Chounghun Kang,Li Li Ji

Laboratory of Physiological Hygiene and Exercise Science,School of Kinesiology,University of Minnesota,Minneapolis,MN 55455,USA

Role of PGC-1α in muscle function and aging

Chounghun Kang,Li Li Ji*

Laboratory of Physiological Hygiene and Exercise Science,School of Kinesiology,University of Minnesota,Minneapolis,MN 55455,USA

This article focuses on the current underlying of molecular mechanisms of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)mediated pathway and discuss possible therapeutic benefits of increased mitochondrial biogenesis in compensating for mitochondrial dysfunction and ameliorating aging and aging-related diseases.PGC-1α is the master transcription regulator that stimulates mitochondrial biogenesis,by upregulating nuclear respiratory factors and mitochondrial transcription factor A,leading to increased mitochondrial DNA replication and gene transcription.PGC-1α also regulates cellular oxidant-antioxidant homeostasis by stimulating the gene expression of superoxide dismutase-2,catalase,glutathione peroxidase 1,and uncoupling protein.Recent reports from muscle-specific PGC-1α overexpression underline the benefit of PGC-1α in muscle atrophy and sarcopenia,during which PGC-1α enhanced mitochondrial biogenic pathway and reduced oxidative damage.Thus,PGC-1α seems to have a protective role against aging associated skeletal muscle deterioration.

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Aging;Mitochondria;Muscle;PGC-1α;Signaling

1.Introduction

Aging is characterized by the progressive decline in cellular, tissue,and organ function.This complex process often manifests as loss of muscular strength,cardiovascular function,and cognitive ability.1Reduction in mitochondrial activity and numbers is implicated in aging and age-related diseases such as neurodegenerative diseases,cancer,and diabetes.2Mitochondria as the most dynamic organelles in the cells,have multiple critical functions to regulate energy production,intracellular signaling,oxidative-antioxidant balance,and apoptosis.2—5Mitochondriain skeletalmuscle experiences rapid and characteristic changes following manipulations of muscle use and environmentalconditions.6Decreased mitochondrial content and functional capacity are common muscle pathophysiologicaltraitsimplicatedindevelopmentofmitochondrial myopathy.

In the past decade,the peroxisome proliferator-activated receptor-γ coactivator-1α(PGC-1α)emerges as a key transcriptional coactivator,which has provided a mechanistic insight into how nuclear regulatory pathways are coupled to the metabolic regulation of mitochondria,antioxidant defense and inflammatory response in skeletal muscle.Mitochondria undergo constant biogenesis controlled primarily by the gene expression and post-translational modification of PGC-1α.7These findings have profound effect on our understanding of signal transduction pathways related to muscle function and provide new insight into potential new strategies for preventive and therapeutic measures against pathophysiological disorders in skeletal muscle.Thus,it is not surprising that the PGC-1αactivated signal transduction pathway has a significant impact on aging.8

2.Role of PGC-1α in skeletal muscle

PGC-1α,a transcriptional coactivator,was first identified as a functional activator of the peroxisome proliferator-activated receptor(PPAR)γ receptor in brown adipose tissue9and has been known to affect numerous metabolic regulations.7,10PGC-1α interacts with nuclear receptors and transcription factors to activate transcription of their target genes and its activity is responsive to multiple stimuli including calcium ion,reactive oxygen species(ROS),insulin,thyroid hormone,estrogen, hypoxia,ATPdemand,andcytokines.11CoactivationofPGC-1α not only stimulates mitochondrial DNA replication but also regulatesothervitalcellulareventssuchasmitochondrial fusion and fission12and antioxidant defense.13

