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Exercise and the Skeletal Muscle Epigenome

Sean L. McGee and Ken R. Walder

Metabolic Research Unit, School of Medicine and Centre for Molecular and Medical Research, Deakin University, Geelong, Victoria 3216, Australia Correspondence: [email protected]

An acute bout of exercise is sufficient to induce changes in skeletal muscle gene expression that are ultimately responsible for the adaptive responses to exercise. Although much re- search has described the intracellular signaling responses to exercise that are linked to transcriptional regulation, the epigenetic mechanisms involved are only just emerging. This review will provide an overview of epigenetic mechanisms and what is known in the context of exercise. Additionally, we will explore potential interactions between metabolism during exercise and epigenetic regulation, which serves as a framework for potential areas for future research. Finally, we will consider emerging opportunities to pharmacologically ma- nipulate epigenetic regulators and mechanisms to induce aspects of the skeletal muscle exercise adaptive response for therapeutic intervention in various disease states.

egular exercise evokes a number of adaptive cle can exert by increasing its contractile units, Rresponses in skeletal muscle that contribute cross-sectional area, and the connective tissue to alterations in muscle function and physical structures that assist in force transmission and fitness. Indeed, skeletal muscle is a highly plastic musclestabilization (Naderet al.2014). Further- tissue that can rapidly adapt to the energetic and more, strength exercise also increases the ability mechanical demands placed on it through of skeletal muscle to produce energy through repeated bouts of exercise. In response to anaerobic pathways (Egan and Zierath 2013). endurance exercise, skeletal muscle increases its Many of these phenotypic adaptations are capacity to produce energy through aerobic me- driven by transient alterations in the expression tabolism by enhancing delivery of substrates of genes involved in various aspects of skeletal

www.perspectivesinmedicine.org and oxygen secondary to increasing capillary muscle function (Egan and Zierath 2013). The density (Clausen and Trap-Jensen 1970). The expression of some genes increases during exer- capacity for skeletal muscle substrate uptake is cise while others increase in the postexercise also enhanced through a greater abundance of period. These transient changes in gene expres- sarcolemmal glucose and fatty acid transporters sion result in persistent alterations in the levels (Glatz et al. 2002). In parallel, the capacity to of the proteins that they encode, which ulti- oxidize these substrates to produce ATP is en- mately produce a change in skeletal muscle phe- hanced through increased mitochondrial size notype (Egan and Zierath 2013). A wealth of and number (Holloszy 1967). In contrast, research has described many of the intracellular strength exercise increases the power that a mus- signaling mechanisms that drive exercise-medi-

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S.L. McGee and K.R. Walder

ated changes in gene expression, which include DNMTs are encoded in many genomes, from activation of kinase cascades, transcription fac- bacteria to plants and mammals. The evolution- tors, and transcriptional coregulators (Egan and ary conservation of these enzymes suggests that Zierath 2013). It is well established that another DNA methylation provides a selective advantage layer of biological regulation, termed epigenet- to the organism. In mammals, DNA methyla- ics, also controls gene expression. Although tion typically occurs at CpG-rich regions of the there is conjecture on the exact definition of genome, known as CpG islands, which are en- the term (Henikoff and Greally 2016), epigenet- riched in the promoters and first exons of genes ics is generally considered to describe heritable (Klose and Bird 2006). When the CpG island changes in gene regulation that occur indepen- becomes methylated, the transcription of the dently of changes in DNA sequence, but instead cognate genes will be blocked (Lister et al. are caused by chemical modification of the var- 2009; Ziller et al. 2013). However, DNA methyl- ious components of chromatin, which regulates ation also occurs outside CpG islands in mam- the access of the transcriptional machinery to mals, and this also contributes the regulation of DNA (Kouzarides 2007). gene transcription, including in skeletal muscle This review will provide a brief overview of (Barres et al. 2009). DNA methylation is gener- the most commonly studied epigenetic mecha- ally associated with a reduction in gene expres- nisms before describing the nascent field of sion, thought to be mediated by affecting the exercise epigenetics. We will also speculate on binding of transcriptional activators to promot- potential interactions between exercise metab- er regions (Fig. 1) (Nakao 2001), although the olism and epigenetic regulation before provid- precise mechanism involved is still under inves- ing an assessment of the potential usage of tigation. drugs that act by modulating epigenetic modi- DNA methylation patterns and the resultant fiers to induce aspects of the exercise adaptive effects on gene transcription are a critical part of response in skeletal muscle. normal development programs, and these pro- cesses are controlled by the precise regulation of the DNMTs. Aberrant DNA methylation, often OVERVIEW OF EPIGENETIC MECHANISMS associated with altered levels or dysfunction of Epigenetic modification of the fundamental the DNMTs, has been observed in a range of components of chromatin, which includes the developmental diseases, such as neural tube de- histone protein core and DNA, influences how fects (Chang et al. 2011), as well as adult dis- surrounding genes are regulated. These modifi- eases, including a range of cancers (Robertson cations can be broadly categorized into those 2005; Hamidi et al. 2015), but also in complex www.perspectivesinmedicine.org affecting DNA, and those affecting histone pro- chronic diseases such as schizophrenia (Gavin teins (Kouzarides 2007). The following section and Sharma 2010) and autism spectrum disor- will provide an overview of the best-character- der (Jiang et al. 2004; Nagarajan et al. 2006). ized epigenetic modifications and how they im- DNMT1 is regarded as a maintenance en- pact on transcriptional regulation. zyme whose primary role is to preserve methyl- ation patterns during DNA replication and mi- tosis, which would otherwise alter methylation DNA Methylation patterns (Denis et al. 2011). DNMT3A and DNA methylation involves the enzymatic addi- DNMT3B are the principal methyltransferases tion of a methyl group to the fifth carbon of involved in establishing de novo DNA methyl- a cytosine residue, yielding 5-methylcytosine ation patterns in somatic and differentiated cell (Nakao 2001). This process is catalyzed by a types (Shen and Laird 2013; Bedi et al. 2014). family of enzymes known as DNA methyltrans- Emerging evidence suggests that DNA methyl- ferases (DNMTs) (Suzuki and Bird 2008), and ation patterns can be dynamically changed in is regarded as one of the fundamental epigenet- response to various physiological challenges, in- ic mechanisms to regulate gene transcription. cluding diet (Amaral et al. 2014; Silva-Martinez

