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 = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, 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 toward a younger state after exercise training interventions, while the transcriptome shifted toward 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.

Skeletal muscle DNA methylation: Effects of exercise and HIV

“…The lack of agreement between our findings and those derived from the Voisin dataset (Voisin et al, 2020(Voisin et al, , 2021(Voisin et al, , 2023 and the EpiTrain dataset (Lindholm et al, 2014) (Field et al, 2018).…”

“…To determine whether our findings agree with other datasets, we contrasted pre-versus postexercise training (12 weeks, HIIT training) skeletal muscle DNA methylation using publicly available Illumina MethylationEPIC BeadChip data for 15 men (Voisin et al, 2020(Voisin et al, , 2021(Voisin et al, , 2023GSE171140). As was done for our dataset, we ran linear models for each probe testing for the effect of pre-post intervention while adjusting for individual subject ID, and bacon-corrected the test statistics.…”

“…In the Voisin exercise training data (Voisin et al, 2020(Voisin et al, , 2021(Voisin et al, , 2023; GSE171140), we identified 86 probes significantly associated with exercise intervention (Table S7). No individual probes overlapped TA B L E 2 Differentially methylated regions in PWH and uninfected controls pre-and postexercise intervention.…”

“…As noted byLindholm et al (2014), the changes in DNA methylation in response to environmental conditions (i.e., exercise) are slight when compared to disease-related conditions (i.e., HIV infection). Nonetheless, aerobic and resistance exercise training are associated with a shift toward a "younger" methylome(Voisin et al, 2023), thus supporting that exercise training triggers some effects that oppose aging.By way of genome-wide analyses, we found that DMPs were hypermethylated in PWH compared to controls before and after exercise training Antoun et al (2022). found that in SkM of older men, 53% of DMPs distinguished by the presence of sarcopenia were hypermethylated.…”

“…Furthermore, in a meta-analysis of six independent cohorts, exercise training resulted in a shift toward a younger SkM DNA methylome and transcriptome in older adults. (Voisin et al, 2023).…”