2.1.PGC-1αmediated mitochondrial biogenesis

Both nuclear and mitochondrial DNA encode mitochondria proteins and this dual genomic organization is coordinated by a set of transcription factors and cofactors.14It is a complex process that requires the synthesis,import,and incorporation of proteins and lipids to the existing mitochondrial reticulum,as well as replication of the mitochondrial DNA(mt DNA).15PGC-1α has been thought to be a master regulator of mitochondrial biogenesis by co-activating several transcription factors that in turn bind to the promoters of distinct sets of nuclear-encodedmitochondrialgenes.3,16ItisknownthatPGC-1αinteractswithseveralnucleartranscriptionfactors,including PPAR family members,nuclear respiratory factor(NRF)-1 and NRF-2,andestrogenrelatedreceptor-α(ERRα),aswellasnonnuclear receptors,such as myocyte enhancer factor 2(MEF2), forkheadboxproteinO(FOXO)1andsterolregulatoryelement binding proteins(SREBP)117,18(Fig.1).For example,PGC-1α co-activation ofNRF-1,2promotes the expression ofnumerous nuclear-encoded mitochondrial proteins(NEMP),as well as mitochondrial transcription factor A(Tfam),which directly stimulates mitochondrial DNA(mtDNA)replication and transcription.7,19,20Over-expression of the PGC-1α in cultured C2C12 myoblasts and other cells induces respiratory subunit mRNAs and increases cytochrome c oxidase subunit 4 (COXIV)and cytochromec(Cyt C)protein levelsaswell as the steady-state level of mtDNA,7as an adaptation to facilitate increased oxygen utilization.In skeletal muscle,PGC-1α also has been shown to regulate skeletal muscle fiber-type switch, glucose transport,and lipid utilization,10,21,22as well as mitochondrial biogenesis and fusion.9,23

2.2.Exercise-induced PGC-1αregulation and mitochondrial adaptation

Fig.1.Regulation of peroxisome proliferator-activated receptor-γ coactivator-1α(PGC-1α)gene expression.PGC-1α,peroxisome proliferator-activated receptor gamma coactivator 1-α;Tfam,mitochondria transcription factor A; MAPK,mitogen-activated protein kinase;MKK6,MAP kinase kinase:CaMK, calcium/calmodulin-dependent protein kinase;CREB,cyclic AMP response element binding protein;MEF,myocyte enhancer factor;ATF,activating transcription factor;NRF,nuclear respiratory factor;ERR,estrogen related receptor;XO,xanthine oxidase;PKC,protein kinase C.55Modified with permission.

Mitochondrial biogenesis is one of the major responses of skeletalmuscletoavarietyofphysiologicalconditionsincluding endurance training.24It is well known that endurance training can increase mitochondrial content and respiratory capacity in skeletal muscle,25resulting in a slower rate of utilization of muscle glycogen and blood glucose,a greater reliance on fat oxidation,and less lactate accumulation during submaximal exercise.26PGC-1αisknowntobeamajorregulatorofexerciseinduced phenotypic adaptation and fiber transformation from type 2 to type 1.10In skeletal muscle,PGC-1α expression is activated during muscle contraction through Ca2+/calmodulindependent protein kinase IV(CamKIV)and calcineurin A, which are activated through calcium ion dynamics within the muscle in response to exercise.27The increased calcium signaling during muscle contraction activates several important transcription factors such as cAMP-response element binding protein(CREB),a target of CamKIV,and MEF2.28Another factor that regulates PGC-1α expression upon exercise involves p38 mitogen activated protein kinase(MAPK),a key MAPK family enzyme which activates MEF2 and activating transcription factor 2(ATF2).29ATF-2 and subsequent interactions of ATF2-CREB appeared tobe an early event inPGC-1α mediated signaling processes.30In addition to transcriptional activation, p38 MAPK also increases PGC-1α co-activating capacity by phosphorylation in response to cytokine stimulation in muscle cells.31Finally,as a metabolic energy deprivation sensor,AMP activated kinase(AMPK)is activated by exercise due to increased AMP:ATP ratio and Ca2+flux during muscle contraction,enhancing PGC-1α transcription as well as activity. It was demonstrated that activation of p38 MAPK-mediated phosphorylation of CREB and subsequent binding to PGC-1α promoter plays a key role in activating PGC-1α expression in response to increased muscle activity.32

Enduranceexerciseisalsoknowntobeapowerfulstimulusto muscle plasticity such as a fiber-type switching towards more oxidativefibers.10,28PGC-1αknockout(KO)miceexhibitashift from oxidative to glycolytic muscle fibers.Moreover,skeletal muscle-specific PGC-1α KO animals have reduced endurance capacity and exhibit fiber damage and elevated markers of inflammation following treadmill running.33In a previous studywe examined the redox-sensitive nature of PGC-1α signaling during acute sprinting exercise and reported that reducing ROS generationwithallopurinoltoinhibit xanthineoxidase(XO),the main ROS source of this type of exercise,attenuated PGC-1α expression and PGC-1α-controlled signaling pathway and mitochondrial biogenesis.34This study suggests that ROS produced during musclecontraction may be a required signaling agent to induce training adaptation.