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Exercise Epigenetics

Exercise metabolism ? ? αHG αKG succinate fumurate TET

Transcriptional Transcription initiation complex repression DNA demethylation

Me Me Me Me

DNA methylation Transcriptional activation

DNMTs + SAM

Methionine

Figure 1. DNA methylation and the regulation of transcription. DNA methylation (Me), controlled by DNA methyltransferases (DNMTs) using S-adenosylmethionine (SAM) as the methyl donor, prevents transcriptional activators such as the transcriptional initiation complex from gaining access to gene regulatory regions. De- methylation of DNA, initiated by the ten-eleven translocation (TET) enzymes, exposes DNA regulatory regions to transcriptional activators. The TET enzymes are activated by the a-ketoglutarate (aKG) metabolites and inhibited by metabolites with similar structures, including 2-hydroxyglutarate (2HG), succinate, and fumurate. It is unclear whether exercise alters the profile of these metabolites in cellular compartments that might affect TET activity.

et al. 2016), exposure to toxins (Tryndyak et al. each of histone 2A, 2B, 3, and 4 (Li et al. 2016), and exercise (Voisin et al. 2015). These 2007). The double-stranded DNA helix wraps changes are induced by altered activity of the around this stable core, which provides struc- DNMTs in concert with changes in active de- tural stability to DNA and has also been hypoth- methylation of DNA, which involves sequential esized to protect DNA from damaging agents modification of the methylated cytosine by hy- and stimuli (Ljungman and Hanawalt 1992). droxylation, deamination, and/or oxidation The physical relationship between DNA and (Bhutani et al. 2011). The base is then replaced surrounding histone proteins determines how www.perspectivesinmedicine.org by DNA repair mechanisms. These processes are surrounding genes are expressed, with a closed mediated by the ten-eleven translocation chromatin formation favoring transcriptional (TET), AID (activation-induced cytosine de- repression while an open chromatin structure aminase)/APOBEC (apolipoprotein B mRNA favors transcriptional activation (Fig. 2) (Li editing enzyme component 1) and the base ex- et al. 2007). Functionally, this is linked to the cision repair (BER) enzymes, respectively (Bhu- ability of the transcriptional machinery, includ- tani et al. 2011). Dynamic changes to DNA ing the basal transcription factors and RNA methylation patterns in response to a range of polymerase, to gain access to gene regulatory physiological stimuli are thought to be integral regions to initiate transcription (Kouzarides to both physiological adaptation and disease 2007). A closed or condensed chromatin struc- pathology. ture is the result of strong electrostatic interac- tions between the negatively charged DNA backbone and positively charged histone pro- Histone Modifications teins. Alterations in histone protein charge Histone proteins form the nucleosome core, through posttranslational modifications are of- which comprises an octamer of two copies ten sufficient to disrupt the interaction with

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S.L. McGee and K.R. Walder

Exercise-induced Excluded acetylated nucleosome substrate flux a a a a a HAT + Acetyl-CoA

Transcriptional Transcription initiation complex repression Histone acetylation

Histone deacetylation Transcriptional activation HDACs

AMPK Lactate βOHB

Exercise-induced energy demand

Figure 2. Histone acetylation, transcription, and potential interactions with exercise metabolism. In their deacetylated state, catalyzed by histone deacetylase (HDAC) enzymes, histones retain a close interaction with DNA, resulting a compacted chromatin structure that is associated with transcriptional repression. Increased histone acetyltransferase (HAT) activity and acetyl-CoA availability increase histone acetylation, resulting in a loose chromatin structure that can result in transient nucleosome exclusion and exposure of regulatory DNA regions to transcriptional activators such as the transcriptional initiation complex. Inhibition of HDAC activity has similar effects. Exercise metabolism could regulate this system through multiple mechanisms, including by influencing acetyl-CoA availability and through regulation of factors that inhibit HDAC activity. These include increased AMP-activated protein kinase (AMPK) activity and increased concentrations of the metabolites lactate and b-hydroxybutyrate (bOHB).

