Molecular Landscape of Sex- and Modality-Specific Exercise Adaptation in Human Skeletal Muscle through Large-Scale Multi-Omics Integration
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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 (VO 2max ), 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.
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While acute exercise initiates immediate metabolic adjustments, chronic activity reinforces and expands these effects, driving lasting improvements in muscle oxidative capacity and energy homeostasis.
“Therefore, while acute exercise initiates immediate metabolic adjustments, chronic activity reinforces and expands these effects, driving lasting improvements in muscle oxidative capacity and energy homeostasis [34].”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [34]
The Discussion (page not specified in our copy) says exercise-related DNA methylation changes recur after each bout and may stabilize with training, potentially contributing to long-term muscle adaptation. It also links exercise-associated molecular pathways to mitochondrial metabolism and energy homeostasis, but does not establish that chronic activity drives lasting improvements in oxidative capacity or energy homeostasis. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMulti-omics analyses and human cohort studies show that trained individuals, regardless of age, presented increased levels of mitochondrial markers and more efficient myokine responses following exercise.
“Multi-omics analyses and human cohort studies further show that trained individuals, regardless of age, presented increased levels of mitochondrial markers and more efficient myokine responses following exercise.”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [34]
The proteome results (page unavailable) link higher VO₂max with higher expression of some proteins and enrichment of mitochondrial-function pathways; the multi-omics results also report greater abundance of mitochondrial-pathway mRNA and proteins. These findings partly support the mitochondrial-marker claim, but the paper does not establish that this holds regardless of age or report more efficient myokine responses in trained individuals after exercise. (LLM, conf=0.84)
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Sanyal, J., Anirudhan, A., Banerjee, T. K., Guha, G., Veerabathiran, R., Murugesan, R., Ahmed, S. S. J. S., & Rao, V. R. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00734-z · Cited by 11 · see citing works
Downregulation of ALDH6A1 is a New Marker of Muscle Insulin Resistance in Type 2 Diabetes Mellitus
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Antwi, S. O., Heckman, M. G., White, L. J., Yan, I. K., Sarangi, V., Lauer, K. P., Reddy, J. S., Ahmed, F. Y., Veliginti, S., Febres, E. D. M., et al. (2023) · Human Molecular Genetics · doi:10.1093/hmg/ddad099 · Cited by 10 · see citing works
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Jacques, M., Landen, S., Alvarez‐Romero, J., Yan, X., Hiam, D., Jones, P. R., Gurd, B. J., Eynon, N., & Voisin, S. A. C. (2022) · European Journal of Sport Science · doi:10.1080/17461391.2022.2048894 · Cited by 9 · see citing works
He, W., Peng, N., Chen, Q., Xiang, T., Wang, P., & Pang, J. (2020) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2020.104107 · Cited by 8 · see citing works
Jameson, T. S. O., Islam, H., Wall, B. T., Little, J. P., & Stephens, F. B. (2022) · Experimental Physiology · doi:10.1113/ep090546 · Cited by 8 · see citing works
Jones, S. H., Schultz, M. G., Tillin, T., Park, C. M., Williams, S., Chaturvedi, N., & Hughes, A. D. (2021) · GeroScience · doi:10.1007/s11357-021-00328-y · Cited by 7 · see citing works
Takeshita, L. Y. C., Davidsen, P. K., Herbert, J. M. J., Antczak, P., Hesselink, M. K. C., Schrauwen, P., Weisnagel, S. J., Robbins, J., Gerszten, R. E., Ghosh, S., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-98792-1 · Cited by 6 · see citing works
Broatch, J. R., Zarekookandeh, N., Glarin, R. K., Strik, M., Johnston, L. A., Moffat, B. A., Bird, L., Gunningham, K., Churilov, L. P., Johns, H. T., et al. (2023) · BMJ Open · doi:10.1136/bmjopen-2022-069413 · Cited by 6 · see citing works
Role of DNA methylation‐based mitotic ageing indices in oral cancer development and recurrence
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Potential regulatory role of epigenetic modifications in aging-related heart failure
Lv, L., Chen, Q., Lü, J., Zhao, Q., Wang, H., Li, J., Yuan, K., & Dong, Z. (2024) · International Journal of Cardiology · doi:10.1016/j.ijcard.2024.131858 · Cited by 6 · see citing works
Wolff, C. A., Konopka, A. R., Suer, M. K., Trappe, T. A., Kaminsky, L. A., & Harber, M. P. (2019) · The Journal of Sports Medicine and Physical Fitness · doi:10.23736/s0022-4707.18.08590-0 · Cited by 5 · see citing works
Nilsen, T. S., Sæter, M., Sarvari, S. I., Reinertsen, K. V., Johansen, S. H., Edvardsen, E. R., Hallén, J., Edvardsen, E., Grydeland, M., Kiserud, C. E., et al. (2023) · JMIR Research Protocols · doi:10.2196/45244 · Cited by 5 · see citing works
Ren, Z., Fu, L., Feng, Z., Song, Z., Liu, Y., Zhang, T., & Wu, N. (2023) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2023.04.002 · Cited by 5 · see citing works
IGUDESMAN, D. A., Mucinski, J. M., Harrison, S. L., Cawthon, P. M., Linge, J., Goodpaster, B. H., Cummings, S. R., Hepple, R. T., Jurczak, M. J., Kritchevsky, S. B., et al. (2024) · The Journals of Gerontology Series A · doi:10.1093/gerona/glae047 · Cited by 5 · see citing works
Increasing circulating levels of Tenascin C in response to the Wingate anaerobic test
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“Therefore, while acute exercise initiates immediate metabolic adjustments, chronic activity reinforces and expands these effects, driving lasting improvements in muscle oxidative capacity and energy homeostasis [34].”
