Journal: Journal of cachexia, sarcopenia and muscle
This experimental study used murine C2C12 and primary human skeletal muscle myotubes to compare how three weight‑loss agents—semaglutide (GLP‑1RA), tirzepatide (dual GLP‑1/GIP agonist), and cagrilintide (amylin analogue)—affect mitochondrial respiration under normal and lipotoxic (palmitic acid–exposed) conditions.
Key findings:
- Palmitic acid alone significantly impaired mitochondrial function, lowering basal oxygen consumption and ATP production.
- Semaglutide and cagrilintide in otherwise healthy myotubes caused a transient 48‑hour reduction in basal respiration and ATP production, accompanied by decreased expression of OXPHOS complexes I, III, and IV; these effects resolved by 5 days.
- Tirzepatide in otherwise healthy myotubes improved mitochondrial performance over time, increasing maximal respiration and spare respiratory capacity at 5 days.
- Under lipotoxic stress, semaglutide and cagrilintide acutely worsened mitochondrial dysfunction (further reducing ATP production) but these adverse effects also normalized by day 5.
- Under lipotoxic stress with tirzepatide, ATP production was initially suppressed but subsequently reversed, leading to higher ATP production, basal respiration, and coupling efficiency after 5 days.
- Mitochondrial DNA copy number was unchanged for all treatments.
- Human myotubes showed a similar pattern: transient suppression of respiration with semaglutide and cagrilintide, and improved maximal respiration with tirzepatide at 5 days.
Overall, these agents have distinct, time‑dependent effects on skeletal muscle bioenergetics, with tirzepatide demonstrating a sustained enhancement of mitochondrial respiration in both normal and lipotoxic settings, suggesting potential benefit for skeletal muscle health in metabolic disease.