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 3

Reductions in skeletal muscle mass induced by semaglutide are blunted by ketone ester co-therapy.

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Reductions in skeletal muscle mass induced by semaglutide are blunted by...
(A–D) Weights of the quadriceps, soleus, gastrocnemius, and tibialis anterior muscles were measured after 3 weeks of treatment (n = 6–13; data were obtained from experiments performed on male C57BL/6N and C57BL/6J mice). (E) Representative images of gastrocnemius muscle cross sections stained with wheat germ agglutinin. Scale bars: 400 μm; zoom, ×1.5. (F) Quantification of mean myocyte cross-sectional area in E. Data presented in E and F were obtained from experiments performed on male C57BL/6N mice. (G–I) Total calorie consumption (G), calories from drink consumption (H), and calories from food consumption (I) at 7, 14, and 21 days after initiation of the study protocol. Data presented in G–I were obtained from experiments performed on male C57BL/6J mice. Groups of mice are represented as vehicle (V), semaglutide (S), and semaglutide combined with ketone ester (S+K). Comparisons between 2 groups were conducted using an unpaired, nonparametric Mann-Whitney test. 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.