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- Authors
- 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., Levinger, I., Teschendorff, A. E., Gillberg, L., Blom, I., Helge, J. W., Harvey, N. R., Haupt, L. M., Griffiths, L. R., Deshmukh, A. S., Pietiläinen, K. H., Piirilä, P., Seaborne, R. A. E., Klevjer, M., Bye, A., Wisløff, U., Jones-Freeman, B., & Eynon, N.
- Affiliations
- Australian Regenerative Medicine Institute (AU)
- Hudson Institute of Medical Research (AU)
- Norwegian School of Sport Sciences (NO)
- Victoria University (AU)
- Monash University (AU)
- University of Helsinki (FI)
- University of Jyväskylä (FI)
- Lund University (SE)
- Deakin University (AU)
- Baker Heart and Diabetes Institute (AU)
- Edith Cowan University (AU)
- Australian Institute for Musculoskeletal Science (AU)
- Chinese Academy of Sciences (CN)
- University of Copenhagen (DK)
- Bond University (AU)
- Queensland University of Technology (AU)
- Max Planck Society (DE)
- King's College London (GB)
- Norwegian University of Science and Technology (NO)
- Corresponding author
- Eynon, Nir
- ORCID
- Jacques, Macsue
- Landen, Shanie
- Sharples, Adam P.
- Garnham, Andrew
- Schittenhelm, Ralf
- Steele, Joel
- Heikkinen, Aino
- Sillanpää, Elina
- Ollikainen, Miina
- Broatch, James
- Zarekookandeh, Navabeh
- Ekström, Ola
- Asplund, Olof
- Lamon, Séverine
- Alexander, Sarah E.
- Smith, Cassandra
- Bauer, Carlie
- Woessner, Mary N.
- Levinger, Itamar
- Teschendorff, Andrew E.
- Gillberg, Linn
- Blom, Ida
- Helge, Jørn Wulff
- Harvey, Nicholas R.
- Haupt, Larisa M.
- Griffiths, Lyn R.
- Deshmukh, Atul S.
- Pietiläinen, Kirsi H.
- Piirilä, Päivi
- Seaborne, Robert A.E.
- Klevjer, Marie
- Bye, Anja
- Wisløff, Ulrik
- Eynon, Nir
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2025-06
- Volume
- 44
- Issue
- 6
- Pages
- 115750
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W4410801366
- Cited by
- 23
- References
- 100
- Citations by year
- 2026: 21 · 2025: 2
- FWCI
- 13.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Työväentutkimus Vuosikirja (acceptedVersion)
- Bond University Research Portal (Bond University) (submittedVersion, cc-by)
- Jyväskylä University Digital Archive (University of Jyväskylä) (submittedVersion, cc-by)
- UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by)
- Australasian Journal of Paramedicine (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Novo Nordisk Fonden
- Sigrid Juséliuksen Säätiö
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen (NNF14CC001)
- Australian Research Council (DP190103081, DP240102155, DP200101830)
- Novo Nordisk Foundation Center for Basic Metabolic Research (NNF18CC0034900)
- Gen Foundation (NNF10OC1013354, NNF17OC0027232, NNF20OC0060547)
- Novo Nordisk A/S
- Minerva Foundation
- National Health and Medical Research Council (APP1194159)
- Monash University
- Diabetestutkimussäätiö
- Suomen Lääketieteen Säätiö
- Bioplatforms Australia
- Paulon Säätiö
- Research Council of Finland (314383, 266286, 335443, 272376)
- Helsingin Yliopisto (307339, 251316, 297908, 328685)
- Team Danmark
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- exercise adaptation, skeletal muscle, sex differences, aerobic exercise, resistance training, muscle disuse, VO2max, DNA methylation, transcription factors, gene expression regulation, multi-omics integration, exercise biomarkers, cardiorespiratory fitness
- MeSH terms
- Multiomics, Adaptation, Physiological, Adult, Female, Humans, Male, Middle Aged, Oxygen Consumption, Sex Characteristics, Sex Factors, Exercise, Muscle, Skeletal, DNA Methylation, Proteome, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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