Exercise Preconditioning Prevents ChemotherapyInduced Alterations to Transport Proteins Required for Mitochondrial Iron Uptake and Metabolism in the Diaphragm
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Doxorubicin (DOX) is an anthracycline antibiotic used in cancer treatment. Unfortunately, the clinical use of this highly efficacious anticancer drug is limited due to the development of respiratory and diaphragm muscle dysfunction in patients. DOXinduced ventilatory impairment is a debilitating condition that promotes the onset of dyspnea, fatigue and exercise intolerance. While the mechanisms responsible for DOXinduced respiratory insufficiency are unclear, it has been proposed that DOX myotoxicity develops as a result of increased cellular reactive oxygen species production and mitochondrial iron accumulation. Conversely, endurance exercise training performed prior to DOX administration has been shown to prevent the chemotherapyinduced diaphragm weakness and mitochondrial dysfunction. While the mechanisms for this protection remain elusive, evidence suggests that exercise may provide protection by attenuating DOXinduced alterations to proteins required to maintain mitochondrial iron homeostasis. Cause and effect were determined by exposing SpragueDawley rats to a twoweek treadmill preconditioning protocol (5 days/week; 60 min/day; 30 m/min). Twentyfour hours following the last exercise training period, animals received either saline or DOX (20mg/kg ip) treatment. Our results demonstrate that DOX administration in sedentary animals results in increased expression of the mitochondrial iron importer mitoferrin1 and a significant reduction in the cellular iron importer transferrin receptor 1 in the diaphragm. In addition, DOX also stimulated a significant decrease in the expression of sideroflexin 2 and SLC25A28, proteins required for mitochondrial heme biosynthesis. Importantly, exercise training prior to DOX administration prevented the DOXinduced increase in mitoferrin1, and also reduced mitoferrin2 below that of sedentary animals treated with DOX. Moreover, diaphragm expression of SLC25A38 was maintained in exercise trained animals receiving DOX. These findings confirm a role for mitochondrial iron accumulation and dysregulation of heme synthesis in the development of DOXinduced respiratory dysfunction, and demonstrate that exercise preconditioning may ameliorate DOXmediated diaphragm muscle pathology through the prevention of mitochondrial iron dysregulation.Support or Funding InformationThis work was supported by NIH R01 HL146443 awarded to AJS
