Document Type
Article
Publication Date
2-2023
Keywords
Ageing; DNA methylation; MYC; Yamanaka factors
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.
Citation
Jones, R. G., Dimet-Wiley, A., Haghani, A., Morena da Silva, F., Brightwell, C. R., Lim, S., Khadgi, S., Wen, Y., Dungan, C. M., Brooke, R. T., Greene, N. P., Peterson, C. A., McCarthy, J. J., Horvath, S., Watowich, S. J., Fry, C. S., & Murach, K. A. (2023). A Molecular Signature Defining Exercise Adaptation with Ageing and in vivo Partial Reprogramming in Skeletal Muscle. The Journal of Physiology, 601 (4), 763-782. https://doi.org/10.1113/JP283836
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