PT  - JOURNAL ARTICLE
AU  - Sarah Voisin
AU  - Kirsten Seale
AU  - Macsue Jacques
AU  - Shanie Landen
AU  - Nicholas R Harvey
AU  - Larisa M Haupt
AU  - Lyn R Griffiths
AU  - Kevin J Ashton
AU  - Vernon G Coffey
AU  - Jamie-Lee M Thompson
AU  - Thomas M Doering
AU  - Malene E Lindholm
AU  - Colum Walsh
AU  - Gareth Davison
AU  - Rachelle Irwin
AU  - Catherine McBride
AU  - Ola Hansson
AU  - Olof Asplund
AU  - Aino E Heikkinen
AU  - Päivi Piirilä
AU  - Kirsi Pietiläinen
AU  - Miina Ollikainen
AU  - Sara Blocquiaux
AU  - Martine Thomis
AU  - Adam P Sharples
AU  - Nir Eynon
TI  - Exercise rejuvenates the skeletal muscle methylome and transcriptome in humans
AID  - 10.1101/2022.12.27.522062
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.12.27.522062
4099  - http://biorxiv.org/content/early/2022/12/29/2022.12.27.522062.short
4100  - http://biorxiv.org/content/early/2022/12/29/2022.12.27.522062.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.