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Skeletal Muscle Mitochondria and Aging: A Review

Journal of Aging Research

July 2012
2012(2):194821

DOI:10.1155/2012/194821

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PubMed

License
CC BY 3.0

Authors:

Courtney M Peterson

University of Alabama at Birmingham

Darcy L Johannsen

Pennington Biomedical Research Center

Aging is characterized by a progressive loss of muscle mass and muscle strength. Declines in skeletal muscle mitochondria are thought to play a primary role in this process. Mitochondria are the major producers of reactive oxygen species, which damage DNA, proteins, and lipids if not rapidly quenched. Animal and human studies typically show that skeletal muscle mitochondria are altered with aging, including increased mutations in mitochondrial DNA, decreased activity of some mitochondrial enzymes, altered respiration with reduced maximal capacity at least in sedentary individuals, and reduced total mitochondrial content with increased morphological changes. However, there has been much controversy over measurements of mitochondrial energy production, which may largely be explained by differences in approach and by whether physical activity is controlled for. These changes may in turn alter mitochondrial dynamics, such as fusion and fission rates, and mitochondrially induced apoptosis, which may also lead to net muscle fiber loss and age-related sarcopenia. Fortunately, strategies such as exercise and caloric restriction that reduce oxidative damage also improve mitochondrial function. While these strategies may not completely prevent the primary effects of aging, they may help to attenuate the rate of decline.

The electron transport system (ETS) of the inner mitochondrial membrane is the primary site of reactive oxygen species (ROS) production and therefore the main source of oxidative stress (damage to proteins, lipids, and DNA) in the mitochondria and in the cell. Free radical superoxide anions (O2∙-) are generated when electrons are donated from complexes I and III of the ETS to O2 instead of the appropriate ETS subunit. 2–4% of total oxygen consumption may go toward the production of ROS instead of energy as ATP. Scavenging enzymes represent an important mitochondrial defense mechanism against oxidative stress by neutralizing O2∙- within the mitochondrial matrix (superoxide dismutase; MnSOD = SOD2) and catalyzing the reduction of mitochondrial SOD2-generated H2O2 to nontoxic H2O in the mitochondria and the cell (glutathione peroxidase and catalase). Mitochondria in young muscle (a) are numerous and efficient. With age (b), muscle mitochondria become less numerous and seem to develop impaired function associated with reduced oxidative capacity. Through lifestyle changes such as exercise, and caloric restriction, and caloric restriction mimetics, we hypothesize that antioxidative enzymes are upregulated, and that most of the above impairments in aged muscle may be improved (c).

…

Mitochondrial processes are both static (a) and dynamic (b). (a) depicts the classical movement of electrons along complexes I–IV embedded in the inner mitochondrial membrane with the generation of a proton gradient (membrane potential). The proton gradient causes hydrogen ions to flow back into the mitochondrial matrix via complex V (ATP synthase), producing ATP in the process. (b) depicts the processes of mitochondrial fusion and fission. Mitochondria can undergo constriction and division (1), mediated by Drp1, which bonds and localizes to the constriction site via an interaction with the receptor-like protein Fis1 (2). During fusion, a tether of the Mfn1/2 to collateral mitochondrial Mfn1/2 conjoins the outer membranes. Opa1, an inner membrane GTPase protein, facilitates the fusion of the inner membrane, cristae formation, and unifying of compartments.

…

This cartoon describes the changes in skeletal muscle with aging on the right side of the figure. Both the mass and function of skeletal muscle are decreased in elderly people. Furthermore, at the mitochondrial level, the number of mitochondria is decreased in parallel with changes in mitochondrial morphology. Mitochondrial DNA, oxidative capacity, biogenesis, and autophagy are all decreased in conjunction with an increased number of DNA mutations and increased levels of apoptosis. Finally, oxidative stress is increased in the muscles of elderly people in association with cellular lipid, protein, and DNA damage. The bottom left of the cartoon shows that exercise, caloric restriction, caloric restriction mimetics, and antioxidants can all delay the aging of skeletal muscle.

…

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Hindawi Publishing Corporation

Journal of Aging Research

Volume 2012, Article ID 194821, 20 pages

doi:10.1155/2012/194821

Review Article

Skeletal Muscle Mitochondria and Aging: A Review

Courtney M. Peterson, Darcy L. Johannsen, and Eric Ravussin

Department of John S. Mclhenny Skeletal Muscle Physiology, Pennington Biomedical Research Center,

6400 Perkins Road, Baton Rouge, LA 70808, USA

Correspondence should be addressed to Darcy L. Johannsen, darcy.johannsen@pbrc.edu

Received 23 March 2012; Accepted 21 May 2012

Academic Editor: Holly M. Brown-Borg

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly

cited.

Aging is characterized by a progressive loss of muscle mass and muscle strength. Declines in skeletal muscle mitochondria are

thought to play a primary role in this process. Mitochondria are the major producers of reactive oxygen species, which damage

DNA, proteins, and lipids if not rapidly quenched. Animal and human studies typically show that skeletal muscle mitochondria

are altered with aging, including increased mutations in mitochondrial DNA, decreased activity of some mitochondrial enzymes,

altered respiration with reduced maximal capacity at least in sedentary individuals, and reduced total mitochondrial content

with increased morphological changes. However, there has been much controversy over measurements of mitochondrial energy

production, which may largely be explained by diﬀerences in approach and by whether physical activity is controlled for. These

changes may in turn alter mitochondrial dynamics, such as fusion and ﬁssion rates, and mitochondrially induced apoptosis, which

may also lead to net muscle ﬁber loss and age-related sarcopenia. Fortunately, strategies such as exercise and caloric restriction that

reduce oxidative damage also improve mitochondrial function. While these strategies may not completely prevent the primary

eﬀects of aging, they may help to attenuate the rate of decline.

1. Introduction

Around the fourth decade of life, both muscle mass and

strength begin to decline [1], and these declines accelerate

with advancing age [2].Thelossofmusclemassoccursat

arateofjustunder1%peryear[3] and appears to be an

unavoidable consequence of aging, although it can be slowed

by exercise, especially resistance training [4–6]. A signiﬁcant

concern is that as one ages, changes in muscle mass and

strength tend to be dissociated. Data from the Baltimore

Longitudinal Study of Aging [7] and the Health ABC study

[3] showed using DXA and CT that muscle strength declined

three times faster than muscle mass, suggesting a decrease

in muscle “quality.” This posits that along with an overall

reduction in tissue mass, changes are occurring within the

skeletal muscle to aﬀect strength. Changes such as accumula-

tion of intra- and extra-myocellular lipids, improper folding

of structural and contractile proteins, and mitochondrial

dysfunction are thought to occur with age and are the topic

of intense scrutiny [8–10].

Dysfunctional mitochondria in particular are thought

to play a key role in muscle function decline, as the

mitochondria are the main producers of both cellular energy

and free radicals. Alterations in mitochondria have been

noted in aging, including decreased total volume, increased

oxidative damage, and reduced oxidative capacity. These

biochemical and bioenergetic changes are accompanied by

perturbations in cellular dynamics, such as a decrease in

mitochondrial biogenesis and an increase in mitochondrially

mediated apoptosis (Figure 1). These changes may underlie

not only a loss of muscle quality with age, but also other

common age-associated pathologies such as ectopic lipid

inﬁltration, systemic inﬂammation, and insulin resistance

[10]. In this paper, we examine the evidence for age-related

changes in skeletal muscle mitochondria, with a focus on

studies conducted in humans.

1.1. Overview of Mitochondria. Mitochondria are double-

membrane encoded organelles with their own genome that

2 Journal of Aging Research

Muscle

Mass ↓

Function ↓

Mitochondria

Number ↓

Morphology changes

DNA mutations ↑

Biogenesis ↓

Oxidative capacity ?

Autophagy ↓

Apoptosis ↑

Oxidative

stress

ROS ↑

Lipid/protein

damage ↑

Antioxidant

system ↓

Aged skeletal muscle

•Exercise

•CR

•CR mimetics

•Antioxidants

Figure 1: This cartoon describes the changes in skeletal muscle with aging on the right side of the ﬁgure. Both the mass and function

of skeletal muscle are decreased in elderly people. Furthermore, at the mitochondrial level, the number of mitochondria is decreased in

parallel with changes in mitochondrial morphology. Mitochondrial DNA, oxidative capacity, biogenesis, and autophagy are all decreased

in conjunction with an increased number of DNA mutations and increased levels of apoptosis. Finally, oxidative stress is increased in the

muscles of elderly people in association with cellular lipid, protein, and DNA damage. The bottom left of the cartoon shows that exercise,

caloric restriction, caloric restriction mimetics, and antioxidants can all delay the aging of skeletal muscle.

consume oxygen and substrates to generate the vast majority

of ATP while producing reactive oxygen species in the

process. They also participate in a wide range of other

cellular processes, including signal transduction, cell cycle

regulation, oxidative stress, thermogenesis, and apoptosis.

In doing so, they are highly dynamic organelles that are

continuously remodeling through biogenesis, ﬁssion, fusion,

and autophagy, thus responding to and modulating cellular

dynamics. For instance, they undergo biogenesis to meet

increased energy demands in response to exercise, and they

ensure cellular quality by initiating an apoptotic program to

remove defective cells.

Mitochondria transduce energy from substrates through

the tricarboxylic acid (TCA) cycle and the electron trans-

port system (ETS) to generate ATP. The ETS consists of

multipolypeptide complexes (I–V) embedded in the inner

mitochondrial membrane (IMM) that receive electrons from

reducing equivalents NADH and FADH2, generated by

dehydrogenase activity in the TCA cycle. The electrons are

transferred along the complexes with O2serving as the

ﬁnal acceptor at complex IV [11](Figure 2). The reduction

potential (propensity to accept an electron) increases along

the chain of complexes, and the energy generated is suﬃcient

to drive the translocation of hydrogen ions across the IMM.

