Cell Reports (Jun 2025)
Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration
- Macsue Jacques,
- Shanie Landen,
- Adam P. Sharples,
- Andrew Garnham,
- Ralf Schittenhelm,
- Joel Steele,
- Aino Heikkinen,
- Elina Sillanpää,
- Miina Ollikainen,
- James Broatch,
- Navabeh Zarekookandeh,
- Ola Hanson,
- Ola Ekström,
- Olof Asplund,
- Séverine Lamon,
- Sarah E. Alexander,
- Cassandra Smith,
- Carlie Bauer,
- Mary N. Woessner,
- Itamar Levinger,
- Andrew E. Teschendorff,
- Linn Gillberg,
- Ida Blom,
- Jørn Wulff Helge,
- Nicholas R. Harvey,
- Larisa M. Haupt,
- Lyn R. Griffiths,
- Atul S. Deshmukh,
- Kirsi H. Pietiläinen,
- Päivi Piirilä,
- Robert A.E. Seaborne,
- Marie Klevjer,
- Anja Bye,
- Ulrik Wisløff,
- Bernadette Jones-Freeman,
- Nir Eynon
Affiliations
- Macsue Jacques
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia; Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia
- Shanie Landen
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Adam P. Sharples
- Institute of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway
- Andrew Garnham
- Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia
- Ralf Schittenhelm
- Monash Proteomics & Metabolomics Platform, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
- Joel Steele
- Monash Proteomics & Metabolomics Platform, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
- Aino Heikkinen
- Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland
- Elina Sillanpää
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland; Wellbeing Services County of Central Finland, Jyväskylä, Finland
- Miina Ollikainen
- Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
- James Broatch
- Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia
- Navabeh Zarekookandeh
- Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia
- Ola Hanson
- 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
- Ola Ekström
- Department of Clinical Sciences, Translational Muscle Research Unit, Lund University Diabetes Center, Lund University, Lund, Sweden
- Olof Asplund
- Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland
- Séverine Lamon
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood, VIC 3125, Australia
- Sarah E. Alexander
- Cardiometabolic Health and Exercise Physiology Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
- Cassandra Smith
- Nutrition & Health Innovation Research Institute, Edith Cowan University, Joondalup, WA, Australia; Medical School, The University of Western Australia, Perth, WA, Australia
- Carlie Bauer
- Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia
- Mary N. Woessner
- Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia
- Itamar Levinger
- Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, Melbourne, VIC, Australia
- Andrew E. Teschendorff
- CAS Key Lab of Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai, China
- Linn Gillberg
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Ida Blom
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Jørn Wulff Helge
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Nicholas R. Harvey
- 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
- Larisa M. Haupt
- 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
- Lyn R. Griffiths
- Max Planck Queensland Centre for the Materials Sciences of Extracellular Matrices, Brisbane, QLD, Australia
- Atul S. Deshmukh
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Kirsi H. Pietiläinen
- 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
- Päivi Piirilä
- Unit of Clinical Physiology, Helsinki University Hospital Diagnostic Center and University of Helsinki, Helsinki, Finland
- Robert A.E. Seaborne
- Centre for Human & Applied Physiological Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK
- Marie Klevjer
- 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
- Anja Bye
- 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
- Ulrik Wisløff
- 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
- Bernadette Jones-Freeman
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
- Nir Eynon
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia; Corresponding author
- DOI
- https://doi.org/10.1016/j.celrep.2025.115750
- Journal volume & issue
-
Vol. 44,
no. 6
p. 115750
Abstract
Summary: 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