2.3.Role of PGC-1αin inflammatory factors and antioxidant enzymes

Recent studies indicate that PGC-1α may also play a role in anti-inflammatory response.PGC-1α null mice indicated that PGC-1α changes local or systemic inflammation and regulate the expression of inflammatory cytokines such as tumor necrosis factor(TNF)-α and interleukin(IL)-6.35,36PGC-1α KO mice showed higher basal mRNA level of TNF-α,IL-6 in skeletal muscle,as well as higher serum IL-6 level than their wild type counterparts(WT).3Conversely,PGC-1α overexpressed mice had lower expression of TNF-α and IL-6 mRNA in skeletal muscle,whereas over-expression of PGC-1α reduced an age-associated increase in TNFα and IL-6 protein content in skeletal muscle and reduced serum TNF-α and IL-6 levels in old mice compared with age-matched WT mice.8These data suggest that PGC-1α has a protective role in inflammatory response by reducing pro-inflammatory cytokine production.Moreover,a single exercise bout elicited a significant increase in skeletal muscle TNF-α mRNA and serum TNF-α content in PGC-1α KO mice,but not in WT mice,3indicating that skeletal muscle PGC-1α normally protects against exercise-induced increases in TNF-α.These findings suggest that the transcriptional regulation by which muscle cells produce these cytokines are enhanced by the recruitment of particular immune cells(polymorphoneutrophil,macrophage),which inflicts an inflammatory response to the muscle stress and damage,whereas PGC-1α usually functions to suppress the production of such inflammatory factors.2

Although the underlying mechanism that links PGC-1αmediated anti-inflammatory effect is still not known,PGC-1αmediated regulation of the anti-oxidant defense can be a significant determinant,as altered oxidative stress due to an impaired balance between ROS production and removal can induce an inflammatory response through activation of the redox sensitive nuclear factor Kappa B(NF-κB).NF-κB is a ubiquitous signaling pathway that is involved in the pathology of inflammatory diseases.37The NF-κB pathway is activated by phosphorylation,ubiquitination,and proteolysis of the inhibitory protein inhibitory kappa B(IκB)which binds and retains the NF-κB p65/p50 heterodimer in the cytosol. Following an activation signal,such as TNFα,inhibitory kappa B kinase(IKK)phosphorylates IκB resulting in the protein’s ubiquitination and proteasome degradation.After the destruction of IκB,p50 and p65 are released and enter the nucleus to affect gene transcription of various proteins involved in immune function,inflammatory response,and antioxidant defense.38

Previous research has shown that ROS induce inflammatory cytokine production in skeletal muscle39and the expression of mitochondrial ROS-detoxifying enzymes was increased by PGC-1α.33,40Down-regulation of the antioxidant genes in muscle-specific PGC-1α knock-out mice increased cytokine expression.33,41Reduced mRNA levels of SOD1(CuZn-SOD), SOD2(Mn-SOD)and/or GPx1,42as well as SOD2 protein content,43,44were observed in skeletal muscle from PGC-1α KO mice compared to WT,while PGC-1α over-expression mice showed an up-regulation of SOD2 protein content in skeletal muscle.8PGC-1α KO fibroblasts exhibit a decrease in SOD2,catalase and GPx1 mRNA content relative to WT fibroblasts and PGC-1α KO mice were more vulnerable to oxidative stress.13In addition,PGC-1α has been shown to regulate the mRNA expression of uncoupling protein(UCP)2 and 3 in cell culture,40suggesting that PGC-1α may also increase the uncoupling capacity and concomitantly reduce mitochondrial ROS production.Furthermore,it has been also shown that PGC-1α promotes NAD-dependent deacetylase sirtuin(SIRT)3 gene expression,which is mediated by an estrogen related receptor(ERR)α binding element mapped to the SIRT3 promoter region.45Increased SIRT3 deacetylates and activates mitochondrial enzymes including SOD2 through a post-translational mechanism.46,47Taken together,PGC-1α seems to have a role in reducing ROS damage by up-regulating antioxidant gene expression and activity.

