Effect of High Intensity Exercise Preconditioning and Training on Antioxidant Enzymes in Cardiomyocytes During Doxorubicin Treatment

Abstract

Doxorubicin (DOX) is a common chemotherapeutic treatment for breast cancer and has been proven to reduce recurrence and mortality. However, a well‐recognized side effect is DOX‐induced cardiac toxicity. This is typically thought to occur due to increased generation of reactive oxygen species (ROS) and oxidative damage within cardiomyocytes. Exercise training has been shown to increase expression of several key intracellular antioxidant enzymes. The purpose of this study was to examine the potential for high‐intensity interval exercise (HIIE) initiated prior to (i.e. preconditioning) and continued throughout (i.e. training) bi‐weekly DOX treatments to preserve antioxidant levels in cardiomyocytes. We hypothesized that DOX treatment would reduce the antioxidant enzymes, Cu‐Zn superoxide dismutase (SOD1), Mn SOD (SOD2) and catalase (CAT) in cardiac tissue whereas exercise would attenuate this response. Eight‐week old female ovariectomized Sprague Dawley rats (N=25) were randomized to one of the four treatments: Exercise+DOX (n=7; Ex‐DOX); Ex+Vehicle (n=6; Ex‐veh); Sedentary+DOX (n=6; Sed‐DOX); and Sed+veh (n=6; Sed‐veh). Dox (4mg/kg) or vehicle (saline) intraperitoneal injections were performed bi‐weekly for a total of 3 injections (cumulative dose 12mg/kg). HIIE consisted of 4×4 min bouts of treadmill exercise at 85–95% of VO2peak separated by 2 min of active recovery. One week prior to the first injection, exercise animals underwent training for 5 days and continued throughout the study duration. Animals were euthanized 5 days following the last injection, following which the heart was extracted and left ventricular tissue was prepared for western blot analyses. Levels of SOD1 (p=0.078) and SOD2 (p=0.052) tended to be higher in hearts from exercising rats, independent of treatment. However, DOX administration for both Ex‐DOX and Sed‐DOX groups had significantly higher CAT levels (p<0.001). These preliminary analyses suggest that exercise preconditioning and training prior to and during DOX administration may raise SOD1 and SOD2 levels in cardiac tissue, whereas DOX administration elevates CAT levels regardless of exercise.