GLP-1 and GIP receptor agonism does not directly drive skeletal muscle atrophy or impair myogenesis in primary human myotubes
Direct GLP-1 and GIP receptor activation does not significantly affect muscle atrophy or myogenesis in human myotubes, suggesting that lean mass loss with these therapies may not be directly pharmacological.
Where it sits
this study against the rest of the semaglutide corpusSummary and findings
This study investigated the effects of semaglutide and GIP peptide on skeletal muscle myotubes derived from older adults with obesity. The primary focus was on atrophy-related gene expression, secretome changes, and myotube morphology. No significant alterations were observed in these parameters following treatment.
Abstract
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.
Background
The study addresses the biological question of whether GLP-1 and GIP receptor agonism contributes to skeletal muscle atrophy or affects myogenesis, which is relevant given the increasing use of these agonists in metabolic disorders. Prior research has shown that these pathways can influence various metabolic processes, but their direct effects on muscle tissue remain unclear. Understanding these effects is crucial for evaluating the overall impact of GLP-1 and GIP therapies on muscle health.
Methods
The study utilized primary human myotubes to assess the direct effects of GLP-1 and GIP receptor agonism. Specific details regarding the study design, sample size (n), doses administered, duration of exposure, and the primary versus secondary outcome measures were not reported in the abstract.
Results
Not reported in abstract.
Interpretation
Without specific numeric findings or effect sizes reported, it is challenging to compare these results to prior literature or assess the clinical significance of the findings. The lack of reported data limits the ability to draw conclusions about the implications for clinical practice. Potential confounds include the absence of detailed methodology and results, which could affect the reliability of the conclusions drawn.
Key findings
- Not reported in abstract.
Limitations
- Not reported in abstract.