Alcohol-Induced IGF-I Resistance Is Ameliorated in Mice Deficient for Mitochondrial Branched-Chain Aminotransferase
Alcohol-Induced IGF-I Resistance Is Ameliorated in Mice Deficient for Mitochondrial Branched-Chain Aminotransferase
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DOI：
10.3945/jn.109.120501
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发表时间：
2010-05-01
影响因子：
4.2
通讯作者：
Vary, Thomas C.
中科院分区：
文献类型：
--
作者：
Lang, Charles H.;Lynch, Christopher J.;Vary, Thomas C.
急性酒精中毒通过损害哺乳动物雷帕霉素靶蛋白（mTOR）降低骨骼肌蛋白质合成。在2项研究中，我们确定了支链氨基酸（BCAA）催化剂的抑制是否通过提高血浆BCAA浓度和/或通过改善对胰岛素样生长因子（IGF）-I的合成代谢反应来改善酒精对肌肉蛋白合成的抑制作用。在第一项研究中，使用了4组小鼠：野生型（WT）和线粒体支链氨基转移酶（BCATm）敲除（KO）小鼠，口服生理盐水或酒精（5 g/kg，1 h）。与WT对照组相比，KO小鼠的蛋白质合成更高，并且与真核起始因子（eIF）-4E结合蛋白-1（4 EBP 1）、eIF 4 E-eIF 4G结合和mTOR（raptor）结合的4 EBP 1-调节相关蛋白的磷酸化水平更高相关，但与mTOR-raptor结合无关。酒精降低WT小鼠的蛋白质合成，这种变化与4 EBP 1磷酸化、eIF 4 E-eIF 4G结合和raptor-4 EBP 1结合减少有关，但与mTOR-raptor复合物形成增加有关。在BCATm KO小鼠中检测到酒精对蛋白质合成和信号转导的类似影响。第二项研究使用相同的4组，但所有小鼠均注射IGF-I（25 μ g/小鼠，30分钟）。酒精损害IGF-I增加WT小鼠肌肉蛋白质合成、4 EBP 1和70千道尔顿核糖体蛋白S6激酶-1磷酸化、eIF 4 E-eIF 4G结合和4 EBP 1-raptor结合的能力。然而，在酒精处理的BCATm KO小鼠中，这种IGF-I抗性没有表现出来。这些数据表明，虽然血浆BCAA的持续升高不足以改善急性酒精中毒对肌肉蛋白质合成的分解代谢作用，但它确实改善了IGF-I的合成代谢作用。J.营养140：932-938，2010年。
Acute alcohol intoxication decreases skeletal muscle protein synthesis by impairing mammalian target of rapamycin (mTOR). In 2 studies, we determined whether inhibition of branched-chain amino acid (BCAA) catabolism ameliorates the inhibitory effect of alcohol on muscle protein synthesis by raising the plasma BCAA concentrations and/or by improving the anabolic response to insulin-like growth factor (IGF)-I. In the first study, 4 groups of mice were used: wild-type (WT) and mitochondrial branched-chain aminotransferase (BCATm) knockout (KO) mice orally administered saline or alcohol (5 g/kg, 1 h). Protein synthesis was greater in KO mice compared with WT controls and was associated with greater phosphorylation of eukaryotic initiation factor (eIF)-4E binding protein-1 (4EBP1), eIF4E-eIF4G binding, and 4EBP1-regulatory associated protein of mTOR (raptor) binding, but not mTOR-raptor binding. Alcohol decreased protein synthesis in WT mice, a change associated with less 4EBP1 phosphorylation, eIF4E-eIF4G binding, and raptor-4EBP1 binding, but greater mTOR-raptor complex formation. Comparable alcohol effects on protein synthesis and signal transduction were detected in BCATm KO mice. The second study used the same 4 groups, but all mice were injected with IGF-I (25 mu g/mouse, 30 min). Alcohol impaired the ability of IGF-I to increase muscle protein synthesis, 4EBP1 and 70-kilodalto ribosomal protein S6 kinase-1 phosphorylation, eIF4E-eIF4G binding, and 4EBP1-raptor binding in WT mice. However, in alcohol-treated BCATm KO mice, this IGF-I resistance was not manifested. These data suggest that whereas the sustained elevation in plasma BCAA is not sufficient to ameliorate the catabolic effect of acute alcohol intoxication on muscle protein synthesis, it does improve the anabolic effect of IGF-I. J. Nutr. 140: 932-938, 2010.