Abstract

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-ÎºB activation.

Degree

PhD

College and Department

Life Sciences; Physiology and Developmental Biology