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Effects of short-term endurance exercise training on acute doxorubicin-induced FOXO transcription in cardiac and skeletal muscle.
MedLine Citation:
PMID:  24947024     Owner:  NLM     Status:  Publisher    
Doxorubicin (DOX) is a potent antitumor agent used in cancer treatment. Unfortunately, DOX can induce myopathy in cardiac and skeletal muscle, which limits its clinical use. Importantly, exercise training has been shown to protect against DOX-mediated cardiac and skeletal muscle myopathy. However, the mechanism(s) responsible for this exercise-induced muscle protection remain elusive. These experiments tested the hypothesis that short-term exercise training protects against acute DOX-induced muscle toxicity, in part, due to decreased Forkhead-box O (FOXO) transcription of atrophy genes. Rats (n=6 per group) were assigned to sedentary or endurance exercise trained groups and paired with either placebo or DOX treatment. Gene expression and protein abundance were measured in both cardiac and skeletal muscles to determine the impact of DOX and exercise on FOXO gene targets. Our data demonstrate that DOX administration amplified FOXO1 and FOXO3 mRNA expression and increased transcription of FOXO target genes (i.e., atrogin-1/MaFbx, MuRF-1, and BNIP3) in heart and soleus muscles. Importantly, exercise training protected against DOX-induced increases of FOXO1 and MuRF-1 in cardiac muscle and also prevented the rise of FOXO3, MuRF-1, and BNIP3 in soleus muscle. Furthermore, our results indicate that exercise increased peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) in both the heart and soleus muscles. This is important because increased PGC-1α expression is known to suppress FOXO activity resulting in reduced expression of FOXO target genes. Together, these results are consistent with the hypothesis that exercise training protects against DOX-induced myopathy in both heart (FOXO1 and MuRF-1) and skeletal muscles (FOXO3, MuRF-1, and BNIP3).
Andreas N Kavazis; Ashley J Smuder; Scott K Powers
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-6-19
Journal Detail:
Title:  Journal of applied physiology (Bethesda, Md. : 1985)     Volume:  -     ISSN:  1522-1601     ISO Abbreviation:  J. Appl. Physiol.     Publication Date:  2014 Jun 
Date Detail:
Created Date:  2014-6-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8502536     Medline TA:  J Appl Physiol (1985)     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014, Journal of Applied Physiology.
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