DNA, resulting in an open chromatin confirma- favors an open chromatin confirmation and tion (Kouzarides 2007). transcriptional activation. Indeed, K9 and K14 Although not exhaustive, characterized acetylation on H3 is associated with transcrip- posttranslational histone modifications on a tional activation (Fig. 2). Histone acetylation www.perspectivesinmedicine.org number of amino acid sites include phosphor- state is determined by the balance between ylation, acetylation, methylation, ubiquitina- histone acetyltransferase (HAT) and histone de- tion, sumoylation, and ADP-ribosylation (Ban- acetylase (HDAC) activities (Saha and Pahan nister and Kouzarides 2011). A wide range of 2006). There are numerous HATand HDAC iso- regulatory enzymes, the activity of which serves forms, each with different substrate specificities, as a control nexus that links cellular signaling signaling pathway responsiveness and gene reg- pathways with epigenetic control of gene ex- ulatory functions. These epigenetic modifiers pression, governs these posttranslational his- are often recruited to specific nucleosome sites tone modifications (Feinberg et al. 2016). One through interactions with DNA-bound tran- of the best-characterized histone modifications scription factors, with various HDAC and is lysine acetylation, particularly to histones 3 HAT isoforms having different affinities for dif- (H3) and 4 (H4). Lysine amino acid (K) side- ferent transcription factors (Kouzarides 2007). chains carry a positive charge when unmodi- This diversity allows control of histone acetyla- fied; however, acetylation neutralizes this posi- tion at specific loci, ensuring specificity in the tive charge, thereby disrupting the electrostatic gene expression response. Histone acetylation interaction with DNA (Ettig et al. 2011). This can work in concert with other histone modifi-

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Exercise Epigenetics

cations to provide precise control over the tran- muscle, which was associated with increased scriptional response (Bannister and Kouzarides transcription of these genes. Interestingly, the 2011). For example, acetylation of K14 on H3 same exercise modality at a lower intensity appears dependent on prior phosphorylation of (40% VO2 max) had no effect on DNA methyl- serine 10 (Lo et al. 2000). Furthermore, H3 acet- ation, suggesting that exercise intensity may be a ylation is often coupled with H3 methylation at critical factor in influencing DNA methylation. K36, which appears to control transcriptional A recent study in mice has replicated some of elongation (Wagner and Carpenter 2012). these findings, showing that exercise reduced Such interactions have coined the term “the his- PGC1a promoter methylation, which was asso- tone code” to describe broader regulatory mod- ciated with increased basal transcription of this ifications controlling specific gene expression gene (Lochmann et al. 2015). Another study has patterns. However, adding further complexity found that 120 min of cycling in healthy sub- to this notion is the fact that subtle variation jects (60% VO2 max) increased methylation at in modifications to the same histone site can the promoters of FABP3 and COX4L1, which confer opposing effects on gene transcription. was associated with decreased expression of For example, methylation of H3 at K9 has the these genes (Lane et al. 2015). opposite effect to acetylation, inducing tran- These studies show that alterations in DNA scriptional repression through inhibition of methylation can occur more rapidly than previ- the p300 HAT (Stewart et al. 2005). These stud- ously thought and clearly indicate that DNA ies highlight the complexity in the “histone methylation may be a crucial component of code” concept and how it might control con- the immediate physiological response to an text-specific gene expression responses. For a acute bout of exercise. The mechanism of alter- full review on details of other histone post- ations in DNA methylation patterns in skeletal translational modifications, their modifying en- muscle following a bout of exercise are un- zymes, the “histone code” concept, and how known, but are likely to involve precise regula- these modifications interact, readers are encour- tion of the DNMTs and the enzymes involved aged to consult the following excellent reviews: in demethylation of DNA. Although little is Bannister and Kouzarides (2011), Carone and known in this area, in vitro knockdown of Rando (2012), and Rando (2012). DNMT3B was shown to prevent saturated fatty The following sections will detail the emerg- acid-induced methylation of the promoter of ing data describing the epigenetics of exer- PGC1a in a muscle cell line (Barres et al. cise, which at present is principally described 2009), and TET1 was induced by hypoxia and through alterations in DNA methylation and associated with the regulation of glycolytic gene www.perspectivesinmedicine.org histone acetylation. expression in various cell lines (Tsai et al. 2014). More research is required to understand the role of DNA methylation and demethylation in the SKELETAL MUSCLE DNA METHYLATION adaptive response to acute exercise, but it ap- AND REGULATING ENZYMES IN RESPONSE pears clear that this system is likely to play a role. TO EXERCISE Of particular interest will be an understanding There are a limited number of studies that have of whether such changes are retained over time, examined the effects of exercise on DNA meth- and how rapidly they are lost before a further ylation in skeletal muscle. The available data bout of exercise is required to have the same suggest that acute exercise causes reduced meth- beneficial effect. ylation in skeletal muscle in a gene-specific There is some evidence in the literature de- manner. For example, Barres et al. (2012) scribing the effects of exercise training on DNA showed that high-intensity exercise (80% VO2 methylation. Nitert et al. (2012) studied first- max) caused an immediate reduction in the degree relatives of patients with T2D and found methylation levels in the promoter regions of altered DNA methylation in skeletal muscle in PGC1a, PDK4, and PPARd in human skeletal pathways, including MAPK, insulin, and calci-