This creates a proton gradient and membrane potential

(collectively termed the proton motive force) that drives

the synthesis of ATP as protons ﬂow back to the matrix

via complex V (ATP synthase). This process is also called

oxidative phosphorylation (OXPHOS). However, the ETS is

not a perfectly eﬃcient system, and signiﬁcant (and highly

variable) proton “leak” occurs by the movement of hydrogen

ions back into the matrix space that is not mediated through

complex V. In this manner, proton transfer can be uncoupled

from ATP phosphorylation, and this ineﬃciency contributes

to the demand for reducing equivalents. Mitochondria are

therefore thought to have a much greater capacity to generate

ATP than what is usually required [12].

Because of this metabolic latitude, many assume that

mild impairment in mitochondrial function per se does

not cause cellular disturbances associated with aging and

with chronic diseases such as insulin resistance and type 2

diabetes [12]. Indeed, whether mitochondrial dysfunction

is a cause or a consequence of cellular impairment and

the aging process is a subject of intense debate. Moreover,

the deﬁnition of mitochondrial dysfunction itself has been

the subject of controversy. For example, alterations in

mitochondrial mRNA transcripts may not result in changes

in protein levels, so it is not wholly clear whether this

state—whether compensatory or not—can be counted as a

disruption in normal function [13].

In this paper, we focus on the aging of skeletal muscle

(SM) mitochondria, with an eye towards the putative role

of mitochondria in SM aging. We look at several diﬀerent

aspects of mitochondrial function—which we deﬁne to mean

any process that involves the mitochondria—and explore

the evidence for dysfunction, which we deﬁne to mean any

deviation from normal function. Section 2 examines the

impact of aging on the biochemical and bioenergetic path-

ways in SM mitochondria. Section 3 explores the changes

in mitochondrial and cellular dynamics, which may further

exacerbate the age-related decline in muscular function. The

review concludes in Section 4 with an overview of strategies

to attenuate the aging of SM mitochondria.

2. Biochemical and Bioenergetic

Aging of Mitochondria

During the aging process, mitochondria are characterized by

changes in oxidative stress, a decay in mitochondrial DNA,

Journal of Aging Research 3

Intermembrane space

4H+4H+2H+

3H+

ATPADP

+Pi

FADH2FAD+

+2H

NAD+

NADH

Matrix H2O

2H+

Intermem

rane s

ace

ATPAD

+ P

FADH

AD+

Matrix

+ 1/2 O2

(a)

Drp1

Fis1

Completion of

ﬁssion

(1) Fission

(division)

(2) Fusion

Opa1

Fusion of inner

membrane

Docking of

Mfn1/2

Constriction

of inner and

outer

membrane

Adapted from Dimmer and Scorrano, 2007

(b)

Figure 2: Mitochondrial processes are both static (a) and dynamic (b). (a) depicts the classical movement of electrons along complexes

I–IV embedded in the inner mitochondrial membrane with the generation of a proton gradient (membrane potential). The proton gradient

causes hydrogen ions to ﬂow back into the mitochondrial matrix via complex V (ATP synthase), producing ATP in the process. (b) depicts

the processes of mitochondrial fusion and ﬁssion. Mitochondria can undergo constriction and division (1), mediated by Drp1, which bonds

and localizes to the constriction site via an interaction with the receptor-like protein Fis1 (2). During fusion, a tether of the Mfn1/2 to

collateral mitochondrial Mfn1/2 conjoins the outer membranes. Opa1, an inner membrane GTPase protein, facilitates the fusion of the

inner membrane, cristae formation, and unifying of compartments.

a reduction in some enzyme activities, and alterations in

mitochondrial respiration. These biochemical changes are

accompanied by phenotypic changes in the mitochondria

themselves. In old age, a signiﬁcant proportion of the

mitochondrial organelles are abnormally enlarged and more

roundedinshape(reviewedin[14,15]). An increasing

proportion of them are also depolarized or nonfunctional,

perhaps indicative of defects in mitochondrial turnover

[15–17]. Within the mitochondria themselves, shortened

mitochondrial cristae and vacuolization of the matrix are

apparent, which lead to homogenization of the materials

within the mitochondrial compartments [14,18]. Coupled

with these morphological changes, the density of mitochon-

dria in SM substantially drops [13,19–21], as shown for

example, by electron microscopy in the vastus lateralis muscle

of people over 60 years of age [20].

2.1. Increased Oxidative Damage: ROS Production and Scav-

enging. Within the cell, the mitochondria constitute the

major source of reactive oxygen species (ROS). Mitochon-

drial complexes I and III are the main sites of superoxide

generation and contribute the most to ROS production [22].

The reactive oxygen species, including O2

•−and H2O2,can

cause oxidative damage to surrounding structures and the

particularly vulnerable mtDNA, which is in close proximity

to the primary site of ROS production. Oxidation by ROS

results in the synthesis of faulty proteins, oxidized lipids,

and mtDNA mutations, which may lead to cellular and

mitochondrial dysfunction. These processes are implicated

in the mitochondrial theory of aging [23,24], which holds

that the accumulation of ROS damage over time leads to

age-associated mitochondrial impairment. In general, ROS

production is found to be increased in aged muscle in

both the subsarcolemmal and intermyoﬁbrillar pools of

mitochondria [25] (though some report a decrease in ROS

production with age [26]). This increase in ROS production

is associated with oxidation of ETS complex V, leading

to decreased ATP production [27,28], increased levels

of 8-oxodeoxyguanosine (8-oxoG) from DNA oxidation

4 Journal of Aging Research

[25,29], increased levels of protein carbonyls, and increased

nitration [30]. In particular, proteomic studies have found

increased nitration of complex II and altered carbonylation

of complex I, complex V, and isocitrate dehydrogenase

(reviewed in [31]).

Cumulative oxidative damage may in part be attributed

to a reduction in ETS activity that would extend the

length of time that electrons remain at complexes I and

III, increasing the potential for donation of electrons to

oxygen [32]. In theory, it could also be attributed to

reduced activity of antioxidant defenses, including man-

ganese superoxide dismutase (MnSOD), catalase (CAT), and

glutathione peroxidase (GPx). These enzymes work together

to convert O2

•−to H2O2, which is then further reduced

to H2O. Data on antioxidant enzyme activity and aging is

mixed, with some studies showing increased activity [33–

35] while others show reduced enzyme activity [36–38].

We recently found in a group of elderly adults aged 70–

84 years that the expression of total superoxide dismutase

(SOD) was unchanged compared to that of a group of

young (20–34 years old) BMI-matched individuals; however,

urinary isoprostanes (a marker of whole-body oxidative

damage) was increased by 38% [10]. Furthermore, TCA

cycle activity measured as citrate synthase (CS) activity

was 19% lower, and mitochondrial capacity was 17% lower

in the elderly, although mitochondrial content (OXPHOS

protein) was unchanged. Safdar et al. recently showed that

the protein content of MnSOD (mitochondria-speciﬁc) was

signiﬁcantly reduced in active and inactive older adults

compared to their younger counterparts; however, MnSOD

activity in the older subjects who were recreationally active

was similar to that of young subjects [39]. Together, these

data suggest that oxidative stress is increased with age

without an accompanying increase in antioxidant activity

and may be linked with mitochondrial dysfunction. Exercise

and caloric restriction may alleviate the age-associated

oxidative stress by upregulating antioxidant enzyme activity

even in the face of reduced antioxidant protein content

(Figure 3).

If oxidative stress contributes to mitochondrial dys-

function, can mitochondrial dysfunction be reversed by

changing the cellular oxidative status? A recent study

attempted to answer this question using a transgenic

mouse model to express human catalase targeted to the

mitochondria (MCAT) [40]. Mitochondrial function was

assessed both in vitr o and in vivo in wildtype young

(3–6 months old) and older (15–18 months old) lean

healthy mice versus age-matched MCAT transgenic lit-

termates. Whereas the older wildtype mice exhibited all

the “usual” deleterious metabolic impairments including

increased oxidative damage, reduced mitochondrial con-

tent (∼30%) and function, increased intramuscular lipid

(∼70%), and marked muscle insulin resistance (∼35%), the

older MCAT mice resembled the young mice and demon-

strated none of the age-associated impairments. These data

suggest that by increasing ROS scavenging and reducing

the oxidized state of the cell, many age-related deﬁcits can

be prevented.

2.2. Increased Uncoupling? Another mechanism to reduce

oxidative stress may be mediated by attenuation of the proton

motive force, thereby decreasing the potential for electrons

to form oxygen radicals. This could be accomplished by

increasing respiration or by increasing proton leak. Rodent

studies on age-associated changes in proton leak are mixed.

Iossa et al. [41] showed that proton leak was decreased

with age, resulting in increased mitochondrial eﬃciency.

Conversely, reduced coupling was found in aged mice using

an in vivo approach to measure the P/O ratio [42]. Data in

aged humans are scarce. We recently found that the in vivo

P/O ratio determined by ATP turnover (demand) and oxygen

uptake of the vastus lateralis was 21% lower in elderly

compared to young adults [10], suggesting that less ATP

was produced per oxygen uptake in the elderly adults. This

lends support to earlier work by Amara et al. [43] showing

that mild uncoupling protects against age-related declines

in mitochondrial function and cellular ATP concentration.

Furthermore, we found that a lower P/O ratio was associated

with lower SOD activity, indicating a possible link between

cellular antioxidant activity and mitochondrial coupling. In

particular, increased oxidative stress with nonupregulated

antioxidant defense may induce mitochondrial uncoupling

in order to reduce the oxidative potential. This potential

adaptive mechanism should be further explored.

2.3. Decay of Mitochondrial DNA. Age appears to aﬀect

both mitochondrial DNA (mtDNA) content and integrity.

