{"doi":"10.1113/jp283836","title":"A molecular signature defining exercise adaptation with ageing and <i>in vivo</i> 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.","journal":"The Journal of Physiology","year":2022,"id":240349,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":46,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":744540,"name":"Andrea Dimet‐Wiley","orcid":"0000-0003-2214-3670","position":1,"is_corresponding":false},{"id":458321,"name":"Amin Haghani","orcid":"0000-0002-6052-8793","position":2,"is_corresponding":false},{"id":678353,"name":"Francielly Morena da Silva","orcid":"0000-0001-5019-2125","position":3,"is_corresponding":false},{"id":628041,"name":"Camille R. Brightwell","orcid":"0009-0002-8257-0789","position":4,"is_corresponding":false},{"id":321271,"name":"Seongkyun Lim","orcid":"0000-0001-7075-5909","position":5,"is_corresponding":false},{"id":867682,"name":"Sabin Khadgi","orcid":"0009-0002-8394-624X","position":6,"is_corresponding":false},{"id":559626,"name":"Yuan Wen","orcid":"0000-0002-3210-1629","position":7,"is_corresponding":false},{"id":282077,"name":"Cory M. Dungan","orcid":"0000-0003-4686-9417","position":8,"is_corresponding":false},{"id":803802,"name":"Robert T. Brooke","orcid":"0000-0001-8492-5198","position":9,"is_corresponding":false},{"id":321274,"name":"Nicholas P. Greene","orcid":"0000-0001-9621-2005","position":10,"is_corresponding":false},{"id":235329,"name":"Charlotte A. Peterson","orcid":"0000-0001-9340-0705","position":11,"is_corresponding":false},{"id":282076,"name":"John J. McCarthy","orcid":"0000-0003-4522-5601","position":12,"is_corresponding":false},{"id":38267,"name":"Steve Horvath","orcid":"0000-0002-4110-3589","position":13,"is_corresponding":false},{"id":744544,"name":"Stanley J. Watowich","orcid":"0000-0002-1660-1818","position":14,"is_corresponding":false},{"id":286546,"name":"Christopher S. Fry","orcid":"0000-0002-4207-6594","position":15,"is_corresponding":false},{"id":282073,"name":"Kevin A. Murach","orcid":"0000-0003-2783-7137","position":16,"is_corresponding":false},{"id":868300,"name":"Ronald G. Jones","orcid":null,"position":0,"is_corresponding":true}],"reference_count":160,"raw_metadata":null,"created_at":"2026-07-19T00:22:46.554789Z","pmid":"36533424","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}