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

Rationale 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. Aging increases the risk of cancer, and the use of anticancer medications. 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, or whether the benefit persists into aging. Purpose These experiments were designed to test the hypothesis 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. Methods Cardiac function was assessed in rats specifically selected over 26 generations for their low (LCR) and high (HCR) intrinsic aerobic running capacity. 30 month old HCR/LCR rats received a single doxorubicin (DOX, 7.5mg/kg of body weight) intraperitoneal injection and cardiac performance was studied longitudinally (day 0, day 1, day 4, day 7, and day 10) using echocardiography. Ten days following injection, animals were sacrificed, cardiac mitochondria were isolated and mitochondrial function was assessed through respirometry studies (O2K). Results At this age, HCR animals tended to operate with higher end diastolic volumes, end systolic volumes, stroke volumes, cardiac outputs, but heart rates and ejection fractions were essentially identical, and there were no statistical differences overall under control conditions between HCR and LCR animals. Cardiac volumes tended to increase in the LCRs after DOX, but not in the HCRs. Initial responses HR responses to DOX were significantly different and divergent; tachycardic in HCRs (355 ± 15 vs 412 ± 33, day 0 vs Day 4, p < 0.001), but bradycardic in LCRs (321 ± 14 vs 278 ± 37, p < 0.001). Cardiac output followed the same pattern as heart rate, while ejections fractions were consistently decreased in HCRS at all time points following DOX, but maintained in LCRs. In control animals, isolated mitochondrial oxygen consumption were consistent with those reported in isolated fibers from young rat, and there were no differences between the phenotypes, suggesting that there was no age dependent decrement in cardiac mitochondrial function, and no impact of phenotype on that outcome. DOX caused a significant increase in the oxygen consumption by glutamate malate/ADP/succinate stimulated mitochondria isolated from LCRs but not HCR. DOX did not produce phenotype specific differences in mitochondrial oxygen consumption when stimulated with fatty acid. Summary Age tended to normalize resting control differences in cardiac function between HCRs and LCRs, but exposure to DOX was associated with divergent, phenotypic dependent responses despite aging.