A Molecular Signature Defining Exercise Adaptation with Ageing and in vivo Partial Reprogramming in Skeletal Muscle

Authors

Ronald G. Jones III, University of Arkansas, Fayetteville
Andrea Dimet-Wiley, Ridgeline Therapeutics
Amin Haghani, University of California, Los Angeles
Francielly Morena da Silva, University of Arkansas, FayettevilleFollow
Camille R. Brightwell, University of Kentucky
Seongkyun Lim, University of Arkansas, FayettevilleFollow
Sabin Khadgi, University of Arkansas, Fayetteville
Yuan Wen, University of Kentucky
Corey M. Dungan, University of Kentucky
Robert T. Brooke, Epigenetic Clock Development Foundation
Nicholas P. Greene, University of Arkansas, FayettevilleFollow
Charlotte A. Peterson, University of Kentucky
John J. McCarthy, University of Kentucky
Steve Horvath, University of California, Los Angeles
Stanley J. Watowich, University of Texas Medical Branch
Christopher S. Fry, University of Kentucky
Kevin A. Murach, University of Arkansas, FayettevilleFollow

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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