubb M, World
M (1998) Human gene for physical performance. Nature
393(6682):221–222
Moran CN, Yang N, Bailey MES, Tsiokanos A, Jamurtas A, MacAr-
thur DG, North K, Pitsiladis YP, Wilson RH (2007) Association
analysis of the ACTN3 R577X polymorphism and complex
quantitative body composition and performance phenotypes in
adolescent Greeks. Eur J Hum Genet 15(1):88–93
Morgan DL (1990) New insights into the behavior of muscle during
active lengthening. Biophys J 57(2):209–221
Morse CI, Thom JM, Mian OS, Birch KM, Narici MV (2007) Gas-
trocnemius specific force is increased in elderly males follow-
ing a 12-month physical training programme. Eur J Appl Phys-
iol 100(5):563–570
Morton JP, Kayani AC, McArdle A, Drust B (2009) The exercise-
induced stress response of skeletal muscle, with specific empha-
sis on humans. Sports Med 39(8):643–662
Munzenmaier DH, Greene AS (1996) Opposing actions of angio-
tensin II on microvascular growth and arterial blood pressure.
Hypertension 27(3):760–765
Murase S, Terazawa E, Queme F, Ota H, Matsuda T, Hirate K, Kozaki
Y, Katanosaka K, Taguchi T, Urai H (2010) Bradykinin and
nerve growth factor play pivotal roles in muscular mechanical
hyperalgesia after exercise (delayed-onset muscle soreness). J
Neurosci 30(10):3752–3761
Murphey LJ, Gainer JV, Vaughan DE, Brown NJ (2000) Angiotensin-
converting enzyme insertion/deletion polymorphism modu-
lates the human in vivo metabolism of bradykinin. Circulation
102(8):829–832
Murton AJ, Constantin D, Greenhaff PL (2008) The involvement
of the ubiquitin proteasome system in human skeletal muscle
remodelling and atrophy. Biochim Biophys Acta 1782(12):730–
743. doi:10.1016/j.bbadis.2008.10.011
Musarò A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molin-
aro M, Barton ER, Sweeney HL, Rosenthal N (2001) Localized
Igf-1 transgene expression sustains hypertrophy and regenera-
tion in senescent skeletal muscle. Nat Genet 27(2):195–200
Myerson S, Hemingway H, Budget R, Martin J, Humphries S, Mont-
gomery H (1999) Human angiotensin I-converting enzyme
gene and endurance performance. J Appl Physiol (1985)
87(4):1313–1316
Nazarov IB, Woods DR, Montgomery HE, Shneider OV, Kazakov
VI, Tomilin NV, Rogozkin VA (2001) The angiotensin convert-
ing enzyme I/D polymorphism in Russian athletes. Eur J Hum
Genet 9(10):797–801. doi:10.1038/sj.ejhg.5200711
Nguyen HX, Tidball JG (2003) Interactions between neutrophils and
macrophages promote macrophage killing of rat muscle cells
in vitro. J Physiol 547(1):125–132
Nicol C, Avela J, Komi PV (2006) The stretch–shortening cycle.
Sports Med 36(11):977–999
Nielsen J, Farup J, Rahbek SK, de Paoli FV, Vissing K (2015)
Enhanced glycogen storage of a subcellular hot spot in human
skeletal muscle during early recovery from eccentric contrac-
tions. PLoS One 10(5):e0127808
Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR, Henson D, Utter
A, Davis JM, Williams F, Butterworth DE (1998) Influence of
mode and carbohydrate on the cytokine response to heavy exer-
tion. Med Sci Sport Exerc 30(5):671–678
Nieman DC, Peters EM, Henson DA, Nevines EI, Thompson MM
(2000) Influence of vitamin C supplementation on cytokine
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1622 Eur J Appl Physiol (2016) 116:1595–1625
1 3
changes following an ultramarathon. J Interferon Cytokine Res
20(11):1029–1035
Niemi A-K, Majamaa K (2005) Mitochondrial DNA and ACTN3 gen-
otypes in Finnish elite endurance and sprint athletes. Eur J Hum
Genet 13(8):965–969
Nigro JM, Schweinfest CW, Rajkovic A, Pavlovic J, Jamal S, Dot-
tin RP, Hart JT, Kamarck ME, Rae PM, Carty MD et al (1987)
cDNA cloning and mapping of the human creatine kinase M
gene to 19q13. Am J Hum Genet 40(2):115–125
North KN, Beggs AH (1996) Deficiency of a skeletal muscle isoform
of α-actinin (α-actinin-3) in merosin-positive congenital muscu-
lar dystrophy. Neuromuscular Disord 6(4):229–235
North KN, Yang N, Wattanasirichaigoon D, Mills M, Easteal S, Beggs
AH (1999) A common nonsense mutation results in α-actinin-3
deficiency in the general population. Nat Genet 21(4):353–354
Norrbrand L, Fluckey JD, Pozzo M, Tesch PA (2008) Resistance
training using eccentric overload induces early adaptations in
skeletal muscle size. Euro J Appl Physiol 102(3):271–281
Nosaka K, Clarkson PM (1996) Variability in serum creatine kinase
response after eccentric exercise of the elbow flexors. Int Sport-
med J 17(2):120–127. doi:10.1055/s-2007-972819
Nosaka K, Sakamoto K, Newton M, Sacco P (2001) How long does
the protective effect on eccentric exercise-induced muscle dam-
age last? Med Sci Sport Exerc 33(9):1490–1495
O’Dell SD, Day IN (1998) Insulin-like growth factor II (IGF-II). Int J
Biochem Cell Biol 30(7):767–771
Orchard JW (2001) Intrinsic and extrinsic risk factors for muscle
strains in Australian football. Am J Sports Med 29(3):300–303
Ostrowski K, Schjerling P, Pedersen BK (2000) Physical activity and
plasma interleukin-6 in humans—effect of intensity of exercise.
