BACKGROUND The clinical use of the highly effective chemotherapeutic agent doxorubicin (DOX) is limited by its dose-dependent cardiotoxicity. This cardiotoxicity is associated with a cardiac myosin heavy chain (MHC) isoform shift from the alpha isoform to the beta isoform. Exercise prior to DOX treatment has been shown to attenuate the MHC shift associated with DOX, but little is known about the cardioprotective nature of exercise during DOX treatment. METHODS DOX-treated rats were assigned to normal cage activity (sedentary, SED+DOX) or 24-hour voluntary wheel running access (WR+DOX). All animals received weekly 2.5 mg/kg DOX injections for 6 weeks (15 mg/kg cumulative) and hearts were subsequently excised for determination of MHC isoform expression using sodium dodecyl sulfate polyacrylamide gel electrophoresis. RESULTS At baseline, WR+DOX rats on average ran 62+/-4 km, and at week 6 ran 30+/-5 km, which was significantly lower than baseline (p<0.05). SED+DOX hearts expressed 57+/-7% of MHC as the alpha-MHC isoform and 43+/-7% as the beta-MHC isoform. WR+DOX hearts expressed 76+/-4% as the alpha-MHC and 24+/-4% as the beta-MHC isoform, which was significantly different from that of SED+DOX (p<0.05). CONCLUSIONS DOX treatment significantly reduced wheel running activity, but this reduced running distance deemed to be cardioprotective as hearts from WR+DOX rats contained significantly greater levels of the favorable alpha-MHC isoform than SED+DOX.