Abstract Body: Introduction: Incretin modifying therapies (e.g GLP-1R agonists) have transformed treatment of obesity and type 2 diabetes mellitus and confer substantial cardiovascular benefit in heart failure. These effects were initially attributed to weight loss and systemic metabolic improvement, but emerging evidence suggests additional cardioprotective actions. For example, semaglutide has been shown to enhance cardiac mitochondrial function and alter cardiac metabolism. Whether these arise from systemic effects or from direct, myocardium-specific mechanisms remains incompletely understood. This distinction is clinically important as most current HF therapies target hemodynamic and vascular parameters rather than cardiomyocyte function itself.
Goals: We sought to determine the effects of incretin therapies on cardiomyocyte mitochondrial function, both in intact cells and in isolated mitochondria.
Methods: High resolution respirometry (Oroboros O2K) was used to measure oxygen flux (JO₂) in intact cultured neonatal (NRVMs; n=5) and adult (ARVMs; n=5) rat cardiomyocytes treated with vehicle or GLP-1R family agonists (semaglutide, tirzepatide, retatrutide). Energetic substrates were added sequentially to interrogate electron transport system function. Receptor activation was confirmed by Western blot in NRVMs (pCREB). Additionally, we measured mitochondrial respiratory function in isolated human left ventricular mitochondria derived from failing explants and nonfailing donor hearts, treated acutely with vehicle or 500nM semaglutide.
Results: In NRVMs and ARVMs, JO₂ increased relative to vehicle following semaglutide treatment (500nM) but not tirzepatide or retatrutide (p<0.05). In NRVMs, 500nM semaglutide robustly increased CREB phosphorylation (p<0.001), suggesting adequate GLP-1R activation. In isolated human mitochondria, acute semaglutide treatment did not alter the respiratory function of failing and nonfailing cardiac tissue.
Conclusions: These data indicate that incretin therapies may directly modulate cardiomyocyte mitochondrial function. Increased JO₂ in intact cells but not in isolated mitochondria treated with semaglutide suggests cellular-level signaling cascades may be required rather than direct mitochondrial effects.
Implications: This work supports a myocardium-intrinsic component of incretin-mediated cardioprotection and provides a foundation for defining cardiac-specific molecular and metabolic mechanisms in disease-relevant contexts.