Exercise Preconditioning Prevents Chemotherapy‐Induced Alterations to Transport Proteins Required for Mitochondrial Iron Uptake and Metabolism in the Diaphragm

Abstract

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. DOX‐induced ventilatory impairment is a debilitating condition that promotes the onset of dyspnea, fatigue and exercise intolerance. While the mechanisms responsible for DOX‐induced 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 chemotherapy‐induced diaphragm weakness and mitochondrial dysfunction. While the mechanisms for this protection remain elusive, evidence suggests that exercise may provide protection by attenuating DOX‐induced alterations to proteins required to maintain mitochondrial iron homeostasis. Cause and effect were determined by exposing Sprague‐Dawley rats to a two‐week treadmill preconditioning protocol (5 days/week; 60 min/day; 30 m/min). Twenty‐four 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 mitoferrin‐1 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 DOX‐induced increase in mitoferrin‐1, and also reduced mitoferrin‐2 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 DOX‐induced respiratory dysfunction, and demonstrate that exercise preconditioning may ameliorate DOX‐mediated diaphragm muscle pathology through the prevention of mitochondrial iron dysregulation.Support or Funding InformationThis work was supported by NIH R01 HL146443 awarded to AJS