Exercise and the Skeletal Muscle Epigenome

Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press 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 research 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- Editors: Juleen R. Zierath, Michael J. Joyner, and John A. Hawley Additional Perspectives on The Biology of Exercise available at www.perspectivesinmedicine.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a029876 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press 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 methylation 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 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a029876 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press 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

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