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

3rd Jones R. G., A. Dimet-Wiley, A. Haghani, F. M. da Silva, C. R. Brightwell, S. Lim, S. Khadgi, Y. Wen, C. M. Dungan, R. T. Brooke, N. P. Greene, C. A. Peterson, J. J. McCarthy, S. Horvath, S. J. Watowich, C. S. Fry, K. A. Murach

Research output: Contribution to journalArticlepeer-review


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.
Original languageAmerican English
Pages (from-to)763-782
Number of pages20
JournalJournal of Physiology
Issue number4
StatePublished - 2023

Bibliographical note

Jones, Ronald G 3rd Dimet-Wiley, Andrea Haghani, Amin da Silva, Francielly Morena Brightwell, Camille R Lim, Seongkyun Khadgi, Sabin Wen, Yuan Dungan, Cory M Brooke, Robert T Greene, Nicholas P Peterson, Charlotte A McCarthy, John J Horvath, Steve Watowich, Stanley J Fry, Christopher S Murach, Kevin A eng R00 AG063994/AG/NIA NIH HHS/ R21 AG063056/AG/NIA NIH HHS/ R00 AG063994/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England 2022/12/20 J Physiol. 2023 Feb;601(4):763-782. doi: 10.1113/JP283836. Epub 2023 Jan 24.


  • Animals Humans Mice *Cellular Reprogramming/genetics Disease Models, Animal DNA Methylation *Exercise/physiology Gene Expression Profiling Membrane Proteins/metabolism Mitochondrial Proteins/metabolism *Muscle, Skeletal/metabolism *Aging/genetics/physiology Myc Yamanaka factors ageing


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