Mammalian cells typically contain on the order of 1,000–

10,000 copies of mtDNA, which code for less than 10% of all

mitochondrial proteins; the rest is encoded by nuclear DNA

[44,45]. At 16.6 kbp long, each double-stranded circular

mtDNA molecule encodes 13 genes involved in the ETS

(subunits of complexes I, III, IV, and V), 22 tRNAs, and

2rRNAs[46]. A majority of studies [47–50], though not

all [51], report that mtDNA copy number decreases with

age in human SM and may be caused at least in part by

oxidative damage, as the age-associated decline in mtDNA

copy number tends to be greater in more oxidative ﬁbers

[52].

The decline in mtDNA is also accompanied by an

increase in mtDNA damage, particularly deletions and

oxidative lesions, but also point mutations, tandem duplica-

tions, and rearrangements (reviewed in [53,54]; in particular

[36–38,48,55–64]). mtDNA is particularly susceptible to

oxidative damage because it is near the major site of ROS

production, lacks protective histones, and has weaker DNA

repair mechanisms [65,66]. One study found that deletions

aﬀect up to 70% of mtDNA molecules in the SM of

individuals aged 80 years and older [56]. However, there are

disagreements over mtDNA mutation frequencies (reviewed

in [54]) and to what extent ROS production is responsible;

there is increasing evidence that perhaps a majority of

mutations are due to the inherent error rate of mtDNA

polymerase gamma (Pol gamma) [67].

ThefunctionalimpactofmtDNAdamageisstillamatter

of debate both in general (reviewed in [54,67,68]) and

in the context of sarcopenia (reviewed in [69]). Is mtDNA

Journal of Aging Research 5

Mitochondria in young muscle

ADP ATP

Little oxidative damage

Mitoch.

efﬁciency

Oxidative

capacity

+++ Good Good

Mitoch.

number

III

III IV

O2H2O

(a)

Mitochondria in older muscle

ADP ATP

ROS

Ox. damage

III

III IV

O2H2O

(b)

Mitochondria in older muscle + antioxidant mechanism

ADP ATP

ROS Oxidative

damage

III

III IV

O2H2O

(c)

Figure 3: The electron transport system (ETS) of the inner mitochondrial membrane is the primary site of reactive oxygen species (ROS)

production and therefore the main source of oxidative stress (damage to proteins, lipids, and DNA) in the mitochondria and in the cell.

Free radical superoxide anions (O2

•−) are generated when electrons are donated from complexes I and III of the ETS to O2instead of the

appropriate ETS subunit. 2–4% of total oxygen consumption may go toward the production of ROS instead of energy as ATP. Scavenging

enzymes represent an important mitochondrial defense mechanism against oxidative stress by neutralizing O2

•−within the mitochondrial

matrix (superoxide dismutase; MnSOD =SOD2) and catalyzing the reduction of mitochondrial SOD2-generated H2O2to nontoxic H2Oin

the mitochondria and the cell (glutathione peroxidase and catalase). Mitochondria in young muscle (a) are numerous and eﬃcient. With

age (b), muscle mitochondria become less numerous and seem to develop impaired function associated with reduced oxidative capacity.

Through lifestyle changes such as exercise, and caloric restriction, and caloric restriction mimetics, we hypothesize that antioxidative enzymes

are upregulated, and that most of the above impairments in aged muscle may be improved (c).

damage a consequence or a cause of the aging process? On

one hand, the onset of a mitochondrial decline in energy

production occurs before mtDNA mutations are often

detectable [70]. On the other hand, several studies in humans

reveal strong correlations between mtDNA mutation rates

and bioenergetic deﬁciency (typically complex IV) or muscle

ﬁber atrophy [43,55,62,63,71–74]. In addition, speciﬁc

point mutations cluster at mtDNA replication control sites,

which may reduce gene transcription and be at least partially

responsible for declining levels of protein synthesis with

age [60,75]. Other evidence comes from mtDNA mutator

mice, which are genetically engineered to have defects in

the proofreading function of Pol gamma. They accumulate

mtDNA mutations at an accelerated rate, have more abnor-

mal mitochondria, and exhibit premature aging, sarcopenia,

and reduced lifespan [76–78].

2.4. Alterations in Mitochondrial mRNA and Protein Levels.

The expression of most mitochondrial genes, including

cytochrome c [79], does not change with age. However,

declines in gene transcripts are observed for several of

the polypeptide components of complexes I, IV, and V,

whereas for complexes II and III, declines are evident for

6 Journal of Aging Research

only a couple components with most being unchanged

[73,80–84]. In addition, the transcripts of some nuclear

genes encoding mitochondrial regulatory proteins, a few

TCA proteins (including one transcript variant of citrate

synthase), and some glycolysis enzymes appear to be altered

in aged human SM [48,52,80,83,84]. Many similar

changes in gene expression (or lack thereof) have been

observed in monkeys and rats [52,85–87]. However, there

are discrepancies among reports, which are at least in part

explained by muscle-speciﬁc diﬀerences in gene expression

[52,88]. Whether these alterations in gene transcripts of

energy-producing pathways aﬀect muscle aging is unclear.

While much evidence points to a functional role, Giresi et

al. found that the key genes associated with sarcopenia are

involved in inﬂammation, apoptosis, and regulating mRNA

splicing, not in OXPHOS [89].

Of course, age-related alterations in mRNA levels may

not induce similar changes in protein abundances, which are

controlled by the balance between synthesis and degradation

[13,90]. Both mitochondrial protein synthesis [75]and

proteolysis via ubiquitin-proteasome and lysosomal degra-

dation systems (reviewed in [91,92]) are known to decline

with age. The majority of mitochondrial proteins, including

polypeptide components of the ETS complexes, have not

been found to change with age [10,93]. Notable exceptions

include complex II, which tends to increase with age at least

in rodents [86,94,95], and complex IV, which tends to

decrease with age in both humans [50,96,97] and rodents

[86,98]. This is supported by observations of increased

complex IV-deﬁcient and complex II-hyperactive ﬁbers with

age [99–101]. For complexes I, III, and V, proteomic analysis

shows that the occurrence of abnormal polypeptides tends to

increase with age in both human [102] and rodent SM [86,

94,98,103], but is decreased in human studies using other

approaches [48,50,96]. Proteins involved in glycolysis tend

to be unchanged or reduced with age, which is consistent

with the observed shift from glycolytic to more oxidative

metabolism, while the data on TCA proteins (in particular,

citrate synthase and isocitrate dehydrogenase) is mixed [48,

50,86,94–96,98,102,103].

2.5. A Decline in Mitochondrial Energy Production? It is

unclear whether these age-related changes in turn aﬀect

mitochondrial energy production. When physical activity is

not a criterion in subject selection, substantial declines in

enzyme activity are often found to occur with age. Most such

studies in human SM report that complex I and complex IV

activities decrease substantially, perhaps because these two

complexeshavemoreoftheirsubunitsencodedbythemore

vuinerable mtDNA than the other complexes [1,21,56,58,

75,79,90,97,104,105]. Similar results have been reported

in rodents and dogs [2,5,52,106–112], though there have

been exceptions both in humans [93,113,114] and rodents

[86,94,109]. The activity of complex II, which is encoded

entirely by the nuclear genome, appears not to change with

age in either human [1,56,64,113,114] or animal [2,

86,108] SM, with a few exceptions [39,79,94,105]. Data

regarding complex III activity is both less available and more

mixed, with some studies reporting no change in human

[113,114] or animal [2,108] SM, but others reporting a

decrease in activity [5,56]. Interestingly, one study found

evidence of an age-related decline in complex III activity in

females but not males [90]. Finally, the activities of enzymes

involved in the TCA cycle and glycolytic pathways tend to

be unchanged or decline with age, and in some cases (e.g.,

citrate synthase), the trend is not clear [10,21,26,39,48,56,

75,93,96,97,104,105,111–113,115–120]. Some of these

discrepancies may be explained by the diﬀerential impact of

aging on diﬀerent muscles. For example, one study in rats

found a decrease in complex IV activity in the lateral but

not medial gastrocnemius [52], and a study in humans found

that citrate synthase activity was negatively correlated with

age in the gastrocnemius but not the vastus lateralis [121].

Other inconsistencies may be explained by diﬀerences in

isolation or techniques, or in the normalization of enzymatic

activity. For example, Picard et al. found that measurements

on isolated mitochondria tend to exaggerate the declines in

mitochondrial function in comparison to measurements in

intact mitochondria in permeabilized myoﬁbers [86].

Enzymatic changes may in turn aﬀect mitochondrial

respiration and ATP ﬂux. Short et al. found that the maximal

capacity for ATP synthesis drops by 8% per decade or

5% when normalizing to mitochondrial protein content

[48]. Similar results concerning mitochondrial respiration

were reported by Trounce et al. [122]. But other human

studies have found no evidence of a decline in mitochondrial

respiration [26,93,115,117], and there is no consistent

pattern regarding how the respiratory control ratio—the

ratio of states III and IV respiration activities—changes with

age. Similarly, there are conﬂicting reports on fatty acid-

linked mitochondrial respiration including reduced carnitine

palmitoyltransferase-dependent and -independent pathways

with age (particularly nonphosphorylating respiration [48,

86,108]), while others see no age-related changes [26,115,

117]. In vivo techniques have also been used to measure

oxidative capacity. In vivo measurements of SM oxidative

activity are typically performed using phosphorous magnetic

resonance spectroscopy (31P-MRS) to probe the kinetics

of phosphocreatine and its recovery time following muscle

contraction. Some in vivo studies in older humans [10,20,

118,120], but not all [119,123,124], and at least one in mice

[125] have found evidence of reductions in maximal ATP

ﬂux. In particular, Conley et al. found that elderly adults have

a 50% reduction in oxidative capacity per muscle volume

and a 30% reduction per mitochondrial volume [20]. An

MRS study on basal ATP ﬂux in humans, however, found no

decline in ﬂux with aging [43].

However, it has become increasingly clear that most

of the declines in mitochondrial function attributed to

chronological age are instead a result of physical inactivity.