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S.L. McGee and K.R. Walder

um signaling, and in several genes known to sponse to 60 min of cycling in humans (McGee have metabolic functions, including PRKAB1. et al. 2009). This study showed that H3 K36 After a 6-month exercise intervention in these acetylation was increased immediately after ex- healthy but sedentary subjects, which consisted ercise, while there was no change in H3 K9/14 primarily of endurance exercise, decreased DNA acetylation. The physiological relevance of al- methylation in skeletal muscle was observed for terations in global acetylation is not entirely retinol metabolism and calcium signaling path- clear given that acetylation at specific gene ways and a number of genes with known meta- loci are most closely associated with gene-spe- bolic function such as MEF2A and NDUFC2 cific transcription. However, other studies have (Nitert et al. 2012). The reduced DNA methyl- examined histone acetylation at specific gene ation was associated with increased gene expres- loci in response to exercise. For example, re- sion in many pathways, but particularly those peated bouts of swimming in rats increased associated with mitochondrial function. Fur- H3 K9/14 acetylation at the GLUT4 promoter thermore, Alibegovic et al. (2010) showed that in triceps muscle (Smith et al. 2008). Further 9 days of enforced bed rest tended to increase understanding of the role of chromatin remod- DNA methylation in the promoter region of eling in the regulation of exercise adaptations PPARGC1A, a key regulator of mitochondrial will require future studies to examine multiple biogenesis and function, and that this was asso- histone modifications with approaches such as ciated with down-regulation of many genes ChIP-seq. As these technologies are becoming involved in mitochondrial function and partic- more accessible, so too are the opportunities ularly oxidative phosphorylation. When the to decipher the molecular regulation of muscle same subjects underwent 4 weeks of exer- adaptation. cise retraining (supervised cycle ergometry at Histone modifications are controlled by a 70% of VO2 max), DNA methylation in the diverse number of enzymes that are also regu- PPARGC1A promoter tended to decrease (Ali- lated by various signaling mechanisms. These begovic et al. 2010). include HATs and HDACs, histone methyltrans- More research is required to understand ferases (HMTs) and demethylases (HDMs), and the role of DNA methylation and demethyla- histone kinases and histone ligases (Bannister tion in the adaptive response to exercise, but and Kouzarides 2011), to name a few. Many of it appears clear that this system is likely to these chromatin remodeling enzymes exist as play a prominent role. Of particular interest larger multipeptide transcriptional regulatory will be an understanding of whether such complexes and control of their activity is regu- changes are retained over time, and how rap- lated through complex cofactor exchanges, lo- www.perspectivesinmedicine.org idly they are lost before a further bout of calization, and posttranslational modifications exercise is required to have the same beneficial (Bannister and Kouzarides 2011). Just as his- effect. tone acetylation has served as a starting point for understanding how epigenetic modifica- tions might influence skeletal muscle adapta- SKELETAL MUSCLE HISTONE tion to exercise, a number of studies have also MODIFICATIONS AND REGULATING examined the regulation of chromatin remod- ENZYMES IN RESPONSE TO EXERCISE eling enzymes that control histone acetylation Just as histone acetylation is the most widely in response to exercise. For example, we have studied histone modification in epigenetics, it previously found that 60 min of cycling exercise is one of the few histone modifications that in humans reduces the nuclear abundance of have been examined in the context of responses the class IIa HDACs in skeletal muscle (McGee to exercise. We have previously examined skel- and Hargreaves 2004; McGee et al. 2009), which etal muscle global H3 K9/14 and K36 acetyla- has been implicated in the regulation of muscle- tion, which are associated with transcriptional specific genes via repression of the MEF2 tran- initiation and elongation, respectively, in re- scription factor (McKinsey et al. 2000). This is

