Abstract
Skeletal muscle is a central determinant of organismal health. Preserving muscle quality is therefore critical for preventing disease and sustaining quality of life across the lifespan. Despite its central role, the field lacks a unifying framework that defines the core properties of skeletal muscle health. Here, we propose a conceptual framework for muscle homeostasis built around seven interconnected hallmarks—metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and cross-talk—that collectively govern muscle integrity, adaptability and resilience. Each hallmark is mechanistically grounded, quantifiable and potentially modifiable. This framework provides a unifying blueprint for the next generation of precision diagnostics and targeted therapies for preserving skeletal muscle health.
Subjects
- Ageing
- Metabolism
- Musculoskeletal system
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Acknowledgements
This work was supported by the Next Generation EU initiative in the context of the National Recovery and Resilience Plan, Project CN00000041 (CUP C93C22002780006, Spoke 4 ‘Metabolic and Cardiovascular diseases’), the Next Generation EU initiative in the context of the National Recovery and Resilience Plan, Investment PE8 – Project Age-It: ‘Ageing Well in an Ageing Society’ (PE0000015 Decree of the Ministry of University and Research 1557, 11 October 2022, CUP C13C22000660001); Associazione Italiana per la Ricerca sul Cancro (AIRC; grants 23257 and 30366); the Italian Ministry of Health (PRIN 2022, grant 2022LZARA3); CARIPARO; ERC-2024-ADG Decode-And-Treat (grant 101201488) and AFM-Téléthon (grant 22982) to M.S. B.B. is supported by AFM-Téléthon (grant 24357) and AIRC (grant 27007). K.D.B. is endowed by the Schulthess Foundation. E.N.O. is supported by the National Institutes of Health (NIH; grants R01HL157281, P01HL160488 and P50HD087351), the Leducq Foundation Transatlantic Network of Excellence, the Robert A. Welch Foundation (grant 1-0025) and the British Heart Foundation Big Beat Challenge CureHeart award (BBC/F/21/220106). C.A.C.O. is supported by the NIH (grant R01HL121500). E.A.R. is supported by the Novo Nordisk Foundation (grants NNF20OC0063709 and NNF23OC0084246), and the Independent Research Fund Denmark (grant 2034-00102B). L.S. is supported by AFM telethon (MyoNeurALP) and ANR (RHU SMART, ANR-21-RHUS-0007).
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Authors and Affiliations
Craft Science Inc., Toronto, Ontario, Canada
Anna Vainshtein
Department of Biomedical Sciences, University of Padova, Padova, Italy
Bert Blaauw & Marco Sandri
Veneto Institute of Molecular Medicine, Padova, Italy
Bert Blaauw & Marco Sandri
Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland
Katrien De Bock
Altos Labs Inc, Discovery Science, San Diego, CA, USA
Pura Munoz-Canoves
Department of Medicine and Life Sciences, Pompeu Fabra University (UPF), Barcelona, Spain
Pura Munoz-Canoves
Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX, USA
Eric N. Olson
Department of Physiology, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands
Coen A. C. Ottenheijm
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
Coen A. C. Ottenheijm
Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
Erik A. Richter
Department of Pharmacology and Frankel Institute for Heart & Brain Health, University of Michigan Medical School, Ann Arbor, MI, USA
Jorge L. Ruas
Université Lyon1, Laboratory of Pathophysiology and Genetics of Neuron and Muscle, UMR5261 CNRS, Inserm, Lyon, France
Laurent Schaffer
Center of Cell Biology, Hospices Civils de Lyon, Lyon, France
Laurent Schaffer
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
Bruce Spiegelman
Department of Cell Biology, Harvard Medical School, Boston, MA, USA
Bruce Spiegelman
Department of Medicine, McGill University, Montreal, Quebec, Canada
Marco Sandri
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Contributions
A.V. and M.S. conceived and developed the hallmarks framework and led manuscript development. A.V. coordinated and integrated contributions across all sections and led overall manuscript development and revision. M.S., B.B., K.D.B., P.M.-C., E.N.O., C.A.C.O., E.A.R., J.L.R., L.S. and B.S. each wrote their respective hallmark sections, participated in consensus evaluation of the proposed hallmarks, and critically reviewed and revised the full manuscript. All authors approved the final version for submission.
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Competing interests
A.V. is the founder and director of Craft Science Inc., a medical communications and scientific strategy consultancy. P.M.-C. is an employee of Altos Labs. B.S. is a cofounder and consultant of Aevum Therapeutics, which is developing exercise-induced molecules including irisin for therapeutic purposes. E.N.O. is a consultant for Vertex Pharmaceuticals, Cardurion and Tenaya Therapeutics. B.B., K.D.B., C.A.C.O., E.A.R., J.L.R., L.S. and M.S. declare no competing interests
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Supplementary Tables 1–7 with references, Supplementary Table 8 with references and Supplementary Fig. 1
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Vainshtein, A., Blaauw, B., De Bock, K. et al. The hallmarks of skeletal muscle health.
Nat Metab (2026). https://doi.org/10.1038/s42255-026-01595-9
Received:01 April 2026
Accepted:27 July 2026
Published:20 August 2026
Version of record:20 August 2026
DOI
:https://doi.org/10.1038/s42255-026-01595-9
