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
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
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Research Article Metabolism Muscle biology

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

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.

Authors

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

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Figure 1

Ketone ester co-administration prevents semaglutide-induced lean mass loss without impacting fat loss.

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Ketone ester co-administration prevents semaglutide-induced lean mass lo...
(A) Intraperitoneal glucose tolerance testing (IPGTT) was performed on male C57BL/6N and C57BL/6J mice after 15 weeks of high-fat diet (HFD) or standard chow (STD) (n = 10–30). (B) Glucose clearance represented by the area under the curve (AUC) of the IPGTT of A. (C) Blood β-hydroxybutyrate (ketone) concentrations were measured in obese mice following either vehicle administration (V) or twice-daily administration of 0.114 g/mL ketone ester in drinking water (V+K). (D) Schematic of the treatment timeline and group allocations. Created with BioRender.com. (E) The starting body weights of the studied groups, vehicle (V), semaglutide (S), and semaglutide combined with ketone ester (S+K). (F) IPGTT was repeated after 3 weeks of treatment with vehicle (V), semaglutide (S), or semaglutide combined with ketone ester (S+K) (n = 7–10). (G) Glucose clearance represented by the AUC of the IPGTT of F. (H) Fasting insulin levels. (I) Daily body weight measurements throughout the duration of the study. (J–L) Changes in body weight, fat mass, and lean mass were assessed following the 3-week intervention period using EchoMRI (n = 6–13). For comparisons among 3 groups, 1-way ANOVA was performed followed by Tukey’s multiple-comparison test (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001). All data are expressed as mean ± SEM. Data presented in this figure were obtained from experiments performed on male C57BL/6N and C57BL/6J mice.