Empagliflozin attenuates ISO-induced myocardial injury through PGC-1α-mediated mitochondrial biogenesis and improved fatty acid metabolism

Empagliflozin, as a sodium-glucose cotransporter 2 inhibitor (SGLT2i), has demonstrated beneficial cardioprotective effects in patients with heart failure. However, the cardiac benefits of empagliflozin are not entirely dependent on the classical SGLT2 receptor-mediated mechanism and may also be associated with the improvement of cardiomyocyte mitochondrial function and fatty acid metabolism. This study aimed to evaluate the effects of empagliflozin on cardiac function and elucidate its potential targets and underlying mechanisms. Rats with ISO-induced myocardial injury were subsequently treated with empagliflozin by intragastric administration. Compared with the model group, empagliflozin improved cardiac function and alleviated pathological changes, including myocardial hypertrophy and fibrosis. Empagliflozin significantly reduced the expression levels of cytochrome c (Cyt c), Bax, and cleaved-caspase-3, increased Bcl-2 expression, attenuated cardiomyocyte apoptosis, and decreased serum levels of BNP, sST2, and cTnT. Empagliflozin preserved mitochondrial morphology and cristae structure, reduced myocardial ROS levels, significantly increased mitochondrial membrane potential and mtDNA copy number, and upregulated the expression of PGC-1α, NRF1, NRF2, and TFAM. Following empagliflozin intervention, the expression levels of PPARα, CPT1, CPT2, and MCAD were increased, promoting fatty acid utilization in myocardial tissue and enhancing ATP production. In the ISO-induced H9c2 cell model, empagliflozin exerted biological effects similar to those of a PGC-1α agonist, promoting mitochondrial biogenesis, facilitating the utilization of accumulated fatty acids in cardiomyocytes, improving energy metabolism, and reducing apoptosis. Importantly, siRNA-mediated knockdown of PGC-1α attenuated the effects of empagliflozin on mitochondrial biogenesis, fatty acid utilization, energy metabolism, and cardiomyocyte apoptosis. Empagliflozin improves cardiac function and attenuates myocardial remodeling in ISO-induced HF rats. Its cardioprotective effects may involve PGC-1α-mediated mitochondrial biogenesis, which promotes fatty acid utilization and oxidation, improves energy metabolism, and reduces cardiomyocyte apoptosis. This study provides new experimental evidence for the cardioprotective mechanisms of empagliflozin.