Eur J Appl Physiol 83(6):512–515
Owens DJ, Fraser WD, Close GL (2014) Vitamin D and the athlete:
emerging insights. Eur J Sport Sci 15(1):73–84
Patel JA, Nair S, Ochoa EE, Huda R, Roberts NJ Jr, Chonmaitree T
(2010) Interleukin-6 −174 and tumor necrosis factor α −308
polymorphisms enhance cytokine production by human mac-
rophages exposed to respiratory viruses. J Interferon Cytokine
Res 30(12):917–921
Patel HP, Al-Shanti N, Davies LC, Barton SJ, Grounds MD, Tellam
RL, Stewart CE, Cooper C, Sayer AA (2014) Lean mass, mus-
cle strength and gene expression in community dwelling older
men: findings from the Hertfordshire sarcopenia study (HSS).
Calcif Tissue Int 95(4):308–316
Paul AC, Rosenthal N (2002) Different modes of hypertrophy in skel-
etal muscle fibers. J Cell Biol 156(4):751–760
Paulsen G, Crameri R, Benestad HB, Fjeld JG, Mørkrid L, Hallen
J, Raastad T (2010) Time course of leukocyte accumulation in
human muscle after eccentric exercise. Med Sci Sport Exerc
42(1):75–85
Paulsen G, Mikkelsen UR, Raastad T, Peake JM (2012) Leucocytes,
cytokines and satellite cells: what role do they play in muscle
damage and regeneration following eccentric exercise. Exerc
Immunol Rev 18(1):42–97
Peake J, Suzuki K (2004) Neutrophil activation, antioxidant supple-
ments and exercise-induced oxidative stress. Exerc Immunol
Rev 10(1):129–141
Peake J, Nosaka KK, Suzuki K (2005) Characterization of inflamma-
tory responses to eccentric exercise in humans. Exerc Immunol
Rev 11:64–85
Peake J, Della Gatta P, Cameron-Smith D (2010) Aging and its
effects on inflammation in skeletal muscle at rest and fol-
lowing exercise-induced muscle injury. Am J Physiol Reg I
298(6):R1485–R1495
Peake J, Della Gatta P, Suzuki K, Nieman D (2015) Cytokine expres-
sion and secretion by skeletal muscle cells: regulatory mecha-
nisms and exercise effects. Exerc Immunol Rev 21:8–25
Pedersen BK (2011) Muscles and their myokines. J Exp Biol
214(2):337–346
Pedersen BK, Febbraio MA (2008) Muscle as an endocrine
organ: focus on muscle-derived interleukin-6. Physiol Rev
88(4):1379–1406
Pedersen BK, Fischer CP (2007) Beneficial health effects of exer-
cise—the role of IL-6 as a myokine. Trends Pharmacol Sci
28(4):152–156
Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard
P, Febbraio M, Saltin B (2003) Searching for the exercise factor:
is IL-6 a candidate? J Muscle Res Cell Motil 24(2–3):113–119
Pegoraro E, Hoffman EP, Piva L, Gavassini BF, Cagnin S, Ermani
M, Bello L, Soraru G, Pacchioni B, Bonifati MD, Lanfranchi
G, Angelini C, Kesari A, Lee I, Gordish-Dressman H, Devaney
JM, McDonald CM, Cooperative International Neuromus-
cular Research G (2011) SPP1 genotype is a determinant of
disease severity in Duchenne muscular dystrophy. Neurology
76(3):219–226. doi:10.1212/WNL.0b013e318207afeb
Pereira DS, Garcia DM, Narciso FMS, Santos MLAS, Dias JMD,
Queiroz BZ, Souza ER, Nobrega OT, Pereira LSM (2011)
Effects of 174 G/C polymorphism in the promoter region of the
interleukin-6 gene on plasma IL-6 levels and muscle strength in
elderly women. Braz J Med Biol Res 44(2):123–129
Pereira DS, Mateo ECC, de Queiroz BZ, Assumpção AM, Miranda AS,
Felício DC, Rocha NP, dos Anjos DMdC, Pereira DAG, Teixeira
AL (2013) TNF-α, IL6, and IL10 polymorphisms and the effect
of physical exercise on inflammatory parameters and physical per-
formance in elderly women. Age 35(6):2455–2463
Petersen AMW, Pedersen BK (2005) The anti-inflammatory effect of
exercise. J Appl Physiol 98(4):1154–1162
Philippou A, Maridaki M, Theos A, Koutsilieris M (2012) Cytokines
in muscle damage. Adv Clin Chem 58:49
Phillips MI, Speakman EA, Kimura B (1993) Levels of angiotensin
and molecular biology of the tissue renin angiotensin systems.