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Exercise Epigenetics

consistent with phosphorylation-dependent ing mechanism involving multiple histone nuclear export of the class IIa HDACs being a modifications to regulate transcriptional re- major mechanism controlling class IIa HDAC sponses. repressive activity. Once exported from the nu- Another link between exercise and epige- cleus, MEF2 is derepressed, which activates netic regulation comes from the class III MEF2-dependent transcription (McKinsey HDACs, termed sirtuins. Unlike the class I et al. 2000). An interesting aspect of class IIa and II HDACs that are Zn2þ-dependent, the HDAC biology is that they do not possess in- Sirtuin family are dependent on NADþ for trinsic deacetylase activity themselves, but full activity, making this group of HDACs ex- instead require a corepressor complex that in- quisitely sensitive to alterations in cellular me- cludes N-Cor/SMRT and HDAC3 (Fischle tabolism and redox state (Chang and Guarente et al. 2002). A reduction in HDAC activity and 2014). There are seven identified sirtuins, each an increase in HAT activity has also been ob- with different subcellular localizations and sub- served in the hippocampus of rats following a strate specificities (Houtkooper et al. 2012). single session of treadmill exercise (Elsner et al. Once activated, the Sirtuins enhance a number 2011). of aspects of metabolism, including enhanced Perhaps the most obvious link between ex- oxidative flux and capacity, by deacetylat- ercise-regulated signal transduction and epige- ing both histone and nonhistone proteins netic regulation comes from the kinases that are (Houtkooper et al. 2012). The effects of exercise able to phosphorylate the class IIa HDACs, re- on various sirtuin isoforms are difficult to as- sulting in class IIa HDAC nuclear export. We sess in activity assays, as allosteric activation by found that the exercise-responsive AMP-acti- NADþ is rapidly lost. However, a number of vated protein kinase (AMPK) is a class IIa sirtuin targets are deacetylated during exercise HDAC kinase. Phosphorylation of HDAC5 by and there is evidence that sirtuin activity during AMPK was also shown to increase H3 K9/14 exercise is controlled by AMPK (Canto et al. acetylation and transcription of the GLUT4 2009). Knockout of various sirtuin isoforms gene (McGee et al. 2008). The importance of in mice has had limited effects on metabolic this signaling nexus to exercise adaptations adaptations to exercise (Menzies et al. 2013), was highlighted by our identification of redun- possibly indicating that further redundancy in dancy and compensation in class IIa regulation this adaptive response exists. Whether sirtuin in the absence of AMPK signaling (McGee et al. activation during exercise contributes to adap- 2014). Indeed, a number of other exercise-re- tive responses through direct histone deacetyla- sponsive kinases are also class IIa HDAC ki- tion or through deacetylation of nonhistone www.perspectivesinmedicine.org nases, such as the calcium/calmodulin depen- proteins such as PGC-1a or Foxo1 (Canto dent protein kinase II (CaMKII) (Rose and et al. 2009) also remains to be established. Al- Hargreaves 2003; Backs et al. 2006). Through though no studies to our knowledge have the use of the KN93 inhibitor, CaMKII has examined whether exercise modulates other been implicated in the acetylation of H3 at the chromatin remodeling enzymes that control GLUT4 promoter during swimming exercise in methylation, ubiquitination, etc., it would rats (Smith et al. 2008). Another interesting link seem likely that there is a coordinated response between these exercise-responsive kinases and to control exercise adaptions by regulating a regulation of histone modifications is that number of chromatin remodeling enzymes. In- many of these same kinases are also H3 kinases deed, just as the field of epigenetics is starting to (McGee and Hargreaves 2008; Bungard et al. unravel aspects of this “histone code” and how 2010). This is particularly intriguing given it regulates specific transcriptional responses, that phosphorylation of H3 at S10 is required the field of exercise physiology will also have before acetylation of K9 and 14 can occur in a to design appropriate studies to unravel this number of different cellular contexts (Cheung code and its potential contribution to skeletal et al. 2000). This suggests a coordinated signal- muscle adaptations to exercise.

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EXERCISE-MEDIATED EPIGENETIC et al. 2016; King-Himmelreich et al. 2016), ALTERATIONS IN OTHER TISSUES further supporting the idea that circulating fac- tors might be important. Interestingly, the ge- Transcriptional adaptive responses to exercise nomic loci and genes regulated in blood cells by occur in a number of tissues in addition to skel- these different exercise modalities are divergent. etal muscle. For example, global gene expression This suggests that specific systemic signaling alterations immediately following treadmill mechanisms are used to ensure an appropriate running in mice are more profound in the liver physiological response to the particular exercise than in skeletal muscle (Hoene et al. 2010). modality. Therefore, epigenetic mechanisms must also be engaged in nonmuscle tissues during exer- cise. Intriguingly, a number of studies have ex- SKELETAL MUSCLE METABOLISM AND amined histone modifications in various brain EPIGENETIC INTERACTIONS AND THEIR regions in response to exercise. Forced swim- POTENTIAL ROLE IN EXERCISE ADAPTIVE RESPONSES ming induces H3 K14 acetylation and serine 10 phosphorylation in spatially distinct regions Although epigenetic mechanisms regulate the of the dentate gyrus in a time dependent man- expression of metabolic gene networks in re- ner (Chandramohan et al. 2008). In addition, sponse to exercise, there is emerging evidence voluntary exercise in rats increases H3 acetyla- that metabolism can influence epigenetic pro- tion at the brain-derived neurotrophic factor cesses by controlling the availability of sub- (BDNF) promoter in the hippocampus (Go- strates used for epigenetic modifications and/ mez-Pinilla et al. 2011). These studies were or the activity of epigenetic modifiers. The ma- among the first to associate changes in histone jor substrate for DNA methylation is S-adeno- modifications with alterations in exercise-in- sylmethionine (SAM), which is produced in the duced gene expression. However, whether these methionine-recycling pathway (Sauter et al. modifications are a result of exercise per se or a 2013). Changes in the cellular levels of SAM psychological stress response to exercise remains result in altered levels of DNA methylation, unclear. There is a dearth of information on how with concomitant effects on gene transcription epigenetic mechanisms might regulate gene ex- (Ables et al. 2016). Ultimately, the methyl pression programs in noncontracting tissues groups required for DNA methylation are de- during exercise, although local alterations in en- rived from a range of dietary sources, and alter- ergy balance, blood flow, and hypoxia are all ing the availability of dietary methyl donors candidate stimuli. Evidence is emerging that cir- such as folate and selenium has been shown to www.perspectivesinmedicine.org culating factors could be involved in systemic affect DNA methylation and gene expression, regulation of epigenetic processes during exer- including improving diseases such as neural cise. For example, exercise-conditioned plasma tube defects associated with DNA hypomethy- reduced the nuclear abundance of DNMT3B in lation (Chango and Pogribny 2015). Although isolated peripheral blood mononuclear cells there are numerous studies that have investigat- (Horsburgh et al. 2015). Although the exact cir- ed the impact of increasing or decreasing die- culating factors involved remain to be deter- tary methionine, which has impacts including mined, a number of bona fide myokines that extending life span in a number of species fol- are released from contracting muscle during lowing dietary methionine restriction (Ables exercise have been identified (Whitham and et al. 2016), there is no information regarding Febbraio 2016). How such circulating factors whether any of the phenotypic differences seen might regulate epigenetic processes in response may be mediated by altered levels of DNA meth- to exercise are only just emerging. However, ylation. Similarly, the effects of exercise on the other studies have noted altered DNA methyla- methionine-recycling pathway are currently un- tion in response to both endurance and resis- known. Although ATP is required for the con- tance exercise in various blood cells (Denham version of SAM to methionine (Sauter et al.

