Insulin fails to stimulate muscle protein synthesis in sepsis despite unimpaired signaling to 4E-BP1 and S6K1.
Insulin fails to stimulate muscle protein synthesis in sepsis despite unimpaired signaling to 4E-BP1 and