Regul Pept 43(1–2):1–20
Pimenta EM, Coelho DB, Cruz IR, Morandi RF, Veneroso CE, de Azam-
buja Pussieldi G, Carvalho MRS, Silami-Garcia E, Fernández
JADP (2012) The ACTN3 genotype in soccer players in response
to acute eccentric training. Eur J Appl Physiol 112(4):1495–1503
Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zier-
ath JR, Pedersen BK (2005) Tumor necrosis factor-α induces
skeletal muscle insulin resistance in healthy human subjects
via inhibition of Akt substrate 160 phosphorylation. Diabetes
54(10):2939–2945
Ploutz-Snyder LL, Giamis EL, Formikell M, Rosenbaum AE (2001)
Resistance training reduces susceptibility to eccentric exercise-
induced muscle dysfunction in older women. J Gerontol A Biol
56(9):B384–B390
Powers SK, Jackson MJ (2008) Exercise-induced oxidative stress:
cellular mechanisms and impact on muscle force production.
Physiol Rev 88(4):1243–1276
Proske U, Morgan DL (2001) Muscle damage from eccentric exer-
cise: mechanism, mechanical signs, adaptation and clinical
applications. J Physiol 537(2):333–345
Pruna R, Artells R, Ribas J, Montoro B, Cos F, Muñoz C, Rodas G,
Maffulli N (2013) Single nucleotide polymorphisms associated
with non-contact soft tissue injuries in elite professional soccer
players Influence on degree of injury and recovery time. BMC
Musculoskelet Disord 14(1):221
Przybyla B, Gurley C, Harvey JF, Bearden E, Kortebein P, Evans
WJ, Sullivan DH, Peterson CA, Dennis RA (2006) Aging
alters macrophage properties in human skeletal muscle both at
rest and in response to acute resistance exercise. Exp Gerontol
41(3):320–327
Qi L, Zhang C, van Dam RM, Hu FB (2007) Interleukin-6 genetic
variability and adiposity: associations in two prospective
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1623Eur J Appl Physiol (2016) 116:1595–1625
1 3
cohorts and systematic review in 26,944 individuals. J Clin
Endocrinol Metab 92(9):3618–3625
Quinlan KG, Seto JT, Turner N, Vandebrouck A, Floetenmeyer M,
Macarthur DG, Raftery JM, Lek M, Yang N, Parton RG (2010)
α-Actinin-3 deficiency results in reduced glycogen phosphory-
lase activity and altered calcium handling in skeletal muscle.
Hum Mol Genet 19(7):1335–1346
Raastad T, Owe SG, Paulsen G, Enns D, Overgaard K, Crameri R,
Kiil S, Belcastro A, Bergersen L, Hallen J (2010) Changes in
calpain activity, muscle structure, and function after eccen-
tric exercise. Med Sci Sports Exerc 42(1):86–95. doi:10.1249/
MSS.0b013e3181ac7afa
Ramaswamy KS, Palmer ML, van der Meulen JH, Renoux A, Kostro-
minova TY, Michele DE, Faulkner JA (2011) Lateral transmis-
sion of force is impaired in skeletal muscles of dystrophic mice
and very old rats. J Physiol 589(5):1195–1208
Rankinen T, Wolfarth B, Simoneau JA, Maier-Lenz D, Rauramaa
R, Rivera MA, Boulay MR, Chagnon YC, Perusse L, Keul J,
Bouchard C (2000) No association between the angiotensin-
converting enzyme ID polymorphism and elite endurance ath-
lete status. J Appl Physiol (1985) 88(5):1571–1575
Reeves ND, Narici MV, Maganaris CN (2004) Effect of resistance
training on skeletal muscle-specific force in elderly humans. J
Appl Physiol 96(3):885–892
Reid MB (2005) Response of the ubiquitin-proteasome pathway to
changes in muscle activity. Am J Physiol Regul Integr Comp
Physiol 288(6):R1423–R1431. doi:10.1152/ajpregu.00545.2004
Reid MB, Li YP (2001) Tumor necrosis factor-alpha and muscle
wasting: a cellular perspective. Respir Res 2(5):269–272
Rein T, Förster R, Krause A, Winnacker E-L, Zorbas H (1995) Organ-
ization of the-globin promoter and possible role of nuclear fac-
tor I in an-globin-inducible and in a noninducible cell line. J
Biol Chem 270(33):19643–19650
Renzi D, Pellegrini B, Tonelli F, Surrenti C, Calabro A (2000) Sub-
stance P (neurokinin-1) and neurokinin A (neurokinin-2) recep-
tor gene and protein expression in the healthy and inflamed
human intestine. Am J Pathol 157(5):1511–1522
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier
F (1990) An insertion/deletion polymorphism in the angio-
tensin I-converting enzyme gene accounting for half the vari-
ance of serum enzyme levels. J Clin Invest 86(4):1343–1346.
