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 6

Ketone ester supplementation prevents mitochondrial OXPHOS complex protein expression and gene expression while suppressing atrophy- and stress-associated transcripts in semaglutide-treated muscle.

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Ketone ester supplementation prevents mitochondrial OXPHOS complex prote...
(A) Representative immunoblot analysis of the mitochondrial OXPHOS complexes (I–V) and anti–voltage-dependent anion channel (anti-VDAC) from lysates of gastrocnemius muscle samples taken from groups of mice (C57BL/6N and C57BL/6J) represented as vehicle (V), semaglutide (S), or semaglutide combined with ketone ester (S+K). Total protein staining of the membrane is shown below as a loading control. (B) Gastrocnemius transcript expression of the mitochondrial electron transport–related genes Cox7a1, Atp5e, Uqcrq, Cox20, Smdt1, and Uqcr11 normalized to Rpl32 and Ywhaz, relative to vehicle-treated mice (n = 10–14). Dotted line indicates data for vehicle controls. (C) Gastrocnemius transcript expression of the atrophy-related genes Fbxo32, Trim63, and Tnfrsf12a normalized to Rpl32 and Ywhaz, relative to vehicle-treated mice (n = 5–14). Dotted line indicates data for vehicle controls. Data presented in B and C were obtained from experiments performed on male C57BL/6N and C57BL/6J mice. (D–G) RNA-seq–derived normalized counts for Eef1, Igf1r, Klf15, and Gpx3 (n = 3–5). Data presented in D–G were obtained from experiments performed on male C57BL/6N mice. 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). Total normalized counts were compared using 1-way ANOVA followed by Tukey’s multiple-comparison post hoc test. A value of P < 0.05 was considered statistically significant. All data are expressed as mean ± SEM. Cox7a1, cytochrome c oxidase subunit 7A1; Atp5e, ATP5F1E ATP synthase F1 subunit ε; Uqcrq, ubiquinol–cytochrome c reductase, complex III subunit VII; Cox20, cytochrome c oxidase assembly factor; Smdt1, single-pass membrane protein with aspartate-rich tail 1; Uqcr11, ubiquinol–cytochrome c reductase, complex III subunit XI; Fbxo32, atrogin-1; Trim63, muscle RING-finger protein 1; Tnfrsf12a, TNF-related weak inducer of apoptosis; Rpl32, ribosomal protein L32; Ywhaz, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein ζ; Eef1, eukaryotic elongation factor 1 gene; Igf1r, insulin-like growth factor 1 receptor gene; Klf15, Krüppel-like factor 15 gene; Gpx3, glutathione peroxidase 3 gene.