3.Protective role of PGC-1α in the muscle atrophy and aging

3.1.Skeletal muscle disuse atrophy

Aging is associated with decreased activity of muscle contraction.There is evidence that many of the cellular events during the development of sarcopenia are similar to those associated with prolonged muscle disuse,such as bed rest, casting,and microgravity.Thus,study on muscle immobilization(IM)may provide some useful insight into the mechanism of sarcopenia.

Muscle atrophy caused by prolonged IM appears to be ahighlyorderedandregulatedprocesswhichischaracterizedby decreased muscle fiber cross-sectional area,reduced force production,increased fatigability and insulin resistance.48These alterations also include decreased protein synthesis, increased oxidative stress,increased protein degradation,and suppression of biogenesis associated with mitochondrial dynamics.49Different signaling pathways may be involved in causing muscle atrophy depending on the upstream perturbations,such as decreased IGF1-AKT-FoxO signaling,inflammatory cytokines and NF-κB signaling and reduced nutrition and energy input.During muscle IM,atrophy is associated with acommontranscriptionalprofileandactivationoftheubiquitinproteasome pathway.Imbalance of ROS production and antioxidant defense resulting in oxidative stress plays an important role in protein breakdown in skeletal muscle during periods of inactivity.50New evidence suggests that mitochondria may be an important source of ROS production in inactive muscle.51Adown-regulation of PGC-1α was observed in muscle atrophy of different models and thought to be a major molecular mechanismforenhancedFoxOphosphorylation,NF-κBactivationand protein loss.52Indeed,PGC-1α KO mice displayed higher basal expression of TNFα and IL-6 than wild type.33,53Conversely, transgenicmicewithPGC-1α over-expressionhavebeen shown to have a decreased inflammatory cytokine production and protein degradation caused by denervation.8,52Previous studies suggest that PGC-1α has a protective role against protein catabolism and muscle wasting in a variety of contexts.For instance,denervation-induced muscle atrophy and the effects of Duchenne’s muscular dystrophy are greatly ameliorated when the amount of PGC-1α is maintained at normal levels or increased.52,54Inactivity induced deficit of PGC-1α in skeletal muscle results in a chronic systemic inflammatory state,which hasseriouspathologicalconsequences.Interestingly,restoration ofmusclemovement(RM)resultedinaninitialincreaseinROS generation,pro-inflammatorycytokineexpressionandoxidative stress,which all prevent muscle recovery and prolongs functional impairment of performance.55Using a mouse hindlimb IM followed by RM model,we have recently found that overexpressionofPGC-1α via localelectroporationandtransfection increased mitochondrial biogenesis and ATP production,lowered inflammatory cytokine TNF and IL-6 expression,and reduced NF-κB activation in response to IM-RM.55These improvements were accompanied by less ROS generation and oxidative stress,and elevated SOD2 activity.PGC-1α overexpressed mice had significantly higher mtDNA content and ATP production compared to their empty vesicle injected controls after a 19-day IM-RM regimen.55

3.2.Benefit of PGC-1αin aging-associated mitochondrial dysfunction

Skeletal muscle aging in rodents is associated with mitochondrial dysfunction similar to that described in aging humans.56—60In rats,the age dependent increase in mtDNA mutations and oxidative phosphorylation(OXPHOS)defects in individual skeletal muscle fibers contribute to the splitting, atrophy,and eventual breakage of muscle fibers during aging.56Transcriptionalprofilesofskeletalmuscleshowadecreaseinthe expression of mitochondrial genes with age61and result in an age-related accumulation of old,damaged,or impaired mitochondria by the reduction of mitochondria turnover.62While aging is known to alter several important cellular functions that are affected by altered PGC-1α expression,it seems reasonable totargetonthiskeyregulatorforpreventingsarcopenia.Arecent study showed that aged WT mice decreased oxidative capacity, enzymeexpression,andmitochondrialATPproduction,whereas inflammatory cytokine levels(TNF-α,IL-6)and apoptotic activity(caspase-3 and Bax:Bcl ratio)were increased.8This aging profile was accompanied with a reduction of antioxidant capacity and increase of NF-κB nuclear binding.On the other hand,all these changes characteristic of muscle sarcopenia were corrected with over-expression of PGC-1α.Interestingly,the transgenic mice also preserved muscle mass, insulin resistance and showed a healthier neuromuscular junction.Several points may be noteworthy from the above study.First,a reduction of PGC-1α signaling activity appears to initiate the aging“cascade”in skeletal muscle,although the upper stream mechanism is still unknown.Second, increased ROS production and oxidant/antioxidant imbalance with aging is a major consequence of decreases PGC-1α level,as it decreases SIRT1 and SIRT3 signaling and hence decrease SOD2 and PGC-1α activity by enhanced acetylation escalating the problem.Third,increased pro-inflammatory cytokine production and hence enhanced NF-κB signaling is a main propagator for age-associated deterioration due to increased proteolysis of muscle and mitochondrial proteins. Elevation of PGC-1α level appears to be a key to restoring not only some of the most prevalent changes in muscle but also whole-body functional capacity at old age.

