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

Abstract

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3,176). We show that: 1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, 2) exercise training leads to significant "rejuvenation" of molecular profiles, and 3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted towards a younger state after exercise training interventions, while the transcriptome shifted towards an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

A novel deep proteomic approach in human skeletal muscle unveils distinct molecular signatures affected by aging and resistance training

“…For instance, weeks to months of resistance training in older participants has been shown to increase tissuelevel and myofiber hypertrophy and muscle satellite cell content (9). Resistance training also catalyzes skeletal muscle mitochondrial biogenesis and remodeling in older participants (10)(11)(12)(13)(14), and weeks to months of resistance training alters nuclear and mitochondrial DNA methylation patterns in older participants which may lead to "rejuvenating" effects on global mRNA expression patterns (11,15,16).…”