doi:10.1172/JCI114844
Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P (2006)
Mutations in RYR1 in malignant hyperthermia and central core
disease. Hum Mutat 27(10):977–989. doi:10.1002/humu.20356
Rodan GA (1995) Osteopontin overview. Ann N Y Acad Sci
760(1):1–5
Roig M, O’Brien K, Kirk G, Murray R, McKinnon P, Shadgan B,
Reid DW (2008) The effects of eccentric versus concentric
resistance training on muscle strength and mass in healthy
adults: a systematic review with meta-analyses. Br J Sports
Med 43:556–568
Rosen CJ, Kurland ES, Vereault D, Adler RA, Rackoff PJ, Craig WY,
Witte S, Rogers J, Bilezikian JP (1998) Association between
serum insulin growth factor-I (IGF-I) and a simple sequence
repeat in IGF-I gene: implications for genetic studies of bone
mineral density. J Clin Endocrinol Metab 83(7):2286–2290
Roth SM, Martel GF, Ivey FM, Lemmer JT, Metter EJ, Hurley BF,
Rogers MA (2000) High-volume, heavy-resistance strength
training and muscle damage in young and older women. J Appl
Physiol 88(3):1112–1118
Roubenoff R, Parise H, Payette HA, Abad LW, D’Agostino R, Jacques
PF, Wilson PW, Dinarello CA, Harris TB (2003) Cytokines,
insulin-like growth factor 1, sarcopenia, and mortality in very
old community-dwelling men and women: the Framingham
Heart Study. Am J Med 115(6):429–435
Rubinstein I, Abassi Z, Coleman R, Milman F, Winaver J, Better OS
(1998) Involvement of nitric oxide system in experimental mus-
cle crush injury. J Clin Invest 101(6):1325
Ruiz JR, Buxens A, Artieda M, Arteta D, Santiago C, Rodríguez-
Romo G, Lao JI, Gómez-Gallego F, Lucia A (2010) The −174
G/C polymorphism of the IL6 gene is associated with elite
power performance. J Sci Med Sport 13(5):549–553
Sacheck JM, Hyatt J-PK, Raffaello A, Jagoe RT, Roy RR, Edgerton
VR, Lecker SH, Goldberg AL (2007) Rapid disuse and den-
ervation atrophy involve transcriptional changes similar to
those of muscle wasting during systemic diseases. FASEB J
21(1):140–155
Santtila S, Savinainen K, Hurme M (1998) Presence of the IL-1RA
allele 2 (IL1RN*2) is associated with enhanced IL-1beta pro-
duction in vitro. Scand J Immunol 47(3):195–198
Schmaier AH (2003) The kallikrein-kinin and the renin-angiotensin
systems have a multilayered interaction. Am J Physiol Reg I
285(1):R1–R13
Schneider BSP, Tiidus PM (2007) Neutrophil infiltration in exercise-
injured skeletal muscle. Sports Med 37(10):837–856
Schoenfeld BJ (2010) The mechanisms of muscle hypertrophy
and their application to resistance training. J Strength Cond
24(10):2857–2872
Schoenfeld BJ (2012) Does exercise-induced muscle damage
play a role in skeletal muscle hypertrophy? J Strength Cond
26(5):1441–1453
September AV, Schwellnus MP, Collins M (2007) Tendon and
ligament injuries: the genetic component. Br J Sports Med
41(4):241–246
Seto JT, Lek M, Quinlan KG, Houweling PJ, Zheng XF, Garton F,
MacArthur DG, Raftery JM, Garvey SM, Hauser MA (2011)
Deficiency of α-actinin-3 is associated with increased suscep-
tibility to contraction-induced damage and skeletal muscle
remodeling. Hum Mol Genet 20(15):2914–2927. doi:10.1093/
hmg/ddr196
Seto JT, Quinlan KG, Lek M, Zheng XF, Garton F, MacArthur
DG, Hogarth MW, Houweling PJ, Gregorevic P, Turner N
(2013) ACTN3 genotype influences muscle performance
through the regulation of calcineurin signaling. J Clin Invest
123(10):4255–4263
Seynnes OR, de Boer M, Narici MV (2007) Early skeletal muscle
hypertrophy and architectural changes in response to high-
intensity resistance training. J Appl Physiol 102(1):368–373
Sharples AP, Stewart CE (2011) Myoblast models of skeletal mus-
cle hypertrophy and atrophy. Curr Opin Clin Nutr Metab Care
14(3):230–236
Shimoda-Matsubayashi S, Matsumine H, Kobayashi T, Nakagawa-
