Lifelong physical activity is associated with promoter hypomethylation of genes involved in metabolism, myogenesis, contractile properties and oxidative stress resistance in aged human skeletal muscle

Abstract

Lifelong regular physical activity is associated with reduced risk of type 2 diabetes (T2D), maintenance of muscle mass and increased metabolic capacity. However, little is known about epigenetic mechanisms that might contribute to these beneficial effects in aged individuals. We investigated the effect of lifelong physical activity on global DNA methylation patterns in skeletal muscle of healthy aged men, who had either performed regular exercise or remained sedentary their entire lives (average age 62 years). DNA methylation was significantly lower in 714 promoters of the physically active than inactive men while methylation of introns, exons and CpG islands was similar in the two groups. Promoters for genes encoding critical insulin-responsive enzymes in glycogen metabolism, glycolysis and TCA cycle were hypomethylated in active relative to inactive men. Hypomethylation was also found in promoters of myosin light chain, dystrophin, actin polymerization, PAK regulatory genes and oxidative stress response genes. A cluster of genes regulated by GSK3β-TCF7L2 also displayed promoter hypomethylation. Together, our results suggest that lifelong physical activity is associated with DNA methylation patterns that potentially allow for increased insulin sensitivity and a higher expression of genes in energy metabolism, myogenesis, contractile properties and oxidative stress resistance in skeletal muscle of aged individuals.

Recurrent training rejuvenates and enhances transcriptome and methylome responses in young and older human muscle

“…However, the investigators were unable to find methylation changes after 12 weeks of RT, probably due to the low sample size, the strict FDR adjustment and the limited number of CpGs tested. We hypothesized that training would reverse the ageing-induced hypermethylation, predominantly found in older muscle tissue in literature 8,9 , based on the hypomethylating effect of aerobic exercise [10][11][12][13] , lifelong physical activity 15 and RT in young to middle-aged adults 13,81 . However, both in young and older muscle tissue we observed that a first training period induced both hypomethylation and hypermethylation.…”

“…In older muscle, lifelong physical activity induced promoter hypomethylation of genes involved in energy metabolism, myogenesis, contractile properties and oxidative stress. 15 The impact of resistance training (RT) on the muscle methylome is less documented in literature, especially in elderly, but it has been suggested that RT has a distinct effect on the methylation status of, among other, growth-related genes 13,16 . Understanding the impact of RT on the muscle methylome is important, as resistance exercises can contribute to regaining muscle mass and strength and should be part of the exercise program designed to counteract muscle ageing.…”

DNA methylation across the genome in aged human skeletal muscle tissue and stem cells: The role of HOX genes and physical activity

“…Finally, with aging evoking a hypermethylated signature in tissue and aged muscle derived stem cells, it was also interesting to speculate that physical exercise, that has been shown to hypomethylate the genome 20,21,22 , could therefore be 'anti-ageing' at the epigenetic level. Indeed, this hypothesis was supported indirectly in the present study and by previous literature, where the aged tissue analysis in the present study identified the top significantly enriched KEGG pathway as, 'pathways in cancer'.…”

“…This suggests that inflamed proliferative aging in muscle stem cells leads to a retained accumulation of DNA methylation. Finally, lifelong physical activity 20 , endurance and resistance exercise have been associated with predominantly hypomethylation of the genome in young skeletal muscle 21,22 . This contrasts with the hypermethylation observed with aging, suggesting that exercise may reverse some age-related changes in DNA methylation.…”

Transcriptional memory in skeletal muscle. Don't forget (to) exercise

“…Further, by use of methylated DNA immunoprecipitation method coupled with a promoter tiling array, altered methylation levels at promoter sites of several key genes attributed to skeletal muscle homeostasis have been reported to manifest after 6 week of endurance exercise (Nitert et al, 2012). A general trend towards reduced promoter methylation levels of genes involved in energy metabolism, myogenesis, contractile activity, and oxidative stress resistance became apparent when global methylation patterns in skeletal muscle of healthy aged men with a lifelong history of physical activity were compared to “couch potatoes” of the same age group (Sailani et al, 2019). Reciprocally, also “bad memories” inflicted by physical inactivity, unhealthy diet, and prenatal stress have been reported to become reflected by differential DNA methylation patterns in skeletal muscle tissue (Alibegovic et al, 2009; Jacobsen et al, 2012; Jacobsen et al, 2014; Nilsson & Ling, 2017; Nitert et al, 2012; Sharples, Polydorou et al, 2016; Sheppard et al, 2017).…”