Author Identifier (ORCID)

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Abstract

We investigated the molecular mechanisms of exercise adaptations in human muscle by integrating genome, methylome, transcriptome, and proteome data from over 1,000 participants (2,340 muscle samples). We identified distinctive signatures associated with maximal oxygen consumption (VO2max), and multi-omics integration uncovered five key genes as robust exercise markers across layers, with transcription factors functioning as activators, synergizing with DNA methylation to regulate gene expression. Minimal sex differences were observed, while modality-specific analysis highlighted distinct pathways for aerobic and resistance exercise, contrasting with muscle disuse patterns. Finally, we created a webtool, OMAx, featuring our individual omics and integration analysis. These findings provide a comprehensive multi-omics framework for understanding exercise-induced molecular adaptations, offering insights into muscle health, cardiorespiratory fitness, and their roles in aging and disease prevention.

Keywords

CP: Metabolism, DNA methylation, epigenetics, exercise, gene expression, Multi Omics, proteomic, skeletal muscle, transcriptomic, VO2 max

Document Type

Journal Article

Date of Publication

6-24-2025

Article Number

115750

Volume

44

Issue

6

Publication Title

Cell Reports

Publisher

Elsevier

School

Nutrition and Health Innovation Research Institute

Funding Information

This work was supported by Nir Eynon’s National Health and Medical Research Council Investigator Grant (APP1194159) and the Hevolution/AFAR New Investigator Awards in Aging Biology and Geroscience Research. The Gene SMART study is supported by Australian Research Council (ARC) Discovery Project Grants (DP190103081, DP200101830, and DP240102155). This study used BPA-enabled (Bioplatforms Australia)/NCRIS-enabled (National Collaborative Research Infrastructure Strategy) infrastructure located at the Monash Proteomics and Metabolomics Facility. Study PXD023084 was supported by an unconditional donation from the Novo Nordisk Foundation (NNF) to the NNF Center for Basic Metabolic Research (http://www.cbmr.ku.dk) (grant no. NNF18CC0034900), the NNF Center for Protein Research (https://www.cpr.ku.dk/) (grant no. NNF14CC001), and Team Denmark. K.H.P. is supported by the Research Council of Finland (grant nos. 335443, 314383, 272376, and 266286), the Finnish Medical Foundation, the Gen Foundation, the Novo Nordisk Foundation (grant nos. NNF20OC0060547, NNF17OC0027232, and NNF10OC1013354), the Finnish Diabetes Research Foundation, the Paulo Foundation, the University of Helsinki and Helsinki University Hospital, and Government Research research Funds. M.O. is supported by the Research Council of Finland (grant nos. 328685, 307339, 297908, and 251316), the Sigrid Jusélius Foundation, Liv O Hälsa r.f., and the Minerva Foundation.

Funding received from the Australian Research Council (ARC)

DP190103081, DP200101830, DP240102155

Funding received from the National Health and Medical Research Council (NHMRC)

APP1194159

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Comments

Jacques, M., Landen, S., Sharples, A. P., Garnham, A., Schittenhelm, R., Steele, J., Heikkinen, A., Sillanpää, E., Ollikainen, M., Broatch, J., Zarekookandeh, N., Hanson, O., Ekström, O., Asplund, O., Lamon, S., Alexander, S. E., Smith, C., Bauer, C., Woessner, M. N., . . . Eynon, N. (2025). Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration. Cell Reports, 44(6), 115750. https://doi.org/10.1016/j.celrep.2025.115750

Recommended Citation

Jacques, M., Landen, S., Sharples, A. P., Garnham, A., Schittenhelm, R., Steele, J., Heikkinen, A., Sillanpää, E., Ollikainen, M., Broatch, J., Zarekookandeh, N., Hanson, O., Ekström, O., Asplund, O., Lamon, S., Alexander, S. E., Smith, C., Bauer, C., Woessner, M. N., . . . Eynon, N. (2025). Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration. Cell Reports, 44(6), Article 115750. https://doi.org/10.1016/j.celrep.2025.115750

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Link to publisher version (DOI)

10.1016/j.celrep.2025.115750