Abstract
BACKGROUND: Doxorubicin (Dox) is one of the most effective chemotherapy agents used to treat adolescent and young adult sarcoma patients. Unfortunately, Dox causes cardiotoxicities that compromise long-term survival. We investigated whether exercise prevented cardiotoxicity and increased survival following myocardial infarction. METHODS: Juvenile mice received Dox, Dox + exercise (Exer), Dox then exercise or were exercised during and after Dox. Mice were evaluated by echocardiography and histology immediately after therapy and 12 weeks later. Mice subjected to permanent ligation of the left anterior descending artery 90 days after therapy were assessed for survival at 45 and 100 days. RESULTS: Mice treated with Dox, but not Dox + Exer, had decreased ejection fraction (EF) and fractional shortening (FS) immediately after Dox therapy, which continued to deteriorate over 12 weeks with the development of diastolic failure and fibrosis. Acute Dox-induced cardiotoxicity was documented by induction of autophagy and abnormal mitochondria and vascular architecture with decreased pericytes. These abnormalities persisted 12 weeks after therapy. These acute and late changes were not seen in the Dox + Exer group. Initiating exercise after Dox therapy promoted recovery of EF and FS with no functional or histologic evidence of Dox-induced damage 12 weeks after therapy. Survival rates at 100 days after MI were 67% for control mice, 22% for mice that received Dox alone, and 56% for mice that received Dox + Exer. CONCLUSIONS: Exercise inhibited both early and late Dox-induced cardiotoxicity and increased recovery from an ischemic event. Exercise interventions have the potential to decrease Dox-induced cardiac morbidity.