Voluntary exercise attenuates DOX cardiotoxicity VOLUNTARY EXERCISE PROTECTS AGAINST ACUTE DOXORUBICIN CARDIOTOXICITY IN THE ISOLATED PERFUSED RAT HEART

The clinical use of doxorubicin (DOX) is limited by a dose-dependent cardiotoxicity. The purpose of this study was to determine whether voluntary exercise training would confer protection against DOX cardiotoxicity in the isolated perfused rat heart. Female Sprague-Dawley rats were randomly assigned to standard holding cages (SED) or cages with running wheels (VEX) for 8 weeks. Twenty-four hours following the sedentary or voluntary running period, rats were anesthetized with sodium pentobarbital and hearts were isolated and perfused with oxygenated Krebs-Henseleit (KH) buffer at a constant flow of 15 ml⋅min. Following a 20-min stabilization period, hearts were paced at 300 bpm and perfused with KH buffer containing 10 μM DOX for 60 min. A set of control hearts from SED and VEX rats were perfused under identical conditions without DOX for the same period. DOX perfusion led to significant decreases in left ventricular (LV) developed pressure, +dP/dt, and -dP/dt, and significant increases in LV lipid peroxidation in sedentary rats compared to non-DOX controls (P < 0.05). Prior voluntary exercise training attenuated these DOX-induced effects, and was associated with a significant increase (78%, P < 0.05) in heat shock protein (HSP72), but not MnSOD or CuZnSOD protein expression in the hearts of wheel run animals. These data indicate that chronic physical activity may provide resistance against the cardiac dysfunction and oxidative damage associated with DOX exposure, and provide novel evidence of HSP72 induction in the heart following voluntary exercise.