Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters
6 affiliations
- 1Alberta Diabetes Institute,
- 2Cardiovascular Research Centre,
- 3Department of Pediatrics,
- 4Women and Children’s Health Research Institute,
- 5Department of Biochemistry, Faculty of Medicine & Dentistry, and
- 6Faculty Saint-Jean, University of Alberta, Edmonton, Alberta, Canada
Abstract
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 3 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 cotreatment prevented semaglutide-induced changes in mitochondrial and atrophy-related gene expression, suggesting that 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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BibTeX
@article{abuetabh2026semaglutideinduced,
title = {{Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters}},
author = {Yasser Abuetabh and Mya A Schmidt and Masaaki Naganuma and Ramana Vaka and Mahmoud A. El‐Ghiaty and Shelly Braun and Ethan D. Kwan and Matthieu C P Zolondek and Darius Sahid and Laibah Khan and Rajat K. Shandal and Ashley L. Trudeau and Yaning Li and Sufyan O. Malik and Qiuyu Sun and Danica K. Roth and Daniela Y. Morales-Llamas and Jody L. Levasseur and Mourad Ferdaoussi and Richard P. Fahlman and Jason R.B. Dyck},
journal = {JCI Insight},
year = {2026},
month = jun,
doi = {10.1172/jci.insight.201810},
url = {https://doi.org/10.1172/jci.insight.201810},
note = {CC BY},
}
RIS
TY - JOUR
TI - Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters
AU - Yasser Abuetabh
AU - Mya A Schmidt
AU - Masaaki Naganuma
AU - Ramana Vaka
AU - Mahmoud A. El‐Ghiaty
AU - Shelly Braun
AU - Ethan D. Kwan
AU - Matthieu C P Zolondek
AU - Darius Sahid
AU - Laibah Khan
AU - Rajat K. Shandal
AU - Ashley L. Trudeau
AU - Yaning Li
AU - Sufyan O. Malik
AU - Qiuyu Sun
AU - Danica K. Roth
AU - Daniela Y. Morales-Llamas
AU - Jody L. Levasseur
AU - Mourad Ferdaoussi
AU - Richard P. Fahlman
AU - Jason R.B. Dyck
PY - 2026
DA - 2026/06/09
JO - JCI Insight
DO - 10.1172/jci.insight.201810
UR - https://doi.org/10.1172/jci.insight.201810
AB - 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 3 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 cotreatment prevented semaglutide-induced changes in mitochondrial and atrophy-related gene expression, suggesting that 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.
SN - 2379-3708
ER -