Can Exercise Training Alter Human Skeletal Muscle DNA Methylation?

Abstract

Skeletal muscle is highly plastic and dynamically regulated by the body’s physical demands. This study aimed to determine the plasticity of skeletal muscle DNA methylation in response to 8 weeks of supervised exercise training in volunteers with a range of insulin sensitivities. We studied 13 sedentary participants and performed euglycemic hyperinsulinemic clamps with basal vastus lateralis muscle biopsies and peak aerobic activity (VO2 peak) tests before and after training. We extracted DNA from the muscle biopsies and performed global methylation using Illumina’s Methylation EPIC 850K BeadChip. Training significantly increased peak aerobic capacity and insulin-stimulated glucose disposal. Fasting serum insulin and insulin levels during the steady state of the clamp were significantly lower post-training. Insulin clearance rates during the clamp increased following the training. We identified 13 increased and 90 decreased differentially methylated cytosines (DMCs) in response to 8 weeks of training. Of the 13 increased DMCs, 2 were within the following genes, FSTL3, and RP11-624M8.1. Of the 90 decreased DMCs, 9 were within the genes CNGA1, FCGR2A, KIF21A, MEIS1, NT5DC1, OR4D1, PRPF4B, SLC26A7, and ZNF280C. Moreover, pathway analysis showed an enrichment in metabolic and actin-cytoskeleton pathways for the decreased DMCs, and for the increased DMCs, an enrichment in signal-dependent regulation of myogenesis, NOTCH2 activation and transmission, and SMAD2/3: SMAD4 transcriptional activity pathways. Our findings showed that 8 weeks of exercise training alters skeletal muscle DNA methylation of specific genes and pathways in people with varying degrees of insulin sensitivity.

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

“…Note: we only had OMIC data available at the transcriptomic level following muscle disuse. Note 2: summary statistics for the exercise‐ and disuse‐induced mRNA changes came from two recent meta‐analyses (Fanelli et al, 2017 ; Garcia et al, 2022 ).…”

Mini-review: Mitochondrial DNA methylation in type 2 diabetes and obesity

“…Various groups, including our own, have looked at the role of DNMTs in insulin resistance. In our study, we showed that the mRNA expression of DNMTs was unaffected by 8-weeks of exercise training in the skeletal muscle of volunteers with a range of insulin sensitivities ( 63 ). Moreover, a study in pancreatic islets from human donors with and without T2DM revealed no gene expression difference for DNMT1 and DNMT3B ( 64 ).…”

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

“…Note : we only had OMIC data available at the transcriptomic level following muscle disuse. Note 2 : summary statistics for the exercise- and disuse-induced mRNA changes came from two recent meta-analyses 24,25 .…”

“…Finally, we performed a series of OMIC integrations and pathway analyses to identify the molecular pathways affected by age, VO2max, exercise training, and/or muscle disuse across both OMIC layers.Note: we only had OMIC data available at the transcriptomic level following muscle disuse. Note 2: summary statistics for the exercise-and disuse-induced mRNA changes came from two recent meta-analyses24,25 .…”