Endotoxin disrupts the leucine-signaling pathway involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle
Endotoxin disrupts the leucine-signaling pathway involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle
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DOI：
10.1002/jcp.20207
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发表时间：
2005-04-01
影响因子：
5.6
通讯作者：
Frost, RA
中科院分区：
文献类型：
--
作者：
Lang, CH;Frost, RA
内毒素（即，脂多糖，LPS）损害骨骼肌蛋白质合成。虽然这种损伤与血浆总氨基酸浓度的降低并不急性相关，但LPS可能会减弱对氨基酸的合成代谢反应。为了检验这一假设，大鼠腹腔注射LPS或盐水（Sal），4小时后口服亮氨酸（Leu）或Sal。20分钟后取出腓肠肌，以评估在蛋白质合成的翻译控制中重要的信号传导组分。在Sal-Leu组中，肌肉中4 E-BP 1的磷酸化显著增加，与时间匹配的盐水处理对照大鼠的值相比。这种变化与真核起始因子（eIF）4 E从失活的eIF 4F（.）4 E-BPI复合物与活性eIF 4F（.）eIF 4G复合物。在LPS处理的大鼠中，Leu诱导的4 E-BPI磷酸化和eIF 4 E分布的变化被部分或完全消除。LPS还拮抗Leu诱导的S6 K1、核糖体蛋白S6和mTOR磷酸化的增加。LPS和亮氨酸均不改变肌肉中TSC 2的总量或磷酸化。LPS减弱Leu合成代谢作用的能力不能归因于组间胰岛素或Leu血浆浓度的差异。此外，在LPS处理的大鼠中，将血浆胰岛素样生长因子（IGF）-1替换至基础水平也没有改善亮氨酸诱导的S6 K1或S6磷酸化的缺陷，尽管它确实逆转了LPS诱导的mTOR、S6和4 E-BP 1组成性磷酸化的降低。糖皮质激素受体拮抗剂RU 486预处理不能阻止LPS诱导的亮氨酸抵抗。相反，与上述使用亮氨酸的结果相比，LPS没有阻止药理学水平的IGF-1磷酸化4 E-BPI、S6 K1、mTOR的能力或改变eIF 4 E的可用性。因此，LPS通过糖皮质激素非依赖性机制起作用，在骨骼肌中产生亮氨酸抗性，这可能预期会损害这种氨基酸刺激翻译起始和蛋白质合成的能力。(C)2004 Wiley-Liss，Inc.
Endotoxin (i.e., lipopolysaccharide, LPS) impairs skeletal muscle protein synthesis. Although this impairment is not acutely associated with a decreased plasma concentration of total amino acids, LPS may blunt the anabolic response to amino acids. To examine this hypothesis, rats were injected intraperitoneally with LPS or saline (Sal) and 4 h thereafter were orally administered either leucine (Leu) or Sal. The gastrocnemius was removed 20 min later to assess signaling components important in the translational control of protein synthesis. In the Sal-Leu group phosphorylation of 4E-BP1 in muscle was markedly increased, compared to values from time-matched saline-treated control rats. This change was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4F (.) 4E-BPI complex to the active eIF4F (.) eIF4G complex. In LPS-treated rats, the Leu-induced phosphorylation of 4E-BPI and changes in elF4E distribution were partially or completely abrogated. LPS also antagonized the Leu-induced increase in phosphorylation of S6K1, ribosomal protein S6 and mTOR. Neither LPS nor leu altered the total amount or phosphorylation of TSC2 in muscle. The ability of LPS to blunt the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin or Leu between groups. Furthermore, the replacement of plasma insulin-like growth factor (IGF)-1 in LPS-treated rats to basal levels also did not ameliorate the defect in leucine-induced phosphorylation of S6K1 or S6, although it did reverse the LPS-induced decrease in the constitutive phosphorylation of mTOR, S6 and 4E-BP1. Pretreatment with the glucocorticoid receptor antagonist RU486 was unable to prevent the LPS-induced leucine resistance. In contrast, to the abovementioned results with leucine, LPS did not prevent the ability of pharmacological levels of IGF-1 to phosphorylate 4E-BPI, S6K1, mTOR or alter the availability of eIF4E. Hence, LPS working via a glucocorticoid-independent mechanism produces a leucine resistance in skeletal muscle that might be expected to impair the ability of this amino acid to stimulate translation intiation and protein synthesis. (C) 2004 Wiley-Liss, Inc.