Exercise Preconditioning Activates AMPK-ACC Signaling and Attenuates Myocardial Ischemia/Reperfusion-Induced Ferroptosis.

Ferroptosis critically mediates myocardial ischemia/reperfusion (I/R) injury. Exercise training confers cardioprotection, but whether it protects against I/R-induced ferroptosis and the underlying mechanisms remain unclear. In this study, C57BL/6J mice underwent six weeks of treadmill exercise preconditioning (EP) before myocardial I/R induction. Cardiac function, oxidative stress, ferroptosis markers and the phosphorylation of AMPK and ACC were assessed. In vitro, H9C2 cells were subjected to hypoxia/reoxygenation (H/R), and pharmacological modulators were used to investigate the necessity of the AMPK-ACC signaling. Results showed that EP alleviated I/R-induced cardiac dysfunction, reduced oxidative stress and iron deposition, upregulated GPX4 and SLC7A11 expression, downregulated ACSL4 expression, and enhanced the phosphorylation of AMPK and ACC. In H9C2 cells, H/R reduced ACC phosphorylation and induced ferroptosis. AMPK inhibition exacerbated H/R-induced ferroptosis, whereas AMPK activation by AICAR was protective. Critically, blocking ACC enzymatic activity attenuated AICAR's effects. These findings indicate that EP attenuates I/R-induced ferroptosis and the AMPK-ACC signaling may contribute to this protective effect.