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

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. Key points Advances in the last decade related to cellular epigenetic reprogramming (e.g. DNA methylome remodelling) 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, and so we compared the MYC‐controlled transcriptome in muscle to Yamanaka factor‐mediated and exercise adaptation mRNA 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.

The PoWeR of exercise: Exploring the anti‐ageing effects of exercise through epigenetic modifications to skeletal muscle

“…DNA methylation patterns are used in epigenetic clocks to accurately predict DNA methylation age (mDNAge). Using the Horvath Clock and Developmental Muscle Clock, the present study by Jones III et al (2022) found mDNAge to be significantly lower in PoWeR (progressive weighted wheel running)-trained vs. sedentary aged female mice. These findings suggest that exercise can reverse at least some of the muscle-related effects of ageing at the DNA methylation level, further reinforcing exercise as an important factor of healthy ageing.…”

“…Jones III et al. (2022) verified these results in human muscle, where they showed that several mitochondrial transcripts that were downregulated by OKSM and endurance training in mice were also downregulated in the muscle of endurance trained females compared to age‐matched sedentary controls. The functional relevance of this downregulation of mitochondrial transcripts in the context of healthy ageing remains unknown.…”

“…(2019) demonstrated that reprogramming human dermal fibroblasts to pluripotent stem cells by transfection of OKSM reverted mDNAge to zero after 20 days of treatment. The study by Jones III et al (2022) added to this finding, showing a significant overlap (∼25%) between differentially expressed genes in mouse skeletal muscle upon OKSM overexpression and those induced by PoWeR training (Jones III et al., 2022). Interestingly, OKSM and exercise downregulated mitochondrial‐related genes, including those involved in oxidative phosphorylation, which may be a counterintuitive response considering the important role of mitochondria in skeletal muscle health.…”

“…In this issue of The Journal of Physiology , Jones III et al. (2022) report that exercise may not only promote positive adaptations in muscle, but also provide an ‘anti‐ageing’ effect on the muscle DNA methylation signature. Furthermore, they show that, in mice, a hybrid endurance and resistance training protocol and overexpression of OKSM produce a similar transcriptomic profile that may promote a younger muscle phenotype through epigenetic pathways.…”

“…The work by Jones III et al. (2022) highlights a possible role of OKSM in the anti‐ageing effects of exercise and provides interesting directions for future research.…”