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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.
This article was published in the following journal.
Name: American journal of physiology. Endocrinology and metabolism
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Iron or iron compounds used in foods or as food. Dietary iron is important in oxygen transport and the synthesis of the iron-porphyrin proteins hemoglobin, myoglobin, cytochromes, and cytochrome oxidase. Insufficient amounts of dietary iron can lead to iron-deficiency anemia.
Conditions in which there is a generalized increase in the iron stores of body tissues, particularly of liver and the MONONUCLEAR PHAGOCYTE SYSTEM, without demonstrable tissue damage. The name refers to the presence of stainable iron in the tissue in the form of hemosiderin.
The exercise capacity of an individual as measured by endurance (maximal exercise duration and/or maximal attained work load) during an EXERCISE TEST.
Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store IRON in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (APOFERRITINS) made of 24 subunits of various sequences depending on the species and tissue types.
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