Abstract
ABSTRACT
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
p
p
p
p
p
= 0.0087) but reversed these effects by Day 5, significantly improving ATP production (↑27%–30%,
p
p
= 0.0152), and coupling efficiency. mtDNA content remained unchanged across all conditions. Similar responses were noted in human myotubes, with a transient reduction in respiration for semaglutide and cagrilintide (↓30%–62%,
p
p
= 0.0022).
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.