Exercise Preconditioning Protects against Doxorubicin-Induced Cardiac Dysfunction

Abstract

The clinical use of the chemotherapeutic drug doxorubicin (DOX) is limited due to a dose-dependent cardiotoxicity. Evidence is mounting that exercise protects against DOX-related cardiac dysfunction, and as such, it may be possible that prior endurance training promotes defense against DOX cardiotoxicity. To examine the effects of exercise preconditioning on acute DOX-induced cardiotoxicity, and to determine whether any observed cardioprotection was associated with myosin heavy chain (MHC) isoform alterations. Male Sprague-Dawley rats trained on a motorized treadmill, had access to voluntary running wheels, or remained sedentary for 10 wk prior to being injected with either saline or 10 mg.kg(-1) DOX. Left ventricular function was then assessed in vivo using transthoracic echocardiography and ex vivo using the isolated working heart at 5 and 10 d after injection. Additionally, left ventricular MHC isoform expression was analyzed as a possible mechanism to explain exercise-induced cardioprotection. DOX treatment promoted significant in vivo and ex vivo cardiac dysfunction at 5 and 10 d after injection in sedentary animals, and this dysfunction was associated with an upregulation of the beta-MHC isoform. Exercise preconditioning protected against DOX-induced cardiac dysfunction at 5 and 10 d after injection by attenuating beta-MHC upregulation. Endurance training prior to DOX treatment protects against acute DOX cardiotoxicity for up to 10 d, and this protection can potentially be explained by a preservation of MHC isoform distribution.