Multi-Tissue Analysis of Exercise or Metformin on Doxorubicin-Induced Iron Dysregulation.

Doxorubicin (DOX) is an effective chemotherapeutic treatment with lasting side effects in heart and skeletal muscle. DOX is known to bind with iron, contributing to oxidative damage resulting in cardiac and skeletal muscle toxicity. However, major cellular changes to iron regulation in response to DOX are poorly understood in liver, heart and skeletal muscle. Additionally, two co-treatments, exercise (EX) or metformin (MET) were studied for their effectiveness in reducing DOX toxicity through ameliorating iron dysregulation and preventing oxidative stress. The purposes of this study were to (1) characterize the DOX induced changes of the major iron regulation pathway in liver, heart, and skeletal muscle and (2) to determine if EX or MET exert their benefits through minimizing DOX-induced iron dysregulation. Mice were assigned to receive saline or DOX (15 mg/kg) treatments, paired with either EX (5 days) or MET (500 mg/kg), and euthanized three days post DOX treatment. Results suggest that the cellular response to DOX is protective against oxidative stress through reducing iron availability. DOX increased iron storage capacity through elevated ferritin levels in liver, heart, and skeletal muscle. DOX reduced iron transport capacity through reduced transferrin receptor levels in heart and skeletal muscle. EX or MET co-treatments had protective effects in the liver through reduced transferrin receptor levels. At three days post DOX, oxidative stress was mild as shown through normal glutathione and lipid peroxidation levels. Together, these results suggest the cellular response to reduce iron availability in response to DOX treatment is sufficient to match oxidative stress.