A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle.

Advances in the last decade related to cellular epigenetic reprogramming (e.g. DNA methylome remodeling) toward a pluripotent state via the Yamanaka transcription factors Oct3/4, Klf4, Sox2, and Myc (OKSM) provide a window into potential mechanisms for combatting the deleterious effects of cellular ageing Using global gene expression analysis, we compared the effects of in vivo OKSM-mediated partial reprogramming in skeletal muscle fibres of mice to the effects of late-life murine exercise training in muscle Myc is the Yamanaka factor most induced by exercise in skeletal muscle, so we compared the MYC-controlled transcriptome in muscle to Yamanaka factor-mediated and exercise adaptation gene landscapes in mice and humans A single pulse of MYC is sufficient to remodel the muscle methylome We identify partial reprogramming-associated genes that are innately altered by exercise training and conserved in humans, and propose that MYC contributes to some of these responses ABSTRACT: Exercise promotes functional improvements in aged tissues, but the extent to which it simulates partial molecular reprogramming is unknown. Using transcriptome profiling from 1) a skeletal muscle-specific in vivo Oct3/4, Klf4, Sox2, and Myc (OKSM) reprogramming-factor expression murine model, 2) an in vivo inducible muscle-specific Myc induction murine model, 3) a translatable high-volume hypertrophic exercise training approach in aged mice, and 4) human exercise muscle biopsies, we collectively defined exercise-induced genes that are common to partial reprogramming. Late-life exercise training lowered murine DNA methylation age according to several contemporary muscle-specific clocks. A comparison of the murine soleus transcriptome after late-life exercise training to the soleus transcriptome after OKSM induction revealed an overlapping signature that included higher JunB and Sun1. Also, within this signature, downregulation of specific mitochondrial and muscle-enriched genes was conserved in skeletal muscle of long-term exercise-trained humans; among these was muscle-specific Abra/Stars. Myc is the OKSM factor most induced by exercise in muscle and was elevated following exercise training in aged mice. A pulse of MYC rewired the global soleus muscle methylome, and the transcriptome after a MYC pulse partially recapitulated OKSM induction. A common signature also emerged in the murine MYC-controlled and exercise adaptation transcriptomes, including lower muscle-specific Melusin and reactive oxygen species-associated Romo1. With Myc, OKSM, and exercise training in mice as well habitual exercise in humans, the complex I accessory subunit Ndufb11 was lower; low Ndufb11 is linked to longevity in rodents. Collectively, exercise shares similarities with genetic in vivo partial reprogramming. Abstract figure legend Diverse forms of exercise training improve muscle function and whole-body health, even if initiated late in life. Information on conserved exercise-controlled molecular cues that underpin a younger muscle phenotype in aged muscle has potential utility in the development of anti-ageing therapies. Induction of the Yamanaka factors Oct3/4, Klf4, Sox2, and Myc are known to ameliorate ageing hallmarks. Comparison of transcriptomic data from aged exercise-trained mice and humans to muscle fibre-specific genetically driven models of epigenetic reprogramming (e.g. Yamanaka factor or Myc expression) unearthed conserved biomarkers associated with molecular age mitigation. Considering reduced biological age according to DNA methylome analysis, high-volume exercise training can be classified as an epigenetic reprogramming stimulus. Chronic exercise should be considered alongside and/or as a method to inform healthspan-extending longevity approaches such as pharmacologic and dietary interventions. This article is protected by copyright. All rights reserved.