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

Jun 9, 2026JCI insight

Semaglutide’s muscle loss effect is reduced when ketone esters are given together

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GLP-1 Therapies on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Up to 45% of weight loss from semaglutide treatment may come from skeletal muscle loss.

Semaglutide monotherapy resulted in reduced lean mass and impaired muscle strength in mice.
Skeletal muscle samples showed increased expression of atrophy-related genes and decreased expression of mitochondrial genes after semaglutide treatment.
Co-administration of a ketone ester with semaglutide preserved skeletal muscle mass and function.
Ketone ester supplementation prevented the semaglutide-induced changes in mitochondrial and atrophy-related gene expression.
These findings suggest that impaired ketone metabolism may contribute to muscle loss associated with GLP-1 receptor agonists.

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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.