Hattori Y, Shimizu Y, Mizuno Y (1996) Structural dimorphism
in the mitochondrial targeting sequence in the human manga-
nese superoxide dismutase gene. A predictive evidence for
conformational change to influence mitochondrial transport
and a study of allelic association in Parkinson’s disease. Bio-
chem Biophys Res Commun 226(2):561–565. doi:10.1006/
bbrc.1996.1394
Siems W, Capuozzo E, Lucano A, Salerno C, Crifo C (2003) High
sensitivity of plasma membrane ion transport ATPases from
human neutrophils towards 4-hydroxy-2, 3-trans-nonenal. Life
Sci 73(20):2583–2590
Sim M-K, Wong Y-C, Xu X-G, Loke W-K (2014) Des-aspartate-angi-
otensin I attenuates ICAM-1 formation in hydrogen peroxide-
treated L6 skeletal muscle cells and soleus muscle of mice sub-
jected to eccentric exercise. Regul Pept 188:40–45
Smith LL, McCammon M, Smith S, Chamness M, Israel RG, O’Brien
KF (1989) White blood cell response to uphill walking and
downhill jogging at similar metabolic loads. Eur J Appl Physiol
Occup Physiol 58(8):833–837
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1624 Eur J Appl Physiol (2016) 116:1595–1625
1 3
Smith CK 2nd, Janney MJ, Allen RE (1994) Temporal expression of
myogenic regulatory genes during activation, proliferation, and
differentiation of rat skeletal muscle satellite cells. J Cell Phys-
iol 159(2):379–385. doi:10.1002/jcp.1041590222
Smith LL, McKune AJ, Semple SJ, Sibanda E, Steel H, Anderson
R (2007) Changes in serum cytokines after repeated bouts of
downhill running. Appl Physiol Nutr Metab 32(2):233–240.
doi:10.1139/h06-106
Smith C, Kruger MJ, Smith RM, Myburgh KH (2008) The
inflammatory response to skeletal muscle injury: illu-
minating complexities. Sports Med 38(11):947–969.
doi:10.2165/00007256-200838110-00005
Snijders T, Verdijk LB, van Loon LJ (2009) The impact of sarcopenia
and exercise training on skeletal muscle satellite cells. Ageing
Res Rev 8(4):328–338
Somboonwong J, Traisaeng S, Saguanrungsirikul S (2015) Moder-
ate-intensity exercise training elevates serum and pancreatic
zinc levels and pancreatic ZnT8 expression in streptozotocin-
induced diabetic rats. Life Sci 139:46–51. doi:10.1016/j.
lfs.2015.08.008
Song Y, Stål PS, Yu J-G, Lorentzon R, Backman C, Forsgren S (2014)
Inhibitors of endopeptidase and angiotensin-converting enzyme
lead to an amplification of the morphological changes and an
upregulation of the substance P system in a muscle overuse
model. BMC Musculoskelet Disord 15(1):126
Sprouse C, Gordish-Dressman H, Orkunoglu-Suer EF, Lipof JS, Moe-
ckel-Cole S, Patel RR, Adham K, Larkin JS, Hubal MJ, Kearns
AK (2014) SLC30A8 nonsynonymous variant is associated
with recovery following exercise and skeletal muscle size and
strength. Diabetes 63(1):363–368
Staiger H, Machicao F, Stefan N, Tschritter O, Thamer C, Kantartzis
K, Schafer SA, Kirchhoff K, Fritsche A, Haring HU (2007) Pol-
ymorphisms within novel risk loci for type 2 diabetes determine
beta-cell function. PLoS One 2(9):e832. doi:10.1371/journal.
pone.0000832
Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK
(2003) Exercise and IL-6 infusion inhibit endotoxin-induced
TNF-alpha production in humans. FASEB J 17(8):884–886.
doi:10.1096/fj.02-0670fje
Stauber WT, Clarkson PM, Fritz VK, Evans WJ (1990) Extracellular
matrix disruption and pain after eccentric muscle action. J Appl
Physiol 69(3):868–874
Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK
(2003) IL-6 enhances plasma IL-1ra, IL-10, and cortisol in
humans. Am J Physiol Endocrinol Metab 285(2):E433–E437.
doi:10.1152/ajpendo.00074.2003
Stewart CE, Rotwein P (1996a) Growth, differentiation, and survival:
multiple physiological functions for insulin-like growth factors.
