Doxorubicin (DOX) is an effective chemotherapeutic treatment with lasting deleterious side effects in heart and skeletal muscle. As an increased percentage of patients live many years past their cancer treatments, addressing the long-term side effects of chemotherapy treatment becomes critical. In an attempt to prevent heart and skeletal muscle damage caused by DOX, two co-treatments, exercise (EX) or metformin (MET) were studied for their effectiveness in maintaining muscle function, mitochondrial respiration and iron regulation. DOX is known to bind with iron, contributing to oxidative damage resulting in cardiac and skeletal muscle toxicity. However, the degree to which the toxic side effects are due to iron dysregulation is poorly understood. To address this gap in understanding, the changes in proteins involved with iron regulation following DOX treatment with or without EX or MET was examined in liver, heart, and skeletal muscle. To study the effects of EX or MET on DOX muscle toxicity and the effect of DOX on iron regulation, C2C12 myotube cell culture and a mouse model were used. Results from this research suggest that the some of the toxic effects of DOX treatment can be reduced with EX or MET treatments. EX is effective at preventing an impairment in muscle relaxation, promoting positive iron regulation changes in the liver and blunting DOX-induced changes in iron regulation in muscle. MET partially prevents loss of mitochondrial respiration and promotes positive changes in iron regulation in the liver. Additionally, study of DOX on iron regulation in liver, heart, and skeletal muscle suggests that DOX promotes iron dysregulation. However, the cellular response is protective against excessive iron dysregulation and increased oxidative stress. This cellular response is at least partially dependent on NF-κB activation.

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Iron storage disease is a significant cause of liver disease and mortality in captive Egyptian fruit bats (Rousettus aegyptiacus). The nature of the susceptibility in this and other captive exotic species to iron storage disease is not clear. Hepcidin, a key iron regulatory hormone, is involved in the regulation of iron absorption in humans and other mammalian species and a deficiency in hepcidin has been associated with a number of genetic mutations resulting in hemochromatosis in humans. The objectives of this thesis were to identify whether there is a functional mutation in the hepcidin gene in the Egyptian fruit bat that may increase the susceptibility of this species to iron storage disease, and whether there is a functional deficiency in hepcidin gene expression in the Egyptian fruit bat in response to iron challenge. We compared the coding region of the hepcidin gene amongst several species of bats and investigated hepcidin response to intramuscular injection of iron dextran amongst three species of bats with variable susceptibility to iron storage disease; the Egyptian fruit bat, the straw-colored fruit bat (Eidolon helvum), and the common vampire bat (Desmodus rotundus). While a number of genetic differences were identified amongst species, a functional mutation that could result in decreased hepcidin activity was not identified in the Egyptian fruit bat. Bats exhibited marked variation in hepcidin gene expression, with the highest level of hepcidin response to iron challenge in the common vampire bat. While the Egyptian fruit bat exhibited significant hepcidin response to iron challenge, the magnitude of response was lower than that in the common vampire bat and lower than expected based on findings in healthy humans. The straw-colored fruit bat did not exhibit any hepcidin response despite a significant increase in iron stores, which suggests this species may have evolved an alternate mechanism for coping with excessive iron or may be more susceptible to iron overload than previously recognized. / Toronto Zoo Scholarship Fund