Semaglutide-induced Loss of Skeletal Muscle Mass is Blunted by Co-administration of Ketone Esters

Building on our recent work demonstrating that ketone ester therapy prevents semaglutide-induced cardiac mass loss in obese mice, we investigated whether ketone therapy could also preserve skeletal muscle mass during semaglutide treatment. To characterize the molecular changes associated with this treatment, we performed RNA-seq transcriptomic analysis of gastrocnemius muscle from obese mice treated with vehicle, semaglutide, or semaglutide + ketone ester. Our analysis identified 5 dominant transcriptomic clusters enriched for pathways related to mitochondrial function, muscle contraction, translation, proteostasis, and extracellular matrix organization. Semaglutide increased expression of genes related to proteostasis and translation, whereas these changes were normalized with ketone ester co-treatment. In addition, semaglutide suppressed several mitochondrial genes, which were restored with ketone ester co-treatment. Furthermore, semaglutide reduced the expression of genes involved in the mitochondrial electron transport chain while increasing the expression of atrophy related genes, both of which were reversed by ketone ester co-treatment. Collectively, these findings suggest that ketone ester co-therapy mitigates semaglutide-induced transcriptomic alterations in skeletal muscle, providing mechanistic insight into how ketone therapy may help preserve muscle function during GLP-1based weight-loss therapy.