Physiol Rev 76(4):1005–1026
Stewart CE, Rotwein P (1996b) Insulin-like growth factor-II is an
autocrine survival factor for differentiating myoblasts. J Biol
Chem 271(19):11330–11338
Stewart CE, James PL, Fant ME, Rotwein P (1996) Overexpres-
sion of insulin-like growth factor-II induces accelerated myo-
blast differentiation. J Cell Physiol 169(1):23–32. doi:10.1002/
(sici)1097-4652(199610)169:1<23:aid-jcp3>3.0.co;2-g
Stewart CE, Newcomb PV, Holly JMP (2004) Multifaceted roles of
TNF-α in myoblast destruction: a multitude of signal transduc-
tion pathways. J Cell Physiol 198(2):237–247
Steyaert A, Burssens P, Forsyth R, Vanderstraeten G (2010) Qualita-
tive analysis of substance P, NK1-receptor and nerve ingrowth
in substance P-treated ruptured rat Achilles tendon. Acta Orthop
Belg 76(3):387–395
Suzuki YJ, Ford GD (1999) Redox regulation of signal transduction in
cardiac and smooth muscle. J Mol Cell Cardiol 31(2):345–353
Suzuki K, Naganuma S, Totsuka M, Suzuki K-J, Mochizuki M, Shi-
raishi M, Nakaji S, Sugawara K (1996) Effects of exhaustive
endurance exercise and its one-week daily repetition on neutro-
phil count and functional status in untrained men. Int J Sports
Med 17(03):205–212
Suzuki K, Nakaji S, Yamada M, Totsuka M, Sato K, Sugawara K
(2002) Systemic inflammatory response to exhaustive exercise.
Cytokine kinetics. Exerc Immunol Rev 8:6–48
Sweeney HL, Bowman BF, Stull JT (1993) Myosin light chain phos-
phorylation in vertebrate striated muscle: regulation and func-
tion. Am J Physiol 264:C1085
Szczesna D, Zhao J, Jones M, Zhi G, Stull J, Potter JD (2002) Phos-
phorylation of the regulatory light chains of myosin affects
Ca2+ sensitivity of skeletal muscle contraction. J Appl Physiol
(1985) 92(4):1661–1670. doi:10.1152/japplphysiol.00858.2001
Tedesco FS, Dellavalle A, Diaz-Manera J, Messina G, Cossu G
(2010) Repairing skeletal muscle: regenerative potential of skel-
etal muscle stem cells. J Clin Invest 120(1):11–19. doi:10.1172/
JCI40373
Thalacker-Mercer AE, Dell’Italia LJ, Cui X, Cross JM, Bamman MM
(2010) Differential genomic responses in old vs. young humans
despite similar levels of modest muscle damage after resistance
loading. Physiol Genomics 40(3):141–149
Thiebaud RS (2012) Exercise-induced muscle damage: is it detrimen-
tal or beneficial. J Trainol 1:36–44
Thompson WR, Binder-Macleod SA (2006) Association of genetic
factors with selected measures of physical performance. Phys
Ther 86(4):585–591
Tiainen K, Thinggaard M, Jylhä M, Bladbjerg E, Christensen K,
Christiansen L (2012) Associations between inflammatory
markers, candidate polymorphisms and physical performance in
older Danish twins. Exp Gerontol 47(1):109–115
Tidball JG (2005) Inflammatory processes in muscle injury and repair.
Am J Physiol Reg I 288(2):R345–R353
Tidball JG (2011) Mechanisms of muscle injury, repair, and regenera-
tion. Compr Physiol 1:2029–2062
Tidball JG, Villalta SA (2010) Regulatory interactions between mus-
cle and the immune system during muscle regeneration. Am J
Physiol Reg I 298(5):R1173–R1187
Toft AD, Jensen LB, Bruunsgaard H, Ibfelt T, Halkjær-Kristensen J,
Febbraio M, Pedersen BK (2002) Cytokine response to eccen-
tric exercise in young and elderly humans. Am J Physiol Cell
Physiol 283(1):C289–C295
Torrente Y, El Fahime E, Caron NJ, Del Bo R, Belicchi M, Pisati F,
Tremblay JP, Bresolin N (2003) Tumor necrosis factor-alpha
(TNF-alpha) stimulates chemotactic response in mouse myo-
genic cells. Cell Transplant 12(1):91–100
Toumi H, F’guyer S, Best TM (2006) The role of neutrophils in injury
and repair following muscle stretch. J Anat 208(4):459–470
Vaessen N, Heutink P, Janssen JA, Witteman JC, Testers L, Hofman
A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM (2001)
A polymorphism in the gene for IGF-I functional properties
and risk for type 2 diabetes and myocardial infarction. Diabetes
50(3):637–642
Vangsted AJ, Klausen TW, Abildgaard N, Andersen NF, Gimsing P,
Gregersen H, Nexo BA, Vogel U (2011) Single nucleotide poly-
morphisms in the promoter region of the IL1B gene influence
outcome in multiple myeloma patients treated with high-dose
chemotherapy independently of relapse treatment with tha-
lidomide and bortezomib. Ann Hematol 90(10):1173–1181.
