Exercise Training Prevents Doxorubicin-induced Mitochondrial Dysfunction of the Liver

PURPOSE Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of a broad spectrum of cancers. However, clinical use of DOX is limited by irreversible and dose-dependent hepatotoxicity. The liver is the primary organ responsible for the clearance of antineoplastic agents, and evidence indicates that hepatotoxicity occurs as a result of impaired mitochondrial efficiency during DOX metabolism. In this regard, exercise training is sufficient to improve mitochondrial function and protect against DOX-induced cytotoxicity. Therefore, the purpose of this study was to determine if short-term exercise preconditioning is sufficient to protect against DOX-induced liver mitochondrionopathy. METHODS Female Sprague-Dawley rats (4-6 months old) were randomly assigned to one of four groups: 1) sedentary, treated with saline; 2) sedentary, treated with DOX; 3) exercise trained, treated with saline; 4) exercise trained, treated with DOX. Exercise trained animals underwent 5 days of treadmill running habituation followed by 10 days of running for 60 min/day (30 m/min; 0% grade). Following the last training bout, exercise-trained and sedentary animals were injected with either DOX (20 mg/kg; i.p.) or saline. Two days following drug treatment the liver was removed and mitochondria were isolated. RESULTS DOX treatment induced mitochondrial dysfunction of the liver in sedentary animals, due to alterations in mitochondrial oxidative capacity, biogenesis, degradation, and protein acetylation. Furthermore, exercise preconditioning protected against DOX-mediated liver mitochondrionopathy, which was associated with maintenance of mitochondrial oxidative capacity and protein acetylation. CONCLUSION These findings demonstrate that endurance exercise training protects against DOX-induced liver mitochondrial dysfunction, which was attributed to modifications in organelle oxidative capacity and mitochondrial protein acetylation. Corresponding author: Ashley J. Smuder, Department of Exercise Science, University of South Carolina, Public Health Research Center, Room 227, 921 Assembly Street, Columbia, SC 29208. Email: smuder@mailbox.sc.edu J. Matthew Hinkley Present Address: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ABM was supported by NIH T32 HD043730. CONFLICT OF INTEREST: No conflicts of interest, financial or otherwise, are declared by the authors. The results of the present study do not constitute endorsement by ACSM, and are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for publication: 30 December 2018. © 2019 American College of Sports Medicine

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