Endurance Exercise Attenuates Doxorubicin-induced Cardiotoxicity

Purpose Endurance exercise (EXE) preconditioning before DOX treatment confers cardioprotection; however, whether EXE postconditioning (i.e., EXE intervention after the completion of DOX treatment) is cardioprotective remains unknown. Thus, the aim of the present study was to investigate if EXE postconditioning provides cardioprotection by testing the hypothesis that EXE-autophagy upregulation and NADPH oxidase 2 (NOX2) downregulation would be linked to cardioprotection against DOX-induced cardiotoxicity. Methods C57BL/6 male mice were assigned into three groups: control (CON, n = 10), doxorubicin (DOX, n = 10), and doxorubicin + endurance exercise (DOX + EXE, n = 10). Animals assigned to DOX and DOX + EXE groups were intraperitoneally injected with DOX (5 mg center dot kg(-1) each week for 4 wk). Forty-eight hours after the last DOX treatment, the mice assigned to DOX + EXE performed EXE on a motorized treadmill at a speed of 13-15 m center dot min(-1) for 60 min center dot d(-1) for 4 wk. Results EXE prevented DOX-induced apoptosis and mitigated tissue damages. Although DOX did not modulate auto/mitophagy, EXE significantly enhanced its flux (increased LC3-II levels, reduced p62 levels, and increased autophagosomes with mitochondria) along with increased mitochondrial fission (DRP1) and reduced fusion markers (OPA1 and MFN2). Interestingly, EXE-induced autophagy against DOX occurred in the absence of alterations of autophagy inducer AMPK or autophagy inhibitor mTOR signaling. EXE prohibited DOX-induced oxidative damages by suppressing NOX2 levels but without modulating other key antioxidant enzymes including MnSOD, CuZnSOD, catalase, and GPX1/2. Conclusion Our data provide novel findings that EXE-induced auto/mitophagy promotion and NOX2 downregulation are linked to cardioprotection against DOX-induced cardiotoxicity. Importantly, our study shows that EXE postconditioning intervention is effective and efficacious to prevent DOX-induced cardiac injuries.