Abstract
<jats:p>GLP1 and GIP/GLP1 receptor agonists produce substantial weight loss in clinical trials but significant loss of lean body mass is reported. Whether this reflects a direct pharmacological effect on skeletal muscle or an indirect consequence of caloric restriction and reduced mechanical loading is unknown. Primary myoblasts were isolated from skeletal muscle of older adults with obesity undergoing orthopaedic surgery. GIPR and GLP1R expression was characterised by RTqPCR and flow cytometry. Differentiated myotubes were treated with semaglutide or GIP peptide and assessed for atrophy related gene expression (qPCR), secretome perturbation (Olink Reveal), mitochondrial and glycolytic bioenergetics (Seahorse XF Real Time ATP Rate Assay, glucose uptake, lactate secretion) and myotube morphology and myogenesis (immunofluorescence). GIPR mRNA was consistently detected across all donors; GLP1R mRNA was undetectable by PCR, though LUXendin645 flow cytometry identified low level surface GLP1R protein in 51 to 66% of myoblasts. Neither semaglutide nor GIP altered atrophy related gene expression or the secretome, with no proteins reaching significance. Semaglutide reduced glycolytic and total ATP production rates, accompanied by reduced lactate secretion, suggesting modest suppression of glycolytic flux; mitochondrial parameters were unaffected. Neither treatment impaired myotube thickness or differentiation; GIP increased myotube thickness after 8 days. Direct GLP1 and GIP receptor activation does not substantively perturb atrophic signalling, myogenesis, or the secretome of primary human skeletal muscle myotubes. These findings suggest that lean mass loss with incretin based therapies is unlikely to be driven by direct pharmacological action on skeletal muscle, particularly relevant as these agents are increasingly used in older adults at risk of sarcopenia.</jats:p>