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Exercise Epigenetics

2013), it is difficult to conceive that the ATP In addition to substrate availability directly demand during exercise could acutely compro- controlling epigenetic modifications, a number mise methionine availability and methylation of metabolites are known to regulate the activity reactions. In contrast, the activity of the de- of histone modifiers. Indeed, lactate has been methylating TET enzymes is increased by the observed to inhibit HDACs in the context of tricarboxylic acid (TCA) cycle intermediate me- cancer (Latham et al. 2012). It is unknown tabolite a-ketoglutarate, whereas accumulation whether lactate accumulation during intense of metabolites with similar structural features, exercise contributes to the increased local his- such as succinate, fumurate, and 2-hydroxyglu- tone acetylation that has been observed during tarate inhibit TETactivity (Figueroa et al. 2010). endurance-based exercise. Given that lactate Although the effect of exercise on the abun- concentrations of 10–50 mM are required to dance of these metabolites is unclear, particu- reduce total HDAC activity 50%–80% larly in cellular compartments relevant to TET (Latham et al. 2012), it appears unlikely that regulation, this could suggest that metabolite lactate is a key regulator of HDAC activity dur- fluxes are critical for coordinating skeletal mus- ing predominantly aerobic endurance exercise. cle DNA-methylation responses to exercise. However, during intense supramaximal exer- The availability of the two-carbon metabo- cise, muscle lactate concentrations can reach lite acetyl-CoA can also be rate limiting for acet- 60 mM (Jacobs et al. 1983). This suggests ylation reactions (Galdieri and Vancura 2012). that lactate production during intense exercise Acetyl-CoA is principally derived from pyruvate could acutely reduce HDAC activity and con- oxidation and through b-oxidation of fatty ac- tribute to epigenetic regulation in addition to ids, both of which occur in the mitochondria. canonical signaling pathways that control epi- However, acetyl-CoA is unable to diffuse across genetic modifiers, which are activated during phospholipid membranes and mitochondrial supramaximal exercise (Gibala et al. 2009). Ke- citrate is exported from the TCA cycle via the tone bodies such as bOHB can also inhibit citrate transporter to the cytosol and the nucle- HDAC activity (Shimazu et al. 2013). Ketone us. Nucleocytosolic citrate can then be convert- bodies are principally generated in the liver in ed to back to acetyl-CoA by ATP-citrate lyase response to elevated rates of b-oxidation and (ACL) and used in acetylation reactions of his- plasma bOHB increases during prolonged en- tone and nonhistone proteins (Choudhary et al. durance exercise (Bordin et al. 1992). Circulat- 2014). This pathway appears to be particularly ing bOHB is taken up by a number of tissues, important for linking metabolic flux with met- particularly the brain, where it can be converted abolic gene expression. Evidence for this comes back to acetyl-CoA for oxidation. Whether in- www.perspectivesinmedicine.org from experiments in which increases in the ex- creased systemic bOHB contributes to exercise- pression of genes such as GLUT4, HK2, PFK-1, mediated transcriptional regulation in non- and LDH in response to increasing glucose con- muscle tissues, through direct regulation of centrations are abrogated with ACL knockdown HDACs or through generation of acetyl-CoA (Wellen et al. 2009). At present, it is unknown for acetylation reactions, remains to be deter- how the energetic demands of exercise might mined. However, altered gene expression is a influence histone acetylation secondary to in- well-characterized response to exercise in non- creased TCA cycle flux. Given that exercise contracting tissues (Hoene and Weigert 2010; increases skeletal muscle acetyl-CoA levels via Catoire et al. 2012) and is thought to contribute increased substrate catabolism (Constantin- to the many whole body positive health effects Teodosiuet al. 1991), it is tempting to speculate of exercise. that an increased acetyl-CoA pool would con- Collectively, these studies indicate that al- tribute to increased skeletal muscle histone tered metabolism during exercise could have a acetylation in concert with altered activity/ profound impact on the epigenome (Figs. 1 and function of HDACs and HATs to enhance the 2). Future studies will be required to mechanis- transcription of specific genes. tically determine whether this is the case.

