Because doxorubicin (DOX)-containing chemotherapy causes left ventricular (LV) dysfunction and remodeling that can progress to heart failure, strategies to alleviate DOX cardiotoxicity are necessary to improve health outcomes of patients surviving cancer. Although clinical evidence suggests that aerobic exercise training (ET) can prevent cardiotoxicity in patients undergoing DOX chemotherapy, the physiological mechanisms involved have not been extensively studied, nor is it known whether compounds [such as resveratrol (RESV)] have similar beneficial effects. With the use of a murine model of chronic DOX exposure, this study compared the efficacy of modest ET to RESV treatment on exercise performance, LV remodeling, and oxidative stress resistance. Mice were divided into four groups that received saline, DOX (8 mg/kg ip, one time per week), DOX + RESV (4 g/kg diet, ad libitum), and DOX + ET (45 min of treadmill exercise, 5 days/wk) for 8 wk. LV function and morphology were evaluated by in vivo echocardiography. DOX caused adverse LV remodeling that was partially attenuated by modest ET and completely prevented by RESV. These effects were paralleled by improvements in exercise performance. The cardioprotective properties of ET and RESV were associated with reduced levels of atrial natriuretic peptide and the lipid peroxidation by-product, 4-hydroxy-2-nonenal. In addition, ET and RESV increased the expression of cardiac sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a, superoxide dismutase, mitochondrial electron transport chain complexes, and mitofusin-1 and -2 in mice administered DOX. Compared with modest ET, RESV more effectively prevented DOX-induced LV remodeling and was associated with the reduction of DOX-induced oxidative stress. Our findings have important implications for protecting patients against DOX-associated cardiac injury.
Keywords: cardiotoxicity; exercise; oxidative stress; resveratrol.