doi:10.1007/s00277-011-1194-3
Vaughan D, Huber-Abel FA, Graber F, Hoppeler H, Flück M (2013)
The angiotensin converting enzyme insertion/deletion polymor-
phism alters the response of muscle energy supply lines to exer-
cise. Eur J Appl Physiol 113(7):1719–1729
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1625Eur J Appl Physiol (2016) 116:1595–1625
1 3
Venckunas T, Skurvydas A, Brazaitis M, Kamandulis S, Snieckus A,
Moran CN (2012) Human alpha-actinin-3 genotype association
with exercise-induced muscle damage and the repeated-bout
effect. Appl Physiol Nutr Metab 37(6):1038–1046
Vincent B, Windelinckx A, Nielens H, Ramaekers M, Van Leemputte
M, Hespel P, Thomis MA (2010) Protective role of α-actinin-3
in the response to an acute eccentric exercise bout. J Appl Phys-
iol 109(2):564–573
Wahl P, Brixius K, Bloch W (2008) Exercise-induced stem cell activa-
tion and its implication for cardiovascular and skeletal muscle
regeneration. Minim Invasive Ther Allied Technol 17(2):91–99
Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM
(1992) Intracellular compartmentation, structure and function
of creatine kinase isoenzymes in tissues with high and fluctuat-
ing energy demands: the ‘phosphocreatine circuit’ for cellular
energy homeostasis. Biochem J 281(Pt 1):21–40
Walsh S, Liu D, Metter EJ, Ferrucci L, Roth SM (2008) ACTN3 gen-
otype is associated with muscle phenotypes in women across
the adult age span. J Appl Physiol 105(5):1486–1491
Walston J, Arking DE, Fallin D, Li T, Beamer B, Xue Q, Ferrucci L,
Fried LP, Chakravarti A (2005) IL-6 gene variation is not asso-
ciated with increased serum levels of IL-6, muscle, weakness,
or frailty in older women. Exp Gerontol 40(4):344–352
Wang Y-C, Hu Y-W, Sha Y-H, Gao J-J, Ma X, Li S-F, Zhao J-Y, Qiu
Y-R, Lu J-B, Huang C (2015) Ox-LDL upregulates IL-6 expres-
sion by enhancing NF-κB in an IGF2-dependent manner in
THP-1 macrophages. Inflammation 38(6):1–8
Warren GL, Lowe DA, Hayes DA, Karwoski CJ, Prior BM, Armstrong
R (1993) Excitation failure in eccentric contraction-induced
injury of mouse soleus muscle. J Physiol 468(1):487–499
Warren GL, Hulderman T, Jensen N, McKinstry M, Mishra M, Luster
MI, Simeonova PP (2002a) Physiological role of tumor necrosis
factor alpha in traumatic muscle injury. FASEB J 16(12):1630–
1632. doi:10.1096/fj.02-0187fje
Warren JD, Blumbergs PC, Thompson PD (2002b) Rhabdomyolysis:
a review. Muscle Nerve 25(3):332–347
Warren GL, Hulderman T, Mishra D, Gao X, Millecchia L, O’Farrell
L, Kuziel WA, Simeonova PP (2005) Chemokine receptor
CCR2 involvement in skeletal muscle regeneration. FASEB J
19(3):413–415
Wei W, Fareed MU, Evenson A, Menconi MJ, Yang H, Petkova V,
Hasselgren PO (2005) Sepsis stimulates calpain activity in
skeletal muscle by decreasing calpastatin activity but does not
activate caspase-3. Am J Physiol Regul Integr Comp Physiol
288(3):R580–R590. doi:10.1152/ajpregu.00341.2004
Williams AG, Day SH, Folland JP, Gohlke P, Dhamrait S, Mont-
gomery HE (2005) Circulating angiotensin converting enzyme
activity is correlated with muscle strength. Med Sci Sports
Exerc 37(6):944–948
Wilson GJ, Wood GA, Elliott BC (1991) Optimal stiffness of series
elastic component in a stretch–shorten cycle activity. J Appl
Physiol 70(2):825–833
Wilson IA, Brindle KM, Fulton A (1995) Differential localization of
the mRNA of the M and B isoforms of creatine kinase in myo-
blasts. Biochem J 308:599–605
Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW
(1997) Effects of a polymorphism in the human tumor necrosis
factor α promoter on transcriptional activation. Proc Natl Acad
