Abstract
Myostatin negatively regulates skeletal muscle size in multiple species, and therefore, myostatin blockade has been therapeutically explored to promote muscle growth in humans, including to counter the muscle loss seen in obese humans using GLP1R agonists. In this study, we present results from a large multi-cohort genetic association analysis, using data from 1.1 million individuals to examine the effects of function-disrupting mutations in the myostatin gene (MSTN) on traits relevant to body composition and cardiometabolic health. Carriers of function-disrupting variants display decreased adiposity, an increase in lean mass, and increased grip strength and creatinine levels. We further characterize the effects of these variants on body composition using whole-body MRI data from UK Biobank, leveraging deep learning models to perform automated image segmentation for 77,572 individuals. Among mutation carriers increased muscle mass is observed across multiple muscle groups, with heterozygote carriers of loss-of-function-like mutations exhibiting increases in excess of 10%. Our findings demonstrate that lifelong reduction in myostatin function enhances muscle size and strength in humans while decreasing body adiposity, providing insights into the potential benefits and safety of long-term therapeutic blockade of myostatin signaling.
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Data availability
UKB individual-level genotypic and phenotypic data may be accessed by approved investigators via a data access agreement with the UK Biobank (www.ukbiobank.ac.uk/). Additional information about registration for access to the data is available at www.ukbiobank.ac.uk/register-apply/. Regeneron can make individual-level genomic data from the GHS-RGC DiscovEHR collaboration available to qualified academic noncommercial researchers through the REGN pre-clinical Research portal at https://regeneron.envisionpharma.com/vt_regeneron/ under a data access agreement. MDCS data may be available to qualified academic non-commercial researchers to reproduce results reported in this manuscript through the portal at https://www.malmo-kohorter.lu.se/malmo-cohorts, following the principles outlined in this policy https://www.malmo-kohorter.lu.se/sites/malmo-kohorter.lu.se/files/mdcs_mpp_mos_request_form_vermar20.doc. For other cohorts/biobanks included in this manuscript, academic, non-commercial researchers interested in reproducing the results reported in this manuscript may request access to individual-level data via a data access agreement by reaching out to the associated biobank.
Code availability
Code for reproducing the genetic association analyses is publicly available at https://github.com/rgcgithub/regenie. Full details of the data analysis pipeline and additional open-source tools and resources used for each step are provided in the Methods section. Base R packages were used for all other statistical calculations and linear model fits, and ggplot2 was used to generate plots.
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Acknowledgements
This research was funded by Regeneron Pharmaceuticals. The Malmö Diet and Cancer study was funded by grants from the Swedish Medical Research Council, the Swedish Cancer Foundation, the Albert Påhlsson and Gunnar Nilsson Foundations, AFA insurance, and the Malmö city council. O.M. received funding from the European Research Council (ERC-AdG-2019-885003). We would like to thank Len Schleifer and the entire Regeneron community for their support.
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D.J.G., J.M., J.B., G.D.Y., designed the study; J.L.H., P.D., K.L., B.J.G., D.P. performed analyses and prepared figures and tables; J.L.H., P.D., D.P., M.A.E., J.B., D.J.G., G.D.Y. wrote the first draft; J.L.H., P.D., K.L., B.J.G., M.A.E., D.P., M.G., J.W.M., J.R.W., L.A.L., G.R.A., A.B., J.Y.A., M.W.S., O.M., T.S., G.D.Y., J.B., J.M., D.J.G. contributed to interpretation of results, reviewed and edited the manuscript, and agreed to the decision to submit the manuscript for publication.
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Herman, J.L., Dornbos, P., Landheer, K. et al. Humans with function-disrupting variants in the myostatin gene (MSTN) have increased skeletal muscle mass and strength, and less adiposity. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70422-2
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DOI: https://doi.org/10.1038/s41467-026-70422-2
