Lang Charles H, Frost Robert A, Deshpande Nobuko, Kumar Vinayshree, Vary Thomas C, Jefferson Leonard S, Kimball Scot R
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Am J Physiol Endocrinol Metab. 2003 Dec;285(6):E1205-15. doi: 10.1152/ajpendo.00177.2003. Epub 2003 Aug 26.
Acute alcohol (EtOH) intoxication impairs skeletal muscle protein synthesis. Although this impairment is not associated with a decrease in the total plasma amino acid concentration, EtOH may blunt the anabolic response to amino acids. To examine this hypothesis, rats were administered EtOH or saline (Sal) and 2.5 h thereafter were orally administered either leucine (Leu) or Sal. The gastrocnemius was removed 20 min later to assess protein synthesis and signaling components important in translational control of protein synthesis. Oral Leu increased muscle protein synthesis by the same magnitude in Sal- and EtOH-treated rats. However, the increase in the latter group was insufficient to overcome the suppressive effect of EtOH, and the rate of synthesis remained lower than that observed in rats from the Sal-Sal group. Leu markedly increased phosphorylation of Thr residues 36, 47, and 70 on 4E-binding protein (BP)1 in muscle from rats not receiving EtOH, and this response was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4E. 4E-BP1 to the active eIF4E. eIF4G complex. In EtOH-treated rats, the Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E availability were partially abrogated. EtOH also prevented the Leu-induced increase in phosphorylation of eIF4G, the serine/threonine protein kinase S6K1, and the ribosomal protein S6. Moreover, EtOH attenuated the Leu-induced phosphorylation of the mammalian target of rapamycin (mTOR). The ability of EtOH to blunt the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin, insulin-like growth factor I, or Leu. Finally, although EtOH increased the plasma corticosterone concentration, inhibition of glucocorticoid action by RU-486 was unable to prevent EtOH-induced defects in the ability of Leu to stimulate 4E-BP1, S6K1, and mTOR phosphorylation. Hence, ethanol produces a leucine resistance in skeletal muscle, as evidenced by the impaired phosphorylation of 4E-BP1, eIF4G, S6K1, and mTOR, that is independent of elevations in endogenous glucocorticoids.
急性酒精（乙醇）中毒会损害骨骼肌蛋白质合成。尽管这种损害与血浆总氨基酸浓度的降低无关，但乙醇可能会减弱对氨基酸的合成代谢反应。为了验证这一假设，给大鼠给予乙醇或生理盐水（Sal），2.5小时后口服亮氨酸（Leu）或生理盐水。20分钟后取出腓肠肌，以评估蛋白质合成以及蛋白质合成翻译控制中重要的信号成分。口服亮氨酸使生理盐水处理组和乙醇处理组大鼠的肌肉蛋白质合成增加幅度相同。然而，后一组的增加幅度不足以克服乙醇的抑制作用，合成速率仍低于生理盐水-生理盐水组大鼠。亮氨酸显著增加未接受乙醇处理大鼠肌肉中4E结合蛋白（BP）1上苏氨酸残基36、47和70的磷酸化，这种反应与真核起始因子（eIF）4E从无活性的eIF4E·4E-BP1向活性的eIF4E·eIF4G复合物的重新分布有关。在乙醇处理的大鼠中，亮氨酸诱导的4E-BP1磷酸化及eIF4E可用性变化被部分消除。乙醇还阻止了亮氨酸诱导的eIF4G、丝氨酸/苏氨酸蛋白激酶S6K1和核糖体蛋白S6磷酸化增加。此外，乙醇减弱了亮氨酸诱导的雷帕霉素哺乳动物靶标（mTOR）磷酸化。乙醇减弱亮氨酸合成代谢作用的能力不能归因于胰岛素、胰岛素样生长因子I或亮氨酸血浆浓度的差异。最后，尽管乙醇增加了血浆皮质酮浓度，但用RU-486抑制糖皮质激素作用并不能预防乙醇诱导的亮氨酸刺激4E-BP1、S6K1和mTOR磷酸化能力的缺陷。因此，乙醇在骨骼肌中产生亮氨酸抵抗，表现为4E-BP1、eIF4G、S6K1和mTOR磷酸化受损，且这种抵抗与内源性糖皮质激素升高无关。
