Journal
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
Volume 44, Issue 1, Pages 66-77Publisher
WILEY
DOI: 10.1111/acer.14221
Keywords
Alcohol; Cancer-Associated Cachexia; Skeletal Muscle; Myostatin; TNF alpha
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Funding
- NIH [AA024284]
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Background Chronic alcohol consumption enhances cancer-associated cachexia, which is one of the major causes of decreased survival. The precise molecular mechanism of how alcohol consumption enhances cancer-associated cachexia, especially skeletal muscle loss, remains to be elucidated. Methods We used a mouse model of chronic alcohol consumption, in which 20% (w/v) alcohol was provided as sole drinking fluid, and Lewis lung carcinoma to study the underlying mechanisms. Results We found that alcohol consumption up-regulated the expression of MAFbx, MuRF-1, and LC3 in skeletal muscle, suggesting that alcohol enhanced ubiquitin-mediated proteolysis and LC3-mediated autophagy. Alcohol consumption enhanced phosphorylation of Smad2/3, p38, and ERK and decreased the phosphorylation of FOXO1. These are the signaling molecules governing protein degradation pathways. Moreover, alcohol consumption slightly up-regulated the expression of insulin receptor substrate-1, did not affect phosphatidylinositol-3 kinase, but decreased the phosphorylation of Akt and mammalian target of rapamycin (mTOR), and down-regulated the expression of Raptor and p70 ribosomal kinase S6 kinase, suggesting that alcohol impaired protein synthesis signaling pathway in skeletal muscle of tumor-bearing mice. Alcohol consumption enhanced the expression of myostatin in skeletal muscle, plasma, and tumor, but did not affect the expression of myostatin in non-tumor-bearing mice. In TNF alpha knockout mice, the effects of alcohol-enhanced expression of myostatin and protein degradation-related signaling molecules, and decreased protein synthesis signaling in skeletal muscle were abolished. Consequently, alcohol consumption neither affected cancer-associated cachexia nor decreased the survival of TNF alpha KO mice bearing cachectic cancer. Conclusions Chronic alcohol consumption enhances cancer-associated skeletal muscle loss through suppressing Akt/mTOR-mediated protein synthesis pathway and enhancing protein degradation pathways. This process is initiated by TNF alpha and mediated by myostatin.
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