Mitochondrial Adaptations in Skeletal Muscle Following Incretin-Based Therapies: In Vitro.
This in vitro study examined the effects of three incretin-based therapies — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP agonist), and cagrilintide (amylin analogue) — on mitochondrial function in C2C12 skeletal muscle myotubes under both normal and lipotoxic conditions. Lipotoxicity was induced using palmitic acid (PA), which significantly reduced basal oxygen consumption rate and ATP production in treated cells. The study used Seahorse XFp metabolic flux analysis, mitochondrial DNA copy number quantification (qPCR), and oxidative phosphorylation complex protein expression (western blotting), with key findings replicated in primary human skeletal muscle cells. The researchers found that semaglutide and cagrilintide transiently reduced basal respiration in healthy myotubes, while tirzepatide demonstrated more sustained improvements in mitochondrial respiration under both healthy and lipotoxic conditions. The study's primary limitations include its reliance on cell culture models, meaning findings may not directly translate to whole-organism physiology, and the use of a single lipotoxic stimulus. The partial replication in human primary cells adds some translational relevance, but in vivo validation remains absent.
Why this grade: All primary experiments were conducted in C2C12 mouse myotube cell lines and partially replicated in primary human skeletal muscle cells, with no in vivo or clinical human data.
Background Incretin-based therapies such as glucagon-like peptide-1 receptor agonists (GLP-1Ras), dual GLP-1/GIP agonists and amylin analogues have demonstrated significant weight loss benefits. However, their impact on skeletal muscle mitochondrial function, particularly under metabolic stress, remains unclear. This study aimed to investigate the effects of semaglutide (GLP-1RA), tirzepatide (dual GLP-1/GIP agonist) and cagrilintide (amylin analogue) on mitochondrial function in C2C12 skeletal muscle myotubes under both healthy and lipotoxic (palmitic acid-treated) conditions. Methods Differentiated C2C12 myotubes were treated with doses of each drug for 48 h and 5 days. Mitochondrial respiration was assessed using the Seahorse XFp analyser, mitochondrial DNA (mtDNA) copy number and oxidative phosphorylation (OXPHOS) complex protein expression were measured by qPCR and western blotting. Key findings were repeated in primary human skeletal muscle cells. Results Palmitic acid (PA) significantly impaired mitochondrial function, reducing basal oxygen consumption rate (OCR) by 22% (p = 0.0056) and ATP production by 25% (p = 0.0022). In healthy myotubes, semaglutide and cagrilintide transiently reduced basal respiration (↓21%-28%, p Conclusion Incretin-based therapies exert distinct, time and dose-dependent effects on skeletal muscle mitochondrial function. Tirzepatide promoted sustained improvements in mitochondrial respiration under both healthy and lipotoxic conditions, indicating potential benefits for maintaining skeletal muscle bioenergetic function. These findings underscore the need for further mechanistic studies and suggest that tirzepatide may have the potential to support skeletal muscle health in metabolic disease.
Educational summary of published research — not medical advice. License: cc by. Full text is shown only where licensing permits.