When physical activity levels are matched between young

and old subjects or physical activity is otherwise taken

into account, most studies ﬁnd no age-related changes in

mitochondrial enzyme activities, mitochondrial respiration,

or ATP ﬂux [13,39,50,101,126–129]. Interestingly,

those studies that do report age-related declines even after

matching for activity levels tend to involve sedentary young

Journal of Aging Research 7

and old subjects [104,114,130], indicating that declines in

function with aging may occur predominantly in sedentary

individuals. In particular, in ex vivo studies, the activities

of ETS enzymes and citrate synthase and mitochondrial

respiration show strong dependences on physical activity

level that are independent of age [101,131,132]. Similar

results are also reported in mice [98,133]. In vivo MRS

studies on activity-matched subjects also tend to ﬁnd no

evidence of a change in mitochondrial oxidative capacity—

in this case, maximal ATP ﬂux—between young and old

subjects [134–136]. However, one in vivo MRS study in

activity-matched sedentary individuals did report a reduc-

tion in basal oxidation and phosphorylation [130]. Also,

glycolytic ﬂux is lower in older activity-matched people

[135,136], and a recent MRS study showed that oxidative

capacity does indeed change in some muscles with age but

also demonstrated that physical activity is intimately linked

with oxidative capacity [128]. Interestingly, there is evidence

that physical activity can reverse the age-related declines in

most but not all mitochondrial markers of energy production

[50,132], which while encouraging, nonetheless indicates

that there are residual declines in a small subset of markers

that cannot be completely prevented.

3. Age-Related Changes in

Mitochondrial Dynamics

3.1. Decreased Mitochondrial Biogenesis. Once thought of

as relatively static round organelles, mitochondria are now

recognized as highly dynamic, existing in networks that are

constantly being remodeled by biogenesis, fusion and ﬁssion,

and degradative processes such as autophagy. Through these

dynamics, they both respond to and drive cellular processes,

including apoptosis, whose dysregulation is thought to be a

key factor in sarcopenia.

Mitochondrial biogenesis is the expansion of existing

mitochondrial content—whether through growth of the

mitochondrial network (increase in mitochondrial mass)

or division of preexisting mitochondria (increase in mito-

chondrial number; also discussed later in this paper). It

is triggered when the energy demand exceeds respiratory

capacity—in particular, in response to exercise, stress,

hypoxia, nutrient availability, hormones (including insulin),

ROS production, and temperature (reviewed in [137,138]).

Once biogenesis is triggered, the nuclear genome produces

mitochondrial regulatory factors, which are then imported

into the mitochondria to initiate replication and transcrip-

tion of mtDNA, ultimately resulting in expansion of the

mitochondrial network. The initial triggers are thought to

arise from signaling cascades involving the energy sen-

sor AMP kinase (AMPK) and/or alterations in Ca2+ ﬂux

and protein kinases such as calcium/calmodulin-dependent

kinases (CAMKs), protein kinase C (PKC), and p38 MAPK

(particularly in response to muscle contraction) (reviewed

in [138]). These signals in turn induce the expression of the

peroxisome proliferator-activated receptor (PPAR) gamma

coactivator (PGC-1) family of cotranscription factors, par-

ticularly PGC-1α, which is also directly activated by AMPK

[139] and p38 MAPK [140–142], as well as many key

signaling molecules like SIRT1 [143,144] and transducers of

regulated CREB (cAMP response element-binding protein)-

binding proteins (TORCs) [145].

As the master regulator of biogenesis, PGC-1αcoordi-

nates and cooperates with multiple cotranscription factors—

including PPARs, myocyte enhancing factors (MEFs), and

CREB—to induce the transcription of nuclear genes encod-

ing mitochondrial proteins [146,147]. Most importantly,

PGC-1αactivates the nuclear respiratory factors 1 and

2 (Nrf-1, Nrf-2) on the promoters [148,149], thereby

driving the transcription of an even greater assortment of

nuclear-encoded mitochondrial proteins (reviewed in [137,

138,150]), including mitochondrial transcription factor A

(Tfam). Tfam controls mtDNA transcription and content

and organizes mtDNA into nucleoid-like structures, which

are thought to maintain mtDNA integrity [151]. The Tfam

precursor protein, along with numerous other mitochon-

drial precursor proteins, are targeted to the mitochondria

by chaperones and then imported via the mitochondrial

protein import machinery (reviewed in [152–155]). Import

is accomplished through a set of aqueous pores formed from

translocases of the outer membrane (TOMs; e.g., Tom20)

and translocases of the inner membrane (TIMs) through

pathways that depend on whether the polypeptide is destined

for the outer mitochondrial membrane (OMM), IMM,

or mitochondrial matrix. Once imported, the precursor

proteins are modiﬁed, folded, and assembled into their ﬁnal

form. In particular, Tfam can then act on mtDNA driving its

replication through Pol gamma and its transcription through

mitochondrial RNA polymerase [156]. Finally, the translated

ETS polypeptides from the nuclear and mitochondrial

genomes are assembled into multisubunit enzymes.

With increasing age, the density of mitochondria in

SM drops substantially [13,19–21,25], suggesting an

overall decline in mitochondrial biogenesis. Moreover, there

is an impairment in AMPK-stimulated biogenesis in old

age [157]; however, the reasons why are largely unknown.

Declining PGC-1αlevels could explain the reduction in

mitochondrial biogenesis, as overexpression of PGC-1αin

the SM of aged mice improved oxidative capacity, suppressed

mitochondrial degradation, and prevented muscle atrophy

[158]. These improvements were accompanied by attenua-

tion of the age-related increase in inﬂammatory cytokines

and by prevention of insulin resistance [158]. However,

measurements of PGC-1αin aged SM are not deﬁnitive:

one study found a decline in protein abundance in rats

[25], and some studies of gene expression have reported

reduced expression [96,112,157], while others found no

change [10,159]. Similarly, reports on the gene and protein

expressions of both Nrf-1 and Tfam are conﬂicting [25,50,

80,96,159,160]; however, preliminary evidence suggests

that Nrf-1 binding to the Tfam promoter appears to increase

in old age [160].

3.2. Changes in Fission and Fusion? Mitochondrial dynamics

are also inﬂuenced by the balance between ﬁssion and

8 Journal of Aging Research

fusion (Figure 2(b)). Fission, or division, of mitochon-

dria is required to transmit mitochondria among dividing

cells and to meet increased ATP demands. Fission also

plays a key role in maintaining mitochondrial quality and

mtDNA integrity, as it allows dysfunctional mitochondria

to be severed from the network and to be removed by

autophagy [161,162]; indeed, mitochondria excised by

ﬁssion often have a lower membrane potential, a target

for autophagy [16]. In mammals, ﬁssion is known to

be orchestrated by two proteins: Fis1 and the GTPase

dynamin-related protein Drp1. Fis1, which localizes in

the OMM, recruits the cytosolic protein Drp1 [162,163].

Once recruited to the OMM, Drp1 wraps around and

constricts the membrane, initiating ﬁssion (reviewed in

[164]). One study found that activation of the ﬁssion

machinery was suﬃcient to induce muscular atrophy [165],

while another study found that in yeast, increased ﬁssion

leads to a shortened lifespan and a greater sensitivity to

ROS-induced apoptosis [166]. Because Fis1 protein levels

areelevatedinagingratSM[94] and Drp1 transcripts

tend to be lower in older humans [21], age-associated

increases in ﬁssion may indeed contribute to sarcopenia.

On the other hand, suppression of Fis1 or Drp1 produces

elongated mitochondrial networks and a senescent pheno-

type but increases ROS production and mtDNA damage

[163,167,168].

The counterpart of ﬁssion is fusion, which uniﬁes

mitochondria. Fusion allows mixing of mitochondrial com-

partments, facilitating equilibration of OXPHOS proteins,

energy exchange, and complementation of the mitochondrial

genome [169,170]. In aging, this mixing is thought to

prevent mutations in mtDNA from resulting in respiratory

dysfunction; however, it also permits the accumulation of

mutated mtDNA that might otherwise be removed via ﬁssion

and autophagy [170,171]. For these reasons, fusion plays a

role in regulating mtDNA integrity and respiratory function

[172–174]. In humans, fusion is known to be controlled by

optic atrophy 1 (Opa1) and the two GTPases mitofusin 1 and

2 (the isoforms Mfn1 and Mfn2). Mfn1 and Mfn2 are located

in the OMM, where they promote tethering and fusion

[162], while Opa1 facilitates fusion from its localization

on the IMM (reviewed in [164]). Opa1 also assists in

regulating degradative processes: it regulates apoptosis by

keeping the inner mitochondrial cristae junctions tight

to prevent cytochrome c release, which triggers apoptosis

[175,176],anditscleavagemaybeinvolvedinﬂagging

dysfunctional mitochondria for autophagic removal [176].

One study reported that Mfn2 gene expression was lower in

the SM of older humans [21]. Interestingly, muscle-speciﬁc

Mfn1- and Mfn2-knockout mice experience enhanced mito-

chondrial proliferation and increased mutations in and

depletion of mtDNA; these changes occur in parallel with

accelerated muscle loss [177]. A mutation in the other key

fusion protein, Opa1, is associated with reduced oxidative

phosphorylation and ATP production in human SM [178].

Thus, age-associated changes in the dynamical remodel-

ing processes of ﬁssion and fusion likely aﬀect mtDNA

integrity, respiratory function, ROS production, and cellular

senescence.

