Mitochondrial Adaptations in Skeletal Muscle Following Incretin-Based Therapies: In Vitro.

Area of Science:

• Mitochondrial Biology
• Endocrinology
• Pharmacology

Background:

• Incretin-based therapies (GLP-1 RAs, dual GLP-1/GIP agonists, amylin analogues) promote weight loss.
• Their effects on skeletal muscle mitochondrial function under metabolic stress are not well understood.

Purpose of the Study:

• To investigate the impact of semaglutide, tirzepatide, and cagrilintide on skeletal muscle mitochondrial function.
• To assess these effects in both healthy and lipotoxic conditions using C2C12 myotubes and primary human skeletal muscle cells.

Main Methods:

• C2C12 myotubes and human skeletal muscle cells were treated with semaglutide, tirzepatide, and cagrilintide.
• Mitochondrial respiration was measured using Seahorse XFp.
• Mitochondrial DNA copy number and OXPHOS protein expression were analyzed.

Main Results:

• Palmitic acid impaired mitochondrial function; semaglutide and cagrilintide transiently worsened this impairment.
• Tirzepatide demonstrated sustained improvements in mitochondrial respiration and ATP production under both healthy and lipotoxic conditions.
• Effects were dose- and time-dependent, with similar trends observed in human cells.

Conclusions:

• Incretin-based therapies have distinct effects on skeletal muscle mitochondrial function.
• Tirzepatide promotes sustained mitochondrial bioenergetic improvements, suggesting potential benefits for skeletal muscle health in metabolic disease.