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

In vitro study using C2C12 myotubes and primary human skeletal muscle cells

“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.”

C2C12 skeletal muscle myotubes and primary human skeletal muscle cells

“Differentiated C2C12 myotubes were treated with doses of each drug for 48 h and 5 days.”

n = 6 per group

“Data are presented as mean ± SD (n = 6 per group).”

48 hours and 5 days

“Cells were treated in serum‐free media (DMEM with 1% PS), with drugs applied for either 48 h or 5 days (media changed every 2 days).”

Palmitic acid impaired mitochondrial function by reducing basal oxygen consumption rate and ATP production

“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).”

Semaglutide and cagrilintide caused transient reductions in basal respiration and ATP production at 48 hours that resolved by 5 days

“In healthy myotubes, semaglutide and cagrilintide transiently reduced basal respiration (↓21%–28%, p < 0.05) and ATP production (↓24%–31%, p < 0.01) at 48 h, along with reductions in Complexes I, III and IV protein expression, all of which resolved by 5 days.”

Tirzepatide increased maximal respiration and spare respiratory capacity after 5 days in healthy myotubes and improved ATP production in lipotoxic myotubes

“Tirzepatide significantly increased maximal respiration (↑20%–25%, p < 0.005) and spare respiratory capacity (↑22%–30%, p < 0.005) after 5 days.”

Use of in vitro cell models which may not fully recapitulate in vivo skeletal muscle physiology

“A key limitation of this study is the use of C2C12 myotubes as an in vitro model, although the patterns seen in mitochondrial respiration were largely replicated in primary human myotubes.”