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EPIGENETIC THERAPIES TO INDUCE cerns about off-target effects, the increase in his- EXERCISE ADAPTATIONS tone acetylation in other tissues during exercise, such as in the brain (Chandramohan et al. 2008; As the epigenetics of exercise becomes better Gomez-Pinilla et al. 2011), indicates that some understood, opportunities are presented to ex- of these effects might not be considered off-tar- perimentally manipulate aspects of the exercise get. Furthermore, many positive benefits might adaptive response. Clearly, this has many poten- be derived from systemic HDAC inhibition. For tial therapeutic implications for managing example, HDAC inhibitors have been used to chronic diseases underpinned by inactivity, prevent pathological cardiac hypertrophy which include obesity, type 2 diabetes, and car- (Kong et al. 2006), psychiatric diseases (Meylan diovascular and liver diseases. et al. 2016), and cancer (Falkenberg and John- Following from our observations that the stone 2014) in preclinical and clinical studies. repressive actions of the class IIa HDACs are re- Indeed, the wide-ranging positive benefits of duced by exercise (McGee and Hargreaves 2004; HDAC inhibition are consistent with these en- McGee et al. 2009), as signified by disruption of zymes as important regulators of the exercise the class II HDAC corepressorcomplex and their adaptive response in a number of tissues. nuclear export, we have recently examined These studies highlight the value in under- whether manipulating class IIa HDAC activity standing the epigenetic processes regulating could induce exercise adaptations in skeletal skeletal muscle adaptations to exercise. As the muscle. Genetic manipulation of HDAC4 and field continues to progress and defines the roles 5, so that they could not form acorepressorcom- of other epigenetic modifiers such as HATs, plex, increased MEF2 transcriptional activity, HMTs, and HMDs and ubiquitin ligases in the the expression of a program of exercise-respon- exercise adaptive response, there will be more sive metabolic genes and fatty acid oxidation opportunities for therapeutic intervention in (Gaur et al. 2016). Wenext identified an existing chronic diseases driven by inactivity. Given the HDAC inhibitor, termed scriptaid, which was huge burden imparted by such diseases on also able to disrupt the class IIa HDAC corepres- modern societies, such research should be a pri- sor complex. Acute administration of scriptaid ority for the field. to mice increased the expression of exercise- responsive metabolic genes in skeletal muscle, CONCLUDING REMARKS whereas chronic administration increased exer- cise performance, whole-body energy ex- Epigenetic regulation of gene expression is a penditure, and lipid oxidation and reduced major control point for gene expression re- www.perspectivesinmedicine.org plasma glucose and lipids (Gaur et al. 2016). A sponses across all organisms in response to en- number of other studies using various HDAC vironmental stimuli. Methylation of DNA and inhibitors have reported similar enhancements posttranslational modification of histones are in various aspects of muscle and whole-body the major epigenetic control mechanisms that metabolism, including insulin sensitivity (Tan have been characterized to date under experi- et al. 2015) and enhanced oxidative capacity mental conditions. The interaction between (Galmozzi et al. 2013). The exact mechanism DNA methylation and the various histone mod- of action of some of these broad-spectrum ifications at specific gene loci is only just begin- HDAC inhibitors remains to be determined, ning to be understood; however, it is expected but could include inhibition of HDAC3, the that these complex spatially and temporally de- class I HDAC that provides deacetylase activity pendent interactions will become clearer as the to the class IIa HDAC corepressor complex technology to probe these interactions becomes (Fischle et al. 2002; Hudson et al. 2015). System- more accessible. ic administration of these inhibitors could have At present, very little is known about the compound-specific effects in tissues other than epigenetics that contribute to transcriptional skeletal muscle. Although this could raise con- responses and phenotypic adaptations to exer-

