Exercise training inhibits myocardial ischemia-reperfusion-induced ferroptosis via AMPK- dependent ACC phosphorylation

Ferroptosis is critical in the pathogenesis of myocardial ischemia-reperfusion (I/R) injury. Exercise training (ET) protects against myocardial I/R injury, but its impact on ferroptosis and the mechanisms remain incompletely understood. This study explored whether AMP-activated protein kinase (AMPK)-regulated acetyl-CoA carboxylase (ACC) mediates ET-induced cardioprotection by suppressing ferroptosis in I/R mice. 3-month-old male C57BL/6J mice were divided into sedentary and ET groups. Mice in the ET group underwent six weeks of treadmill training before myocardial I/R induction. Cardiac function, oxidative stress, ferroptosis-related proteins expression were measured. H9C2 cardiomyocytes were exposed to hypoxia/reoxygenation (H/R) to simulate I/R. AMPK activity was modulated and ACC phosphorylation was blocked to explore the mechanism. In I/R mice, ET improved cardiac function, activated AMPKα, increased ACC phosphorylation, upregulated the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and downregulated acyl-CoA synthetase long chain family member 4 (ACSL4) expression. In vitro , H/R induced oxidative stress, reduced ACC phosphorylation and the expression of SLC7A11 and GPX4, and upregulated ACSL4 expression. AMPK inhibition reduced ACC phosphorylation, worsened H/R-induced oxidative stress and ferroptosis, while AMPK activation reversed these effects. Blocking ACC phosphorylation abolished the protective effects of AMPK activation and exacerbated H/R-induced ferroptosis. In conclusion, ET reduces I/R-induced ferroptosis, and AMPK-mediated ACC phosphorylation plays an important role in this process.