Exercise Training Prevents Doxorubicin-induced Mitochondrial Dysfunction of the Liver

PURPOSEDoxorubicin (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...

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Bibliographic Details
Published in:Medicine and science in sports and exercise 2019-06, Vol.51 (6), p.1106-1115
Main Authors: HINKLEY, J MATTHEW, MORTON, AARON B, ICHINOSEKI-SEKINE, NORIKO, HUERTAS, ANDRES MOR, SMUDER, ASHLEY J
Format: Article
Language:English
Subjects:
Acetylation
Animals
Antibiotics, Antineoplastic - toxicity
Doxorubicin - toxicity
Female
Mitochondria, Liver - drug effects
Mitochondria, Liver - physiology
Mitochondrial Proteins - metabolism
Mitophagy - physiology
Organelle Biogenesis
Oxidative Stress - physiology
Physical Conditioning, Animal
Random Allocation
Rats, Sprague-Dawley
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Summary:PURPOSEDoxorubicin (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. METHODSFemale Sprague–Dawley rats (4–6 months old) were randomly assigned to one of four groups1) 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. RESULTSDOX 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. CONCLUSIONThese 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.
ISSN:0195-9131
1530-0315
DOI:10.1249/MSS.0000000000001887