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Exercise Epigenetics

cise. Early studies have established roles for Alibegovic AC, Sonne MP, Hojbjerre L, Bork-Jensen J, Ja- acute reductions in DNA methylation and in- cobsen S, Nilsson E, Faerch K, Hiscock N, Mortensen B, Friedrichsen M, et al. 2010. Insulin resistance induced by creases in histone acetylation as contributors to physical inactivity is associated with multiple transcrip- this response. Additional studies also implicate tional changes in skeletal muscle in young men. Am J regulation of the class IIa HDACs as being im- Physiol Endocrinol Metab 299: E752–E763. portant in exercise adaptations. Another emerg- Amaral CL, Crisma AR, Masi LN, Martins AR, Hirabara SM, Curi R. 2014. DNA methylation changes induced by a ing area of research will be how alterations in high-fat diet and fish oil supplementation in the skeletal muscle metabolism impact on epigenetics and muscle of mice. J Nutrigenet Nutrigenomics 7: 314–326. exercise adaptations, given that a number of Backs J, Song K, Bezprozvannaya S, Chang S, Olson EN. 2006. CaM kinase II selectively signals to histone deace- metabolites are known to be rate limiting for tylase 4 during cardiomyocyte hypertrophy. J Clin Invest epigenetic modification reactions or directly 116: 1853–1864. regulate the activity of epigenetic modifiers. Fi- Bannister AJ, Kouzarides T. 2011. Regulation of chromatin nally, an exciting area for future research will be by histone modifications. Cell Res 21: 381–395. whether our understanding of the epigenetics of Barres R, Osler ME, YanJ, Rune A, Fritz T,Caidahl K, Krook A, Zierath JR. 2009. Non-CpG methylation of the PGC- exercise can be leveraged to provide therapeutic 1a promoter through DNMT3B controls mitochondrial targets and ultimately therapies for diseases un- density. Cell Metab 10: 189–198. derpinned by inactivity, such as obesity, type 2 Barres R, Yan J, Egan B, Treebak JT, Rasmussen M, Fritz T, diabetes, and cardiovascular diseases. Future Caidahl K, Krook A, O’Gorman DJ, Zierath JR. 2012. Acute exercise remodels promoter methylation in human studies should systematically examine the ef- skeletal muscle. Cell Metab 15: 405–411. fects of exercise modality, intensity, and dura- Bedi U, Mishra VK, Wasilewski D, Scheel C, Johnsen SA. tion when examining interactions between 2014. Epigenetic plasticity: A central regulator of epithe- epigenetic mechanisms to provide an exercise- lial-to-mesenchymal transition in cancer. Oncotarget 5: 2016–2029. epigenetic roadmap. Incorporating new omics Bhutani N, Burns DM, Blau HM. 2011. DNA demethylation technologies, such as unbiased proteomics en- dynamics. Cell 146: 866–872. compassing posttranslational modifications, to Bordin D, Bottecchia D, Bettini V, Aragno R, Sartorelli L. existing epigenetic pipelines will make this a 1992. Effect of middle-intensity exercise on carnitine and b-hydroxybutyrate plasmatic concentration in men and realistic prospect that could have wide-ranging women. J Sports Med Phys Fitness 32: 394–399. implications for understanding the health ben- Bungard D, Fuerth BJ, Zeng PY,Faubert B, Maas NL, Viollet efits of exercise that could be harnessed for B, Carling D, Thompson CB, Jones RG, Berger SL. 2010. medicine. Signaling kinase AMPK activates stress-promoted tran- scription via histone H2B phosphorylation. Science 329: 1201–1205. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, ACKNOWLEDGMENTS Milne JC, Elliott PJ, Puigserver P,Auwerx J. 2009. AMPK þ www.perspectivesinmedicine.org regulates energy expenditure by modulating NAD me- The authors thank Prof. Mark Hargreaves (The tabolism and SIRT1 activity. Nature 458: 1056–1060. University of Melbourne) and members of their Carone BR, Rando OJ. 2012. Rewriting the epigenome. Cell laboratories for ongoing discussions on the top- 149: 1422–1423. ic of this review. The authors are supported by Catoire M, Mensink M, Boekschoten MV, Hangelbroek R, Muller M, Schrauwen P, Kersten S. 2012. Pronounced grants from the National Health and Medical effects of acute endurance exercise on gene expression Research Council (NHMRC), the Diabetes Aus- in resting and exercising human skeletal muscle. PLoS tralia Research Program (DARP), the National ONE 7: e51066. Breast Cancer Foundation (NBCF), and the Chandramohan Y,Droste SK, Arthur JS, Reul JM. 2008. 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Exercise and the Skeletal Muscle Epigenome

Sean L. McGee and Ken R. Walder

Cold Spring Harb Perspect Med published online March 20, 2017

Subject Collection The Biology of Exercise

Exosomes as Mediators of the Systemic Effects of Exercise and Aging on Skeletal Muscle Adaptations to Endurance Exercise Giovanna Distefano and Bret H. Goodpaster Adeel Safdar and Mark A. Tarnopolsky Molecular Basis of Exercise-Induced Skeletal Muscle-Adipose Tissue Cross Talk Muscle Mitochondrial Biogenesis: Historical Kristin I. Stanford and Laurie J. Goodyear Advances, Current Knowledge, and Future Challenges Christopher G.R. Perry and John A. Hawley Exercise Metabolism: Fuels for the Fire Performance Fatigability: Mechanisms and Task Mark Hargreaves and Lawrence L. Spriet Specificity Sandra K. Hunter Health Benefits of Exercise Adaptations to Endurance and Strength Training Gregory N. Ruegsegger and Frank W. Booth David C. Hughes, Stian Ellefsen and Keith Baar Molecular Regulation of Exercise-Induced Muscle The Bioenergetics of Exercise Fiber Hypertrophy P. Darrell Neufer Marcas M. Bamman, Brandon M. Roberts and Gregory R. Adams Physiological Redundancy and the Integrative Effects of Exercise on Vascular Function, Responses to Exercise Structure, and Health in Humans Michael J. Joyner and Jerome A. Dempsey Daniel J. Green and Kurt J. Smith On the Run for Hippocampal Plasticity Control of Muscle Metabolism by the Mediator C'iana Cooper, Hyo Youl Moon and Henriette van Complex Praag Leonela Amoasii, Eric N. Olson and Rhonda Bassel-Duby Molecular Basis for Exercise-Induced Fatigue: Theoretical and Biological Evaluation of the Link The Importance of Strictly Controlled Cellular Ca between Low Exercise Capacity and Disease Risk 2+ Handling Lauren Gerard Koch and Steven L. Britton Arthur J. Cheng, Nicolas Place and Håkan Westerblad

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