Sci 94(7):3195–3199
Wilson EM, Hsieh MM, Rotwein P (2003) Autocrine growth factor
signaling by insulin-like growth factor-II mediates MyoD-stim-
ulated myocyte maturation. J Biol Chem 278(42):41109–41113
Woods D, Hickman M, Jamshidi Y, Brull D, Vassiliou V, Jones
A, Humphries S, Montgomery H (2001) Elite swimmers
and the D allele of the ACE I/D polymorphism. Hum Genet
108(3):230–232
Woolfson AM, Heatley RV, Allison SP (1979) Insulin to inhibit pro-
tein catabolism after injury. N Engl J Med 300(1):14–17
Yahiaoui L, Gvozdic D, Danialou G, Mack M, Petrof BJ (2008) CC
family chemokines directly regulate myoblast responses to skel-
etal muscle injury. J Physiol 586(16):3991–4004. doi:10.1113/
jphysiol.2008.152090
Yamin C (2009) Reply to “IL6 genotype and creatine kinase response
to exercise”. Eur J Appl Physiol 107(3):375
Yamin C, Amir O, Sagiv M, Attias E, Meckel Y, Eynon N, Sagiv
M, Amir RE (2007) ACE ID genotype affects blood cre-
atine kinase response to eccentric exercise. J Appl Physiol
103(6):2057–2061
Yamin C, Duarte JAR, Oliveira JMF, Amir O, Sagiv M, Eynon
N, Sagiv M, Amir RE (2008) IL6 (−174) and TNFA (−308)
promoter polymorphisms are associated with systemic cre-
atine kinase response to eccentric exercise. Eur J Appl Physiol
104(3):579–586
Yamin C, Oliveira J, Meckel Y, Eynon N, Sagiv M, Ayalon M, Alves
AJ, Duarte JA (2010) CK-MM gene polymorphism does not
influence the blood CK activity levels after exhaustive eccen-
tric exercise. Int Sportmed J 31(3):213–217. doi:10.105
5/s-0029-1243256
Yang SY, Goldspink G (2002) Different roles of the IGF-I Ec peptide
(MGF) and mature IGF-I in myoblast proliferation and differen-
tiation. FEBS Lett 522(1):156–160
Yang J, Xu X (2012) alpha-Actinin2 is required for the lateral align-
ment of Z discs and ventricular chamber enlargement dur-
ing zebrafish cardiogenesis. FASEB J 26(10):4230–4242.
doi:10.1096/fj.12-207969
Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal
S, North K (2003) ACTN3 genotype is associated with human
elite athletic performance. Am J Hum Genet 73(3):627–631
Yang M, Ramachandran A, Yan HM, Woolbright BL, Copple BL,
Fickert P, Trauner M, Jaeschke H (2014) Osteopontin is an ini-
tial mediator of inflammation and liver injury during obstruc-
tive cholestasis after bile duct ligation in mice. Toxicol Lett
224(2):186–195. doi:10.1016/j.toxlet.2013.10.030
Yu ZB (2013) Tetanic contraction induces enhancement of fatigabil-
ity and sarcomeric damage in atrophic skeletal muscle and its
underlying molecular mechanisms. Zhongguo ying yong sheng
li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chin J
Appl Physiol 29(6):525–533
Zalin R (1972) Creatine kinase activity in cultures of differentiating
myoblasts. Biochem J 130:79
Zammit PS (2008) All muscle satellite cells are equal, but are some
more equal than others? J Cell Sci 121(Pt 18):2975–2982.
doi:10.1242/jcs.019661
Zanotti S, Gibertini S, Di Blasi C, Cappelletti C, Bernasconi P, Man-
tegazza R, Morandi L, Mora M (2011) Osteopontin is highly
expressed in severely dystrophic muscle and seems to play
a role in muscle regeneration and fibrosis. Histopathology
59(6):1215–1228
Zanou N, Gailly P (2013) Skeletal muscle hypertrophy and regenera-
tion: interplay between the myogenic regulatory factors (MRFs)
and insulin-like growth factors (IGFs) pathways. Cell Mol Life
Sci 70(21):4117–4130
Zhang B-T, Yeung SS, Allen DG, Qin L, Yeung EW (2008) Role
of the calcium-calpain pathway in cytoskeletal damage after
eccentric contractions. J Appl Physiol 105(1):352–357
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com