FGF21/sirtuin 1 axis mediates the cardioprotective effects of high‐intensity interval training against doxorubicin‐induced cardiotoxicity by reducing inflammatory and oxidative stress

Abstract

Doxorubicin (DOX) is a potent anthracycline chemotherapeutic agent, but its clinical use is limited by cumulative cardiotoxicity. Exercise, particularly high‐intensity interval training (HIIT), has emerged as an effective non‐pharmacological strategy to counteract chemotherapy‐induced cardiac injury. However, the molecular mechanisms underlying the cardioprotective effects of HIIT remain unclear. This study aimed to determine whether HIIT attenuates DOX‐induced cardiotoxicity via activation of the fibroblast growth factor 21 (FGF21)/sirtuin 1 (SIRT1) signalling pathway in rats. Thirty‐three male Wistar rats (200–250 g) were randomly assigned to three groups ( n  = 11 each): control (CONTROL), DOX‐treated sedentary (DOX‐Sed) and DOX‐treated HIIT (DOX‐HIIT). DOX‐induced cardiotoxicity was induced by intraperitoneal DOX injections (12 mg/kg cumulative dose over 12 days). After confirmation of cardiac dysfunction by echocardiography, the DOX‐HIIT group completed an 8 week treadmill HIIT programme (three sessions per week, five intervals of 4 min at 85%–90% of maximal O ₂ uptake separated by 2 min at 50%–60% of maximal O ₂ uptake). Cardiac function, oxidative stress markers, inflammatory cytokines, plasma levels of FGF21 and protein expression of FGFR1 and the SIRT1/AMPK/Nrf2 pathway were assessed. HIIT improved survival (81.8% vs. 63.6% in DOX‐Sed), prevented weight loss and ameliorated left ventricular systolic dysfunction, as evidenced by increased ejection fraction and fractional shortening ( P  < 0.05). HIIT reduced cardiac interleukin‐6, tumor necrosis factor‐α, interleukin‐1β and malondialdehyde levels while elevating antioxidant enzyme activities. Mechanistically, HIIT increased plasma FGF21 and phosphorylated FGFR1 and upregulated SIRT1, LKB1 and phosphorylated AMPK, leading to activation of the Nrf2/HO‐1 antioxidant pathway. Therefore, HIIT‐induced FGF21 has a potential therapeutic effect on cardiac function in DOX‐induced cardiotoxicity through activation of the FGF21/SIRT1/LKB1/AMPK/Nrf2/HO‐1 signalling pathway.