3.3. Alterations in Mitochondrial Turnover. Mitochondrial

turnover is executed predominantly by the autophagy-

lysosome system, a cellular housekeeping system that

degrades mitochondria as well as other cellular compo-

nents. Removal of mitochondria through the autophagy-

lysosome system is known as “mitophagy.” In mitophagy,

dysfunctional mitochondria are recognized and engulfed

in a double-membrane structure called a phagophore or

preautophagosome. Once the engulﬁng process is complete,

vesicles called autophagosomes form. The autophagosomes

then fuse with the lysosome, producing autolysosomes,

and the contents are hydrolytically degraded and recycled

(reviewed in [16,179,180]). The process is mediated through

a collection of several autophagy gene (Atg) products. In

yeast, the recognition process is enacted through Atg32,

a mitophagy-speciﬁc receptor on the OMM [181], and

through other key players, such as Atg8 and its activator

Atg7. Mitophagy in mammals has been less well char-

acterized, but the mammalian homologues to Atg32 and

Atg8 are believed to be Nix and LC3, respectively [180,

182]. In addition, mitophagy in mammalian cells may

be carried out through ubiquitination of OMM proteins,

followed by recognition via an LC3 complex (reviewed in

[180]).

Relative to other mitochondrial dynamics, there is less

known about the role of mitophagy in the aging of SM.

Evidence suggests that mitophagy selectively removes defec-

tive mitochondria that are depolarized or produce excessive

ROS (reviewed in [16,17,179,183]). In corroboration,

suppression of autophagy results in increased ROS pro-

duction, reduced oxygen consumption, and higher mtDNA

mutation rates [184,185]. With age, autophagy has been

found to decline both in general (reviewed in [186]) and

in the SM of aged rats [187]. While the repercussions are

still unknown, mitophagy has been negatively correlated

with oxidative damage and apoptosis [187], suggesting

that reduced autophagy rates may contribute to muscular

dysfunction. This is conﬁrmed by studies on muscle-speciﬁc

Atg7 knockout mice, who accumulate abnormal mitochon-

dria, have lower resting oxygen consumption, and experience

increased oxidative stress and higher rates of apoptosis;

these mice also suﬀer from muscle atrophy, weakness, and

myoﬁbril degeneration [188,189]. Furthermore, studies in a

few species indicate that enhanced autophagy may increase

lifespan (reviewed in [190]).

Mitochondrial quality control and degradation are also

modulated by the ubiquitin-proteasome system, which

removes oxidized proteins and short-lived proteins (reviewed

in [191]). Evidence from studies in mammals has suggested

that ubiquitin-proteasome activity declines with age in

SM and may contribute to muscular atrophy (reviewed

in [91,192]). However, aging may diﬀerentially aﬀect the

components of the ubiquitin-proteasome system [193], as

some genes involved—including some proteasome subunits

and ubiquitin-speciﬁc proteases—are expressed at higher

levels in SM from older humans, yet others are unchanged

or decreased with age [49,84,94,194–196]. Finally, changes

in proteasomal activity may be ﬁber type-speciﬁc [197]:

in particular, one study in humans reported that ubiquitin

Journal of Aging Research 9

protein levels increase in fast-twitch muscle ﬁbers, which

may explain why type II ﬁbers atrophy faster with age [198].

3.4. Increased Mitochondria-Mediated Apoptosis. Mitochon-

dria also respond to and modulate cellular dynamics through

apoptotic signaling, which is activated when either OXPHOS

or their redox potential is disrupted, or in response to

proapoptotic signals (reviewed in [199]). Mitochondria

can induce apoptosis through either caspase-dependent

or caspase-independent signaling mechanisms (reviewed

in [199–201]). Caspase-dependent signaling is dependent

on the release of cytochrome c from within the mito-

chondria, which triggers a cascade of actions by cysteine

proteases called caspases that results in apoptosis. In brief,

cytochrome c and other proapoptotic factors are released

from the mitochondria. Once released, cytochrome c joins

with apoptotic protease activating factor-1 (Apaf-1) and

procaspase-9 to form a complex called the apoptosome. The

apoptosome then cleaves and activates procaspase-9, which

acts on caspase-3. Caspase-3 in turn activates a caspase-

activated DNase (CAD) to degrade DNA and initiates

cellular degradation. In the caspase-independent pathway,

which is also known as “mitoptosis,” the mitochondria

release apoptosis-inducing factor (AIF) and endonuclease

G (EndoG), which then induce chromatin condensation

and DNA fragmentation. There are multiple points in these

pathways that are regulated by pro- and anti-apoptotic

proteins. In particular, the release of apoptotic triggers

appears to be modulated through two mechanisms: (1)

the balance of proapoptotic (e.g., Bax) and anti-apoptotic

proteins (e.g., Bcl-2), particularly from the Bcl-2 family,

which control OMM stability and form the mitochondrial

apoptosis-induced channel (MAC), and (2) the mitochon-

drial permeability transition pore (mPTP). One example of

the direct connection between mitochondrial and cellular

dynamics is that mitochondrial fragmentation occurs around

the time that proapoptotic factors are released from the

mitochondria, and this step is contingent upon increased

ﬁssion through Drp1 as well as a block in mitochondrial

fusion (reviewed in [202]).

Apoptosis increases signiﬁcantly with age and likely

contributes to sarcopenia and other age-associated declines

(reviewed in [201,203,204]). Though it is diﬃcult to

prove this conclusively, many studies have correlated rates

of apoptosis with markers of sarcopenia or SM function

(reviewed in [201,203,204]). In humans, the percent of

apoptotic cells tends to increase with age, though generally

more so in type II ﬁbers [194,205,206]. The weight of

evidence from both human and animal studies suggests that

the caspase-independent pathway is upregulated with age,

while the caspase-dependent pathway is not (reviewed in

[201]). In particular, one study found an increase in AIF

gene transcripts in SM from older people, but no change in

Bax, Bcl-2, or caspase-3 expression [207], and another study

in humans reported no change in caspase-3 or -7 activity

[194]. This is also supported by animal studies, which have

found that the mPTP becomes more susceptible towards

being opened [25,208,209] and that the levels and activities

of caspase-independent apoptotic proteins AIF and EndoG

increase [25,112,210–213] with age. Recent evidence in rats

suggests that apoptotic susceptibilities and markers are age-

and ﬁber type-speciﬁc, which may explain some of the mixed

results, particularly in regard to the caspase-dependent

pathway [25,214–216]. Interestingly, a study showed that

disuse atrophy increased caspase-3 activity in young rats but

not old and dramatically increased EndoG levels in old rats

but not young, indicating that older SM likely responds to

apoptotic stimuli through diﬀerent signaling pathways than

younger SM [212].

4. Strategies to Attenuate

Mitochondrial Aging

4.1. Exercise. Exercise training has long been known to

induce mitochondrial biogenesis, upregulate SM gene

expression and protein synthesis, and increase SM oxidative

capacity [217,218]. It is apparent from previous research that

physical activity decreases during aging [219]. Therefore, it

remains unclear whether the abnormalities in mitochondrial

function are a primary eﬀect of aging or are due to

the associated decline in physical activity. This issue is

compounded by the cross-sectional nature of some studies

without objective control for activity level [130,220–222].

For example, we recently found that mitochondrial capacity

was reduced in elderly subjects compared to their young

BMI-matched counterparts [10]. In this study, we included

only sedentary individuals, deﬁned as less than 2 hours

of intentional physical activity per week. Despite careful

screening for activity levels using questionnaires, we found

that daily physical activity was signiﬁcantly lower than

reported in the elderly group. This suggests that independent

of exercise training, simply living an active lifestyle may have

a signiﬁcant impact on mitochondrial function; however,

we cannot determine the cause and eﬀect due to the cross-

sectional nature of the analysis.

There is strong evidence that exercise training can

improve SM mitochondrial function in elderly adults [84,

96,97,223–225] and may also protect against age-associated

apoptosis [226]. Short et al. found that 4 months of

aerobic exercise in older adults increased protein synthe-

sis, mitochondrial enzyme activity (citrate synthase and

cytochrome c oxidase), and expression of genes involved in

mitochondrial content and biogenesis to levels similar to

those in younger adults [97,227]. In a separate study, 12

weeks of aerobic exercise training increased mitochondrial

content and activity, particularly in the subsarcolemmal

fraction [224]. Exercise has also been shown to increase

the activity of antioxidant enzymes and heat shock proteins

[228], potentially reducing ROS production and decreasing

the potential for mitochondrial oxidative damage thought

to occur during aging. Indeed, Parise et al. showed that

resistance exercise in older adults increased antioxidant

content (but not activity), decreased oxidative damage (8-

OHdG), and increased complex IV activity [229,230].

Despite these signiﬁcant diﬀerences in mitochondrial

parameters, most data show that some impairment remains.

10 Journal of Aging Research

For example, the usual age-associated decline in mitochon-

drial oxidative capacity was absent in older adults who were

chronically endurance trained. However, chronic exercise

did not completely restore the expression of mitochondrial

proteins, mtDNA content, and mitochondrial transcription

factors to the levels of younger subjects, suggesting a

persisting, independent eﬀect of age [50]. Supporting this,

Melov et al. used an “omics” approach to show that after

6 months of exercise training, the transcriptional signature

of aging was substantially but incompletely reversed back to

the transcriptome of younger adults [84]. In all, the results

to date indicate that exercise can help to attenuate age-

associated changes in SM mitochondria. However, it does

not completely prevent these changes. The data available

are rather limited and apply mostly to short-term exercise

interventions (i.e., 12–24 weeks) rather than chronic exercise.

In addition, the impact of active lifestyle changes—for exam-

ple, decreasing sedentary time and increasing “nonexercise”

activity—on mitochondrial function in elderly adults may

be signiﬁcant [231] and needs further investigation, as this

may be a more logical approach rather than prescribing an

exercise regimen.

4.2. Caloric Restriction. Caloric restriction, which typically

involves consuming 20–40% fewer calories than normal, also

preserves mitochondrial health and attenuates SM decline

with age. Caloric restriction (CR) is recognized as the most

robust intervention that retards both primary aging (natural

age-related deterioration) and secondary aging (accelerated

aging due to disease and negative lifestyle behaviors), thereby

increasing both median and maximal lifespan in many

species. While CR studies in primates and humans are

largely ongoing, studies in rodents consistently show that CR

extends maximum life span by up to 50% and reduces the

incidence of many age-associated diseases, including cancer

and metabolic diseases (reviewed in [232]). Preliminary

evidence in rhesus monkeys indicates similar eﬀects can be

expected in primates [231].

