Impact of an Exercise Intervention on DNA Methylation in Skeletal Muscle From First-Degree Relatives of Patients With Type 2 Diabetes

Abstract

To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome-wide in skeletal muscle from individuals with (FH+) or without (FH−) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P ≤ 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of FH+ compared with FH− men. We further validated our findings from FH+ men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both FH+ men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the FH+ and FH− individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 × 10−6) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome.

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

“…Indeed, we observed widespread DNA methylation changes in skeletal muscle from healthy young men after 5 days of HFO [7]; in contrast, there were no significant epigenetic changes in matched LBW men after HFO [13]. We also observed extensive DNA methylation changes in subcutaneous adipose tissue (SAT) and skeletal muscle after regular exercise [10,11]. However, genome-wide DNA methylation plasticity in response to overfeeding in human SAT has not been explored.…”

“…Additionally, young, healthy LBW men develop more severe peripheral insulin resistance when exposed to 5 days of high-fat overfeeding (HFO) compared with men with a normal birthweight (NBW) [1]. Lifestyle-related factors may alter epigenetic and transcriptional patterns [5][6][7][8][9][10][11][12], and thereby affect the risk of metabolic diseases. Indeed, we observed widespread DNA methylation changes in skeletal muscle from healthy young men after 5 days of HFO [7]; in contrast, there were no significant epigenetic changes in matched LBW men after HFO [13].…”

Are cultured human myotubes far from home?

“…Thus, acute exercise was found to induce hypomethylation of promoters of several metabolic genes (Barres, et al, 2012), and a 6-month exercise intervention induced decreased methylation of genes involved in e.g. retinol metabolism, calciumsignaling pathway, starch and sucrose metabolism, and the insulin-signaling pathway (Nitert, et al, 2012). Short-term (5 days) high-fat overfeeding introduced widespread DNAmethylation changes, changes that were only partly reversed after 6-8 weeks (Jacobsen, et al, 2012).…”

“…(Bharathy, et al, 2012, Sousa-Victor, et al, 2011). Exercise (Barres, et al, 2012, Nitert, et al, 2012, diet (Jacobsen, et al, 2012) and family history of type 2 diabetes (Nitert, et al, 2012) are all described to influence DNA methylation in human skeletal muscle, traits that may follow the isolated satellite cells into cultured myotubes. Thus, acute exercise was found to induce hypomethylation of promoters of several metabolic genes (Barres, et al, 2012), and a 6-month exercise intervention induced decreased methylation of genes involved in e.g.…”

Of rodents and men: Species-specific glucose regulation and type 2 diabetes research

“…There are links among diet/nutrients, obesity, energy metabolism, physical activity, and gene expression and regulation such as DNA methylation and histone modifications. For example, genetic background (family history of T2DM) and exercise can alter expression and DNA methylation of several genes involved in skeletal muscle glucose regulation (Nitert et al, 2012). Adding another layer of complication is the recent identification of the effects of regulatory small RNAs and micro RNAs on gene regulation and T2DM complications (Kantharidis et al, 2011).…”