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 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 min·d (30 m·min; 0% grade). After the last training bout, exercise-trained and sedentary animals were injected with either DOX (20 mg·kg 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.