The beneﬁts ascribed to CR are believed to be due in large

part to reductions in oxidative stress (reviewed in [233]). In

primates, a decade-long CR intervention resulted in marked

decreases in oxidative damage to lipids and proteins [234]; in

aged rats, CR also reduces ROS production [159,235,236].

As a result, aged CR animals exhibit fewer mtDNA and

nuclear DNA mutations and less oxidative damage to SM

mitochondria than their ad libitum-fed counterparts [99,

236–240]. Some of these ﬁndings have been replicated in the

still ongoing CR trial in humans, dubbed CALERIE, which

reported that CR subjects had less mtDNA damage and

more mtDNA content than controls [241]. Microarray and

RT-PCR experiments conﬁrm that CR increases transcripts

of genes involved in ROS scavenging, including SOD and

GPx, and decreases transcripts from stress response genes

[196,242].

Calorie restriction appears to modulate mitochondrial

eﬃciency, content, and function. CR lowers energy expendi-

ture in animals and humans by producing mitochondria that

consumelessoxygenyetareabletomaintainnormallevels

of ATP production (reviewed in [232]; in particular, [159,

237,241–243]). It is generally believed that this energetic

adaptation is mediated via decreased proton leak, which

has been conﬁrmed in rodent studies, and that decreased

proton leak is in turn enabled by the shift to a less oxidative

milieu [159,237,244]. In terms of mitochondrial content

and function, CR does not aﬀect the gene expression, protein

level, or activity of citrate synthase, nor the activities of other

TCA proteins [111,112,241,242,245]. However, CR may

aﬀect some ETS enzymes. CR reduced the age-associated

accumulation of complex IV-negative and complex II-

hyperactive ﬁbers in rats [99] and in rhesus monkeys [100].

Only complex IV activity, however, is consistently responsive

to CR, showing increased activity in comparison to that in

aged rodents and usually similar activity to their younger

counterparts [110–112,246]. Nonetheless, CR may prevent

the decline in the activities of complexes I–III in some

muscles [111]. However, a study in rhesus monkeys found

that about 9 years of CR only attenuated the decline in

gene expression of the complex II iron-protein subunit [85],

and a 14-week CR intervention where the rats were fed

at 70% of ad libitum levels found no increases in any

mitochondrial gene transcripts or proteins [245]. CR rodents

did have fewer ETS abnormalities, but the abnormalities

were otherwise similar to controls, suggesting that CR only

aﬀects the onset of ﬁber atrophy [240,247]. However, in

primate studies, CR did not alter the number of ﬁbers with

ETS abnormalities, but nonetheless preserved muscle ﬁber

[100,248].

CR also aﬀects mitochondrial dynamics. In rodent

SM, CR also increases mitochondrial biogenesis relative to

controls by slowing the decline in PGC-1αgene expression

with age, which may be at least partially responsible for

maintaining oxidative capacity in aged CR animals [110,

112]. The CALERIE study in humans also reported increased

transcripts from several genes involved in mitochondrial

biogenesis, including PGC-1α, Tfam, and SIRT1 [241]. It

is not clear, however, whether CR aﬀects the mitochondrial

metabolic regulator AMPK, as there have been mixed results

[249,250]. In addition, CR attenuated the decline in

mitophagy in the SM of old rodents [187] and the decline

in ubiquitin-proteasome activity in monkeys [251]. It also

reduced apoptosis susceptibility by promoting a remodeling

of caspases and caspase-related proteins to favor decreased

likelihood of cytochrome c release from the mitochondria

[187,252–254]. These ﬁndings are particularly important

as mitochondrial dysfunction and apoptosis have been

proposed as key mediators of sarcopenia.

Combined, these results suggest that CR reduces oxida-

tive stress and remodels mitochondrial dynamics to promote

the production of more fuel-eﬃcient mitochondria that

producelessROSandtofavortheremovalofdysfunctional

mitochondria [187,243,255]. Regardless of the underlying

mechanism, CR has repeatedly been shown in rodents to

either partially or fully oppose the hallmarks of sarcopenia,

including the age-related declines in muscle force, ﬁber cross-

sectional area, ﬁber number, and ﬁber type (reviewed in

[99,247,254,256–258]). Similar ﬁndings have been reported

in CR studies in rhesus monkeys [100,248].

Journal of Aging Research 11

4.3. Mimetics. Currently, there is strong interest in using a

CR- or exercise-mimetic to attenuate age-related mitochon-

drial dysfunction. The best known of these is resveratrol

(3,5,4,9-trihydroxystilbene), a phytoalexin that is abundant

in red wine. In the context of secondary aging, resver-

atrol’s eﬀects on mitochondria and SM have been well

studied. In rodent models involving metabolic pathology,

resveratrol improves mtDNA copy number and function,

increases mitochondrial biogenesis, improves exercise capac-

ity and motor function, and mitigates metabolic dysfunction

[259–261]. On a molecular level, resveratrol induces an

increase in the expression of PGC-1α,Tfam,andUCP3,

and increases SIRT1, AMPK, and PGC-1αactivation [259,

260]. In humans, a recent 30-day study of resveratrol

supplementation in 11 obese but metabolically healthy men

reported improved mitochondrial respiration in the presence

of fatty acid-derived substrate, increased AMPK and citrate

synthase activity, and higher SIRT1 and PGC-1αprotein

levels; however, no changes in mitochondrial content were

observed [262]. Interestingly, while resveratrol was originally

identiﬁed as a potent activator of SIRT1, there is controversy

surrounding its mode of action, and it may exert much of its

eﬀects through AMPK [260,263,264].

Rodent studies consistently show improved mitochon-

drial health with resveratrol (reviewed in [265]). For

example, in senescence-accelerated prone mice, those given

resveratrol had higher physical endurance, maximal force

contraction, and oxygen consumption, and higher levels

of transcripts from PGC-1αand ETS genes [266]. Aged

rats given resveratrol exhibited similar responses; they also

displayed reduced levels of oxidative stress but no changes

in most apoptotic markers, indicating the improvements

were mediated through changes in redox status and not

apoptotic pathways [267]. Like CR, resveratrol’s eﬀects on

mitochondrial biogenesis are believed to be mediated in

large part via reductions in mitochondrial ROS production

and via upregulation of fatty acid catabolism coupled with

a downregulation in fatty acid synthesis [137]. However,

one recent study of long-term resveratrol supplementation

in mice did not ﬁnd any improvement in the age-related

declines in PGC-1α, mitochondrial content, muscle mass,

and maximal isometric force production; though resveratrol

did preserve type II ﬁber contractile function and reduce

oxidative stress [268].

5. Conclusions

In summary, animal and human data consistently show that

skeletal muscle mitochondria are altered in aging, includ-

ing increased mutations in mitochondrial DNA, decreased

expression of some mitochondrial proteins, reduced enzyme

activity and altered respiration with reduced maximal capac-

ity in sedentary adults, and reduced total mitochondrial

content with increased morphological changes. Since the

primary role of mitochondria is to produce ATP to maintain

the energy status of the cell, shifts in respiratory activity and

capacity can lower the membrane potential, reduce cellular

ATP concentration, and signal cellular apoptotic events.

Increased apoptosis without correspondingly increased pro-

tein synthesis will eventually lead to net muscle ﬁber loss.

All of these factors probably contribute to age-associated

sarcopenia, and mounting evidence suggests that most

of these age-related changes can be either prevented or

attenuated through increased physical activity.

There is some thought that the accumulation of oxidative

damage caused by long-term ROS production is responsible

for these changes with age. Indeed, blocking ROS formation

by the targeted expression of antioxidant enzymes amelio-

rates age-associated dysfunction and returns mitochondrial

parameters to those of young animals (Figure 3). Whether

this is also true for humans is unknown; however, strategies

that improve mitochondrial function, such as exercise and

caloric restriction, also reduce ROS production and increase

antioxidant defenses. Exercise is also known to be a powerful

stimulant of mitochondrial biogenesis and oxidative capac-

ity, although exercise training in elderly adults probably does

not completely reverse the primary eﬀects of aging. However,

exercise training—even adopting active lifestyle habits—

may clearly reduce the rate of mitochondrial decline and

attenuate the aging phenotype. Whether CR- and exercise-

mimetics, including resveratrol, work as eﬀectively remains

to be determined and is an area of active research.

In conclusion, there is clearly a need for more research in

this ﬁeld and particularly to:

(i) ﬁgure out which age-related changes are universal

and which depend on physical activity or lifestyle

habits or gender;

(ii) unravel how cells compensate for oxidative damage

and mitochondrial dysfunction;

(iii) elucidate how fusion, ﬁssion, and autophagy work

together to ensure quality control and to remove

defective mitochondria; and

(iv) determine which mitochondrial declines can be

slowed down (or even reversed) by healthier lifestyles.

We expect this to continue be a fruitful and exciting area of

study in years to come.

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The Extract of Gloiopeltis tenax Enhances Myogenesis and Alleviates Dexamethasone-Induced Muscle Atrophy

Article

Full-text available

Jun 2024
INT J MOL SCI

The decline in the function and mass of skeletal muscle during aging or other pathological conditions increases the incidence of aging-related secondary diseases, ultimately contributing to a decreased lifespan and quality of life. Much effort has been made to surmise the molecular mechanisms underlying muscle atrophy and develop tools for improving muscle function. Enhancing mitochondrial function is considered critical for increasing muscle function and health. This study is aimed at evaluating the effect of an aqueous extract of Gloiopeltis tenax (GTAE) on myogenesis and muscle atrophy caused by dexamethasone (DEX). The GTAE promoted myogenic differentiation, accompanied by an increase in peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) expression and mitochondrial content in myoblast cell culture. In addition, the GTAE alleviated the DEX-mediated myotube atrophy that is attributable to the Akt-mediated inhibition of the Atrogin/MuRF1 pathway. Furthermore, an in vivo study using a DEX-induced muscle atrophy mouse model demonstrated the efficacy of GTAE in protecting muscles from atrophy and enhancing mitochondrial biogenesis and function, even under conditions of atrophy. Taken together, this study suggests that the GTAE shows propitious potential as a nutraceutical for enhancing muscle function and preventing muscle wasting.

Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia

Article

Full-text available

Mar 2024

Sarcopenia has a complex pathophysiology that encompasses metabolic dysregulation and muscle ultrastructural changes. Among the drivers of intracellular and ultrastructural changes of muscle fibers in sarcopenia, mitochondria and their quality control pathways play relevant roles. Mononucleated muscle stem cells/satellite cells (MSCs) have been attributed a critical role in muscle repair after an injury. The involvement of mitochondria in supporting MSC-directed muscle repair is unclear. There is evidence that a reduction in mitochondrial biogenesis blunts muscle repair, thus indicating that the delivery of functional mitochondria to injured muscles can be harnessed to limit muscle fibrosis and enhance restoration of muscle function. Injection of autologous respiration-competent mitochondria from uninjured sites to damaged tissue has been shown to reduce infarct size and enhance cell survival in preclinical models of ischemia–reperfusion. Furthermore, the incorporation of donor mitochondria into MSCs enhances lung and cardiac tissue repair. This strategy has also been tested for regeneration purposes in traumatic muscle injuries. Indeed, the systemic delivery of mitochondria promotes muscle regeneration and restores muscle mass and function while reducing fibrosis during recovery after an injury. In this review, we discuss the contribution of altered MSC function to sarcopenia and illustrate the prospect of harnessing mitochondrial delivery and restoration of MSCs as a therapeutic strategy against age-related sarcopenia.

Muscle weakness and mitochondrial stress occur before severe metastasis in a novel mouse model of ovarian cancer cachexia

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Jun 2024

Fundamentals of antioxidant capacity in food

Article

Full-text available

May 2024

Este artigo tem como objetivo discutir os conceitos básicos da capacidade/atividade antioxidante nos alimentos e do equilíbrio oxidativo necessário à saúde. A linguagem neste artigo é mantida básica o suficiente para que o público em geral possa entender. O artigo fornece informações condensadas sobre esta área como parte de um esforço mais amplo para popularizar a ciência. O artigo começa discutindo os conceitos básicos de antioxidantes e radicais livres desde os conceitos de química geral. As reações de redução da oxidação são essenciais para a vida, mas também produzem radicais livres nocivos, é a dicotomia básica a ser discutida. O trabalho apresenta então a importância da alimentação no equilíbrio oxidativo do metabolismo humano e como esse equilíbrio é necessário para a manutenção e promoção da saúde, principalmente reduzindo o risco de doenças crônicas não transmissíveis. Por fim, o artigo discute o papel dos antioxidantes no antienvelhecimento e na proteção do DNA.

Uncovering the impact of UV radiation on mitochondria in dermal cells: a STED nanoscopy study

Article

Full-text available

Apr 2024

Mitochondria are essential organelles in cellular energy metabolism and other cellular functions. Mitochondrial dysfunction is closely linked to cellular damage and can potentially contribute to the aging process. The purpose of this study was to investigate the subcellular structure of mitochondria and their activities in various cellular environments using super-resolution stimulated emission depletion (STED) nanoscopy. We examined the morphological dispersion of mitochondria below the diffraction limit in sub-cultured human primary skin fibroblasts and mouse skin tissues. Confocal microscopy provides only the overall morphology of the mitochondrial membrane and an indiscerptible location of nucleoids within the diffraction limit. Conversely, super-resolution STED nanoscopy allowed us to resolve the nanoscale distribution of translocase clusters on the mitochondrial outer membrane and accurately quantify the number of nucleoids per cell in each sample. Comparable results were obtained by analyzing the translocase distribution in the mouse tissues. Furthermore, we precisely and quantitatively analyzed biomolecular distribution in nucleoids, such as the mitochondrial transcription factor A (TFAM), using STED nanoscopy. Our findings highlight the efficacy of super-resolution fluorescence imaging in quantifying aging-related changes on the mitochondrial sub-structure in cells and tissues.

Unveiling Ageing-Associated and Caloric Restriction-Associated Changes in miRNA Expression in Rat Skeletal Muscle and the Mechanisms Mediating their Effects on Muscle Cell Function

Preprint

Full-text available

Apr 2024

The mechanisms underlying skeletal muscle ageing, whilst poorly understood, are thought to involve dysregulated micro (mi)RNA expression. Using young and aged rat skeletal muscle tissue, we applied high-throughput RNA sequencing to comprehensively study alterations in miRNA expression occurring with age, as well as the impact of caloric restriction (CR) on these changes. Furthermore, the function of the proteins targeted by these age- and CR-associated miRNAs was ascertained. Numerous known and novel age-associated miRNAs were identified of which CR normalised 45.5% to youthful levels. Our results suggested miRNAs upregulated with age to downregulated proteins involved in muscle tissue development and metabolism, as well as longevity pathways, such as AMPK and autophagy. Furthermore, our results found miRNAs downregulated with age to upregulate pro-inflammatory proteins, particularly those involved in innate immunity and the complement and coagulation cascades. Interestingly, CR was particularly effective at normalising miRNAs upregulated with age, rescuing their associated protein coding genes but was less effective at rescuing anti-inflammatory miRNAs downregulated with age. Lastly, the effects of a specific miRNA, miR-96-5p, identified by our analysis to be upregulated with age, were studied in culture C2C12 myoblasts. We demonstrated miR-96-5p to decrease cell viability and markers of mitochondrial biogenesis, myogenic differentiation and autophagy. Overall, our results provide useful information regarding how miRNA expression changes in skeletal muscle, as well as the consequences of these changes and how they are ameliorated by CR.

Mitochondrial remodeling underlying age-induced skeletal muscle wasting: let’s talk about sex

Article

Apr 2024
FREE RADICAL BIO MED

Sarcopenia is associated with reduced quality of life and premature mortality. The sex disparities in the processes underlying sarcopenia pathogenesis, which include mitochondrial dysfunction, are ill-understood and can be decisive for the optimization of sarcopenia-related interventions. To improve the knowledge regarding the sex differences in skeletal muscle aging, the gastrocnemius muscle of young and old female and male rats was analyzed with a focus on mitochondrial remodeling through the proteome profiling of mitochondria-enriched fractions. To the best of our knowledge, this is the first study analyzing sex differences in skeletal muscle mitochondrial proteome remodeling. Data demonstrated that age induced skeletal muscle atrophy and fibrosis in both sexes. In females, however, this adverse skeletal muscle remodeling was more accentuated than in males and might be attributed to an age-related reduction of 17beta-estradiol signaling through its estrogen receptor alpha located in mitochondria. The females-specific mitochondrial remodeling encompassed increased abundance of proteins involved in fatty acid oxidation, decreased abundance of the complexes subunits, and enhanced proneness to oxidative posttranslational modifications. This conceivable accretion of damaged mitochondria in old females might be ascribed to low levels of Parkin, a key mediator of mitophagy. Despite skeletal muscle atrophy and fibrosis, males maintained their testosterone levels throughout aging, as well as their androgen receptor content, and the age-induced mitochondrial remodeling was limited to increased abundance of pyruvate dehydrogenase E1 component subunit beta and electron transfer flavoprotein subunit beta. Herein, for the first time, it was demonstrated that age affects more severely the skeletal muscle mitochondrial proteome of females, reinforcing the necessity of sex-personalized approaches towards sarcopenia management, and the inevitability of the assessment of mitochondrion-related therapeutics. Open access | Full article here: https://doi.org/10.1016/j.freeradbiomed.2024.04.005

Unveiling the Mechanisms for Statin- Associated Sleep Problems and Myopathy Statin Medication, Sleep Problems and Myopathy Mechanisms

Thesis

Full-text available

May 2024

Mohamed Hamid Al-Sabri

Doktoravhandling, med artikler (Annet vitenskapelig) Fritextbeskrivning Abstract [en] Statins (3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR, inhibitors) comprise the gold standard for the management of hypercholesterolaemia and prevention of cardiovascular disease (CVDs). However, they are accompanied by potential adverse effects, notably muscle pain and sleep disturbance. These side effects can significantly impact patient adherence to statin therapy and thus increase the risk for CVDs. Despite extensive research, the underlying mechanisms of statin-associated myopathy and sleep disturbance are poorly understood. In Paper I, we conducted a cross-sectional cohort study to investigate the association between statin use and genetic variants for HMGCR with the risk for insomnia and chronotype using UK biobank cohort data. Statin use, insomnia and chronotype were assessed by a self-report touchscreen questionnaire. Statin treatment was associated with an increased risk of insomnia compared to controls, while genetic variants for HMGCR inhibition were associated with a reduced risk for insomnia. No association with late evening chronotype were observed with statin use or genetic variants for HMGCR. In Paper II, we employed Drosophila melanogaster to examine the effect of statins and the role of central inhibition of Hmgcr on sleep behaviour. Flies were treated with fluvastatin for five days and Hmgcr was knocked down in pan neurons and pars intercerebralis (PI), equivalent to the mammalian hypothalamus. Sleep patterns were recorded and analysed. Pan-neuronal- as well as PI inhibition of Hmgcr recapitulates fluvastatin-induced enhanced sleep latency and reduced sleep duration. In Paper III, we deciphered the underlying mechanisms for statin-induced myopathy using D. melanogaster. We found that fluvastatin treatment induced muscular damage, mitochondrial phenotypes, lowered locomotion, reduced climbing activity and was associated with lipotoxicity, impaired muscle differentiation and regeneration, and lowered expression of skeletal muscle chloride channels. Interestingly, selective inhibition of skeletal muscle chloride channels recapitulates fluvastatin-induced myofibrillar damage and lowered climbing activity, while selective Hmgcr inhibition in the skeletal muscles recapitulates fluvastatin-induced mitochondrial round-shape and reduced locomotion activity. In Paper IV, we explored the sequential events of myofibril damage and mitochondrial phenotypes associated with fluvastatin and examined whether inhibition of Hmgcr in the skeletal muscles recapitulates fluvastatin effects on mitochondrial respiratory parameters using D. melanogaster. Acute fluvastatin treatment was associated with reduced mitochondrial content and roundness of the mitochondria without noticeable myofibrillar damage. Intriguingly, chronic fluvastatin treatment was associated with stronger mitochondrial phenotypes along with severe myofibrillar damage, which suggests that mitochondrial phenotypes precede myofibrillar damage. Moreover, selective Hmgcr inhibition did not impact mitochondrial respiratory functions.

