Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters

Yasser Abuetabh; Mya A. Schmidt; Masaaki Naganuma; Ramana Vaka; Mahmoud A. El-Ghiaty; Shelly Braun; Ethan A. Kwan; Matthieu C.P. Zolondek; Darius Sahid; Laibah Khan; Rajat K. Shandal; Ashley L. Trudeau; Yaning Li; Sufyan O. Malik; Qiuyu Sun; Danica K. Roth; Daniela Y. Morales-Llamas; Jody L. Levasseur; Mourad Ferdaoussi; Richard P. Fahlman; Jason R.B. Dyck

doi:10.1172/jci.insight.201810

¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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¹Cardiovascular Research Centre, University of Alberta, Edmonton, Canada

²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Canada

³Alberta Diabetes Institute, University of Alberta, Edmonton, Canada

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JCI Insight. https://doi.org/10.1172/jci.insight.201810.
Copyright © 2026, Abuetabh et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 9, 2026 - Version history

While glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide are effective in treating obesity, up to 45% of the resulting weight loss can be attributed to skeletal muscle loss. Given the critical role of skeletal muscle in health and mobility, this may have long-term adverse consequences. Herein we investigated whether oral ketone ester supplementation could prevent semaglutide-induced muscle loss and explored the underlying molecular mechanisms. Obese, glucose-intolerant mice received vehicle, semaglutide, or semaglutide plus a β-hydroxybutyrate–generating ketone ester for three weeks. Body composition, muscle strength, and endurance were assessed longitudinally. Semaglutide monotherapy reduced lean mass, impaired muscle strength, and suppressed mitochondrial gene expression while elevating atrophy-related genes in skeletal muscle samples. Co-administration with ketone ester preserved skeletal muscle mass and function without compromising fat loss. Mechanistically, ketone ester co-treatment prevented semaglutide-induced changes in mitochondrial and atrophy-related gene expression, suggesting mitochondrial defects and impaired ketone metabolism contribute to GLP-1RA-induced muscle loss. Together, these findings demonstrate that ketone ester supplementation can maintain muscle mass and performance during semaglutide-driven weight loss. These preclinical findings support ketone therapy as a promising strategy to counteract the sarcopenia-promoting effects of GLP-1RAs and warrant clinical evaluation to assess its translational potential.

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Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters

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