Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration

Macsue Jacques¹, Shanie Landen², Adam P Sharples³, Andrew Garnham⁴, Ralf Schittenhelm⁵, Joel Steele⁵, Aino Heikkinen⁶, Elina Sillanpää⁷, Miina Ollikainen⁸, James Broatch⁴, Navabeh Zarekookandeh⁴, Ola Hanson⁹, Ola Ekström¹⁰, Olof Asplund⁶, Séverine Lamon¹¹, Sarah E Alexander¹², Cassandra Smith¹³, Carlie Bauer⁴, Mary N Woessner⁴, Itamar Levinger¹⁴, Andrew E Teschendorff¹⁵, Linn Gillberg¹⁶, Ida Blom¹⁶, Jørn Wulff Helge¹⁶, Nicholas R Harvey¹⁷, Larisa M Haupt¹⁸, Lyn R Griffiths¹⁹, Atul S Deshmukh²⁰, Kirsi H Pietiläinen²¹, Päivi Piirilä²², Robert A E Seaborne²³, Marie Klevjer²⁴, Anja Bye²⁴, Ulrik Wisløff²⁴, Bernadette Jones-Freeman²⁵, Nir Eynon²⁶

Affiliations

¹ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia; Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia.
² Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, VIC, Australia.
³ Institute of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway.
⁴ Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia.
⁵ Monash Proteomics & Metabolomics Platform, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
⁶ Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland.
⁷ Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland; Wellbeing Services County of Central Finland, Jyväskylä, Finland.
⁸ Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
⁹ Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland; Department of Clinical Sciences, Translational Muscle Research Unit, Lund University Diabetes Center, Lund University, Lund, Sweden.
¹⁰ Department of Clinical Sciences, Translational Muscle Research Unit, Lund University Diabetes Center, Lund University, Lund, Sweden.
¹¹ Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood, VIC 3125, Australia.
¹² Cardiometabolic Health and Exercise Physiology Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
¹³ Nutrition & Health Innovation Research Institute, Edith Cowan University, Joondalup, WA, Australia; Medical School, The University of Western Australia, Perth, WA, Australia.
¹⁴ Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, Melbourne, VIC, Australia.
¹⁵ CAS Key Lab of Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai, China.
¹⁶ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁷ Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, Australia; Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
¹⁸ Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia; ARC Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Brisbane, QLD, Australia; Max Planck Queensland Centre for the Materials Sciences of Extracellular Matrices, Brisbane, QLD, Australia.
¹⁹ Max Planck Queensland Centre for the Materials Sciences of Extracellular Matrices, Brisbane, QLD, Australia.
²⁰ The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²¹ Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Healthy Weight Hub, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
²² Unit of Clinical Physiology, Helsinki University Hospital Diagnostic Center and University of Helsinki, Helsinki, Finland.
²³ Centre for Human & Applied Physiological Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
²⁴ Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Cardiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
²⁵ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia.
²⁶ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia. Electronic address: nir.eynon@monash.edu.

PMID: 40445834
DOI: 10.1016/j.celrep.2025.115750

Free article

Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration

Macsue Jacques et al. Cell Rep. 2025.

Free article

. 2025 Jun 24;44(6):115750.

doi: 10.1016/j.celrep.2025.115750. Epub 2025 May 28.

Authors

Affiliations

¹ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia; Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia.
² Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, VIC, Australia.
³ Institute of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway.
⁴ Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia.
⁵ Monash Proteomics & Metabolomics Platform, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
⁶ Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland.
⁷ Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland; Wellbeing Services County of Central Finland, Jyväskylä, Finland.
⁸ Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
⁹ Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland; Department of Clinical Sciences, Translational Muscle Research Unit, Lund University Diabetes Center, Lund University, Lund, Sweden.
¹⁰ Department of Clinical Sciences, Translational Muscle Research Unit, Lund University Diabetes Center, Lund University, Lund, Sweden.
¹¹ Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood, VIC 3125, Australia.
¹² Cardiometabolic Health and Exercise Physiology Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
¹³ Nutrition & Health Innovation Research Institute, Edith Cowan University, Joondalup, WA, Australia; Medical School, The University of Western Australia, Perth, WA, Australia.
¹⁴ Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, Melbourne, VIC, Australia.
¹⁵ CAS Key Lab of Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai, China.
¹⁶ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁷ Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, Australia; Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
¹⁸ Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia; ARC Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Brisbane, QLD, Australia; Max Planck Queensland Centre for the Materials Sciences of Extracellular Matrices, Brisbane, QLD, Australia.
¹⁹ Max Planck Queensland Centre for the Materials Sciences of Extracellular Matrices, Brisbane, QLD, Australia.
²⁰ The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²¹ Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Healthy Weight Hub, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
²² Unit of Clinical Physiology, Helsinki University Hospital Diagnostic Center and University of Helsinki, Helsinki, Finland.
²³ Centre for Human & Applied Physiological Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
²⁴ Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Cardiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
²⁵ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia.
²⁶ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia. Electronic address: nir.eynon@monash.edu.

PMID: 40445834
DOI: 10.1016/j.celrep.2025.115750

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 (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.

Keywords: CP: Metabolism; DNA methylation; Multi Omics; VO(2 max); epigenetics; exercise; gene expression; proteomic; skeletal muscle; transcriptomic.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration

Affiliations

Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration

Authors

Affiliations

Abstract

Conflict of interest statement

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LinkOut - more resources

Full Text Sources

Medical

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