Exercise Training Prevents Doxorubicin-induced Mitochondrial Dysfunction of the Liver.
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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 whether 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; and 4) exercise trained, treated with DOX. Exercise-trained animals underwent 5 d of treadmill running habituation followed by 10 d of running for 60 mind (30 mmin; 0% grade). After the last training bout, exercise-trained and sedentary animals were injected with either DOX (20 mgkg i.p.) or saline. Two days after drug treatment, the liver was removed and mitochondria were isolated. RESULTS: DOX treatment induced mitochondrial dysfunction of the liver in sedentary animals because of alterations in mitochondrial oxidative capacity, biogenesis, degradation, and protein acetylation. Furthermore, exercise preconditioning protected against DOX-mediated liver mitochondrionopathy, which was associated with the 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.
