Cardiac and Mitochondrial Adaptations in Response to Aging and Doxorubicin in Rats Bred for Divergent Aerobic Capacities

Abstract

Doxorubicin (DOX) remains as one of the most widely prescribed and effective anticancer agents. A major limitation of the therapeutic effectiveness of the drug is the occurrence of irreversible, progressive, dose-dependent cardiotoxicity. Active aerobic running capacity has been shown to protect against DOX-induced cardiac dysfunction, but little is known of the protective effects of intrinsic non-trained aerobic capacity. We hypothesized that a low aerobic capacity running (LCR) phenotype will be more susceptible for cardiac mitochondrial dysfunction and decreased cardiac performance in response to doxorubicin stress, when compared to the high aerobic running capacity (HCR) animals. To test this hypothesis, cardiac function was assessed in rats specifically selected over 26 generations for their low (LCR) and high (HCR) intrinsic aerobic running capacity. HCR/LCR rats received a single doxorubicin (7.5mg/kg of body weight) intraperitoneal injection and cardiac performance was studied longitudinally through echocardiography. On the tenth day, the animal was sacrificed, cardiac mitochondria were isolated and mitochondrial function was assessed through respirometry studies. Our results indicated that animals with low inherent aerobic capacity were susceptible to doxorubicin insult as evidenced by an adaptive mitochondrial response, while the high aerobic capacity animals appeared to have been physiologically primed and therefore did not exhibit an adaptive compensatory response.