Longitudinal association between soft drink consumption and handgrip strength in adults: a prospective analysis from the Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIH) cohort study

Article

Apr 2024

Soft drink consumption has become a highly controversial public health issue. Given the pattern of consumption in China, sugar-sweetened beverage is the main type of soft drink consumed. Due to containing high levels of fructose, a soft drink may have a deleterious effect on handgrip strength (HGS) due to oxidative stress, inflammation and insulin resistance. However, few studies show an association between soft drink consumption and HGS in adults. We aimed to investigate the association between soft drink consumption and longitudinal changes in HGS among a Chinese adult population. A longitudinal population-based cohort study (5-year follow-up, median: 3·66 years) was conducted in Tianjin, China. A total of 11 125 participants (56·7 % men) were enrolled. HGS was measured using a handheld digital dynamometer. Soft drink consumption (mainly sugar-containing carbonated beverages) was measured at baseline using a validated FFQ. ANCOVA was used to evaluate the association between soft drink consumption and annual change in HGS or weight-adjusted HGS. After adjusting for multiple confounding factors, the least square means (95 % CI) of annual change in HGS across soft drink consumption frequencies were −0·70 (–2·49, 1·09) for rarely drinks, −0·82 (–2·62, 0·97) for < 1 cup/week and −0·86 (–2·66, 0·93) for ≥ 1 cup/week (Pfor trend < 0·05). Likewise, a similar association was observed between soft drink consumption and annual change in weight-adjusted HGS. The results indicate that higher soft drink consumption was associated with faster HGS decline in Chinese adults.

Muscle weakness and mitochondrial stress occur before metastasis in a novel mouse model of ovarian cancer cachexia

Preprint

Full-text available

Apr 2024

Objectives: A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice. Methods: Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm ~45, ~75 and ~90 days after EOC injection. Results: Primary ovarian tumour sizes were progressively larger at each time point while robust metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFa61537;), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling. Conclusion: This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-metastatic weakness during EOC in addition to therapies targeting cachexia.

Oxidative capacity of human muscle fiber types: effects of age and training status

Article

Full-text available

Jun 1995

Morphometry and oxidative capacity of slow-twitch (type I) and fast-twitch (type IIa and IIb) muscle fibers obtained from vastus lateralis needle biopsies were compared between younger (21-30 yr) and older (51-62 yr) normal fit (maximal O2 uptake = 47.0 vs. 32.3 ml.kg-1.min-1) and endurance-trained (66.3 vs. 52.7 ml.kg-1.min-1) men (n = 6/group). The older groups had smaller type IIa (31%) and IIb (40%) fiber areas and fewer capillaries surrounding these fibers than did younger groups. The reduced type II fiber areas and capillary contacts associated with aging were also observed in the older trained men. However, the capillary supply per unit type II fiber area was not affected by age but was enhanced by training. Additionally, on the basis of quantitative histochemical analysis, succinate dehydrogenase activities of type IIa fibers in the older trained men [4.07 +/- 0.68 (SD) mmol.min-1.l-1] were similar to those observed in younger trained men (4.00 +/- 0.48 mmol.min-1.l-1) and twofold higher than in older normal fit men (2.01 +/- 0.65 mmol.min-1.l-1; age x fitness interaction, P < 0.05). Type I muscle fibers were unaffected by age but were larger and had more capillary contacts and higher succinate dehydrogenase activities in the trained groups. The findings of this study suggest that aging results in a decrease in type II fiber size and oxidative capacity in healthy men and that this latter effect can be prevented by endurance training. Conclusions regarding the effects of age and training status on muscle capillarization depend largely on how these data are expressed.

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

Article

Full-text available

Mar 2001

The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects ≤40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations.

High‐throughput profiling of the mitochondrial proteome using affinity fractionation and automation

Article

Oct 2000
ELECTROPHORESIS

Recent studies have demonstrated the need for complementing cellular genomic information with specific information on expressed proteins, or proteomics, since the correlation between the two is poor. Typically, proteomic information is gathered by analyzing samples on two‐dimensional gels with the subsequent identification of specific proteins of interest by using trypsin digestion and mass spectrometry in a process termed peptide mass fingerprinting. These procedures have, as a rule, been labor‐intensive and manual, and therefore of low throughput. The development of automated proteomic technology for processing large numbers of samples simulataneously has made the concept of profiling entire proteomes feasible at last. In this study, we report the initiation of the (eventual) complete profile of the rat mitochondrial proteome by using high‐throughput automated equipment in combination with a novel fractionation technique using minispin affinity columns. Using these technologies, approximately one hundred proteins could be identified in several days. In addition, separate profiles of calcium binding proteins, glycoproteins, and hydrophobic or membrane proteins could be generated. Because mitochondrial dysfunction has been implicated in numerous diseases, such as cancer, Alzheimer's disease and diabetes, it is probable that the identification of the majority of mitochondrial proteins will be a beneficial tool for developing drug and diagnostic targets for associated diseases.

High-throughput profiling of the mitochondrial proteome using affinity fractionation and automation

Article

Oct 2000
ELECTROPHORESIS

Recent studies have demonstrated the need for complementing cellular genomic information with specific information on expressed proteins, or proteomics, since the correlation between the two is poor. Typically, proteomic information is gathered by analyzing samples on two-dimensional gels with the subsequent identification of specific proteins of interest by using trypsin digestion and mass spectrometry in a process termed peptide mass fingerprinting. These procedures have, as a rule, been labor-intensive and manual, and therefore of low throughput. The development of automated proteomic technology for processing large numbers of samples simulataneously has made the concept of profiling entire proteomes feasible at last. In this study, we report the initiation of the (eventual) complete profile of the rat mitochondrial proteome by using high-throughput automated equipment in combination with a novel fractionation technique using minispin affinity columns. Using these technologies, approximately one hundred proteins could be identified in several days. In addition, separate profiles of calcium binding proteins, glycoproteins, and hydrophobic or membrane proteins could be generated. Because mitochondrial dysfunction has been implicated in numerous diseases, such as cancer, Alzheimer's disease and diabetes, it is probable that the identification of the majority of mitochondrial proteins will be a beneficial tool for developing drug and diagnostic targets for associated diseases.

Translocation of Proteins into Mitochondria.

Article

Jan 2007

Skeletal muscle oxidative capacity in young and older women and men

Article

Sep 2000

It has been suggested that a decline in skeletal muscle oxidative capacity is a general consequence of aging in humans. However, previous studies have not always controlled for the effects of varying levels of physical activity on muscle oxidative capacity. To test the hypothesis that, when matched for comparable habitual physical activity levels, there would be no age-related decline in the oxidative capacity of a locomotor muscle, the postexercise recovery time of phosphocreatine was compared in the tibialis anterior muscle of young [n = 19; 33.8 +/- 4.8 (SD) yr] and older [n = 18; 75.5 +/- 4.5 yr] healthy women and men of similar, relatively low, activity levels. The intramuscular metabolic measurements were accomplished by using phosphorus magnetic resonance spectroscopy. The results indicate that there was no age effect on the postexercise recovery time of phosphocreatine recovery. thus supporting the stated hypothesis. These data suggest that there is no requisite decline in skeletal muscle oxidative capacity with aging in humans, at least through the seventh decade.

Mitochondrial Fusion and Fission in Mammals

Article

Oct 2007

David C. Chan

Eukaryotic cells maintain the overall shape of their mitochondria by balancing the opposing processes of mitochondrial fusion and fission. Unbalanced fission leads to mitochondrial fragmentation, and unbalanced fusion leads to mitochondrial elongation. Moreover, these processes control not only the shape but also the function of mitochondria. Mitochondrial dynamics allows mitochondria to interact with each other; without such dynamics, the mitochondrial population consists of autonomous organelles that have impaired function. Key components of the mitochondrial fusion and fission machinery have been identified, allowing initial dissection of their mechanisms of action. These components play important roles in mitochondrial function and development as well as programmed cell death. Disruption of the fusion machinery leads to neurodegenerative disease.

Aging-Dependent Large Accumulation of Point Mutations in the Human mtDNA Control Region for Replication

Article

Oct 1999

Progressive damage to mitochondrial DNA (mtDNA) during life is thought to contribute to aging processes. However, this idea has been difficult to reconcile with the small fraction of mtDNA so far found to be altered. Here, examination of mtDNA revealed high copy point mutations at specific positions in the control region for replication of human fibroblast mtDNA from normal old, but not young, individuals. Furthermore, in longitudinal studies, one or more mutations appeared in an individual only at an advanced age. Some mutations appeared in more than one individual. Most strikingly, a T414G transversion was found, in a generally high proportion (up to 50 percent) of mtDNA molecules, in 8 of 14 individuals above 65 years of age (57 percent) but was absent in 13 younger individuals.

Mitochondrial dysfunction in the elderly: Possible role in insulin resistance

Article

Jan 2003

Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1??

Article

Jan 2006
CELL

Skeletal Muscle Mitochondria and Aging: A Review

Abstract and Figures

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