Response of Subsarcolemmal and Intermyofibrillar Mitochondria to Exercise and Doxorubicin‐Induced Cardiotoxicity

Abstract

The chemotherapeutic agent doxorubicin (DOX) is highly effective at limiting cancer progression. However, systemic DOX treatment results in off‐target accumulation within cardiac mitochondria, which can cause aberrant signaling leading to dose‐dependent heart failure in cancer patients and survivors. Exercise has demonstrated preclinical and clinical efficacy in limiting the cardiotoxic effects of DOX by putatively improving mitochondrial quality and function, although this mechanism has not been fully explicated. Therefore, to further understand the molecular determinants of exercise‐mediated protection against DOX‐induced mitochondriopathy and cardiotoxicity we independently examined the cardiac subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial subpopulations. Female Sprague Dawley rats were divided (n=10/group) into 1) Sedentary‐Saline; 2) Sedentary‐DOX; 3) Exercise‐Saline; and 4) Exercise‐DOX groups. Exercise groups underwent 10 days of aerobic treadmill running (~70% VO2max, 1hr/day) with 2 days of rest after day 5. Twenty‐four hours following the last exercise bout animals received saline or DOX (20mg/kg IP) treatment. Dependent measures were evaluated 48 hours post treatment. To demonstrate that the exercise preconditioning protocol was sufficient to elicit cardiorespiratory adaptations, all groups performed an exercise tolerance test (ETT). The ETT revealed a significant increase in cardiorespiratory fitness in both exercise‐trained groups, regardless of saline or DOX treatment. In addition, evaluation of the myocardial performance index supported the premise that exercise preconditioning induces a cardioprotective phenotype against DOX toxicity. Further, analysis of the cardiac SS and IMF mitochondrial subfractions indicate that exercise preconditioning protects against DOX‐induced reactive oxygen species (ROS) emission in the SS fraction. Interestingly, IMF mitochondrial ROS emission was not affected by exercise or DOX treatment. In contrast, the IMF mitochondria respiratory control ratio (RCR) was significantly elevated in Exercise‐Saline animals compared to both sedentary groups, while no differences existed in the SS mitochondria. These findings indicate that 1) exercise preconditioning is a beneficial non‐pharmacological approach to improve cardiac outcomes following DOX treatment and that 2) cardiac mitochondrial subfractions are differentially affected by exercise and DOX treatment.