Exercise and the Skeletal Muscle Epigenome

Abstract

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 manipulate epigenetic regulators and mechanisms to induce aspects of the skeletal muscle exercise adaptive response for therapeutic intervention in various disease states.

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. Demethylation of DNA, initiated by the ten-eleven translocation (TET) enzymes, exposes DNA regulatory regions to transcriptional activators. The TET enzymes are activated by the α-ketoglutarate (αKG) 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.

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 β-hydroxybutyrate (βOHB).