Chronic Alcohol Consumption Enhances Skeletal Muscle Wasting in Mice Bearing Cachectic Cancers: The Role of TNFα/Myostatin Axis
Chronic Alcohol Consumption Enhances Skeletal Muscle Wasting in Mice Bearing Cachectic Cancers: The Role of TNFα/Myostatin Axis
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DOI：
10.1111/acer.14221
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发表时间：
2019-11-11
影响因子：
3.2
通讯作者：
Zhang, Hui
中科院分区：
文献类型：
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作者：
Li, Yuanfei;Zhang, Faya;Zhang, Hui
背景：长期饮酒会增加癌症相关的恶病质，这是降低生存率的主要原因之一。饮酒如何增强癌症相关恶病质，特别是骨骼肌损失的确切分子机制仍有待阐明。方法采用慢性酒精消耗小鼠模型，其中20% （w/v）酒精作为唯一饮用液，并与Lewis肺癌一起研究其潜在机制。结果我们发现，酒精摄入上调骨骼肌中MAFbx、MuRF-1和LC3的表达，表明酒精增强了泛素介导的蛋白水解和LC3介导的自噬。饮酒增强了Smad2/3、p38和ERK的磷酸化，降低了FOXO1的磷酸化。这些是控制蛋白质降解途径的信号分子。此外，酒精摄入可轻微上调胰岛素受体底物-1的表达，不影响磷脂酰肌醇-3激酶，但可降低Akt和哺乳动物雷帕霉素靶蛋白（mTOR）的磷酸化，下调Raptor和p70核糖体激酶S6激酶的表达，提示酒精损害荷瘤小鼠骨骼肌蛋白合成信号通路。饮酒增强了骨骼肌、血浆和肿瘤中肌生长抑制素的表达，但不影响非荷瘤小鼠肌生长抑制素的表达。在TNF α敲除小鼠中，酒精增强肌肉生长抑制素和蛋白质降解相关信号分子的表达以及骨骼肌中蛋白质合成信号的减少的影响被消除。因此，饮酒既不影响癌症相关的恶病质，也不降低患有恶病质癌的TNF α KO小鼠的存活率。结论慢性饮酒通过抑制Akt/ mtor介导的蛋白质合成途径和增强蛋白质降解途径，促进癌症相关骨骼肌损失。这一过程由TNF α启动，并由肌生长抑制素介导。
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.