Abstract 379: Metformin Induces Energetic Reprogramming in Human Cardiomyocytes

Abstract

Introduction: Metformin (Metf) is an oral hypoglycemic agent widely used to treat type 2 diabetes. It also lessens myocardial injury and reduces cardiovascular mortality. However, the exact molecular mechanisms of Metf therapeutic action in the human heart remain obscure. The aim of this study was to evaluate the cardioprotective effect of Metf on cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs). Methods: The hiPSC-CMs were derived from an hiPSC line generated from human dermal fibroblasts and treated with Metf (0-20 mM) for 24 hours. Oxygen consumption rate (OCR) was measured using XF96 Extracellular Flux Analyzer. Metabolites were profiled using a liquid chromatography coupled to tandem mass spectrometry. Tukey’s pairwise comparison and one-way ANOVA were applied for comparison between groups. P < 0.05 was considered significant. Results: At concentrations ≤ 2.5 mM, Metf significantly enhanced the cellular OCR (Fig. A) and enhanced mitochondrial biogenesis (Fig. B) via AMPK signaling (Fig. C). This effect was abrogated by compound C, an inhibitor of AMPK. At concentrations > 5 mM, Metf reduced the cellular OCR and activated glycolysis (Fig. D) and glutaminolysis (Fig. E) in the cardiomyocytes. Conclusion: Thus, in the human heart, Metf might improve cardioprotection owing to its dual effect on mitochondria. At low doses, it activates mitochondrial biogenesis via AMPK signaling and increases the OCR. At high doses, it causes metabolic reprogramming by enhancing glycolysis and glutaminolysis as a compensatory mechanism in response to inhibition of the mitochondrial oxidative phosphorylation.