Endurance exercise has proven to be an effective way to increase mitochondrial oxidative capacity.Recent studies suggest that endurance training can increase muscle PGC-1α level in older animal and humans.63—65Furthermore,older adults that engage in regular resistance exercise training were shown to have a skeletal muscle transcriptional profile similar to that of young adults.3Recently,it was shown that lifelong endurance exercise not only improves OXPHOS enzyme activity and mitochondrial function in the skeletal muscle of the elderly but it also increases angiogenesis.56

Fig.2.Aging affects peroxisome proliferator-activated receptor-γ coactivator-1α(PGC-1α)of rat soleus muscle and 12 weeks endurance training restores PGC-1α protein contents.Western blot detection of PGC-1α and normalized with actin protein content.Each bar represents mean± SEM(n=3). **p＜0.01,young(Y)vs.old(O)or old training(OT);††p＜0.01;old(O)vs. old training(OT).Three groups of Fischer 344/BNF1 rats(young,rested(Y,4 months,n=3);old,rested(O,24 months);and old,subjected to a 12-week treadmill running at 17.5 m/min,10%grade for 45 min/day 5 days/week(OT, 24 months).55Modified with permission.

We investigated whether exercise training can ameliorate age-associated decline of PGC-1α gene expression and mitochondrial biogenesis.55PGC-1α mRNA level was decreased 35%inthesoleusmuscleofoldratsbutwasrestoredbytraining. PGC-1α protein content was 80%lower in old rats than young rats,whereas 12 weeks exercise training resulted in a 2.7-fold higher PGC-1α content in the old rats(Fig.2).As mentionedpreviously,Ca2+homeostasis and its function regulated by the Ca2+-sensitive pathway CREB play an important role in PGC-1α expression.We found that phospho-CREB(p-CREB) contentwas50%loweredinoldratscomparedtoyoungrats,but endurance training increased p-CREB content significantly. Furthermore,CREB binding activity assessed by electro mobilityshiftassaywasloweredinoldratswhereasitslevelwas significantly increased after endurance trainingin oldrats.Both mRNA and protein contents of Tfam and Cyt C in the soleus muscle were lower in the old control rats whereas endurance training significantly elevated Tfam protein expression.These datasuggestthatage-relateddecline ofPGC-1αfunctioncanbe restored by endurance exercise.

4.Conclusion

Over the last decade PGC-1α has been shown to be potent regulator of mitochondrial biogenesis and function.This versatile and master transcriptional regulator has received tremendous attention among scientists from many different fields.Undoubtedly,PGC-1αplaysacriticalroleinmaintaining muscle metabolic function and controls numerous genes that affect a broad range of muscle morphology and physiological function.Inactivity and aging are two important negative factors that down-regulate PGC-1α gene expression and subsequent down-regulation of mitochondrialbiogenesis. Therefore,increased expression of pathways associated with these coactivators could provide effective improvements of mitochondrial dysfunction during aging.

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12 February 2013;revised 25 February 2013;accepted 28 February 2013

*Corresponding author.

E-mail address:llji@umn.edu(L.L.Ji)

Peer review under responsibility of Shanghai University of Sport

2095-2546/$-see front matter Copyright©2013,Shanghai University of Sport.Production and hosting by Elsevier B.V.All rights reserved. http://dx.doi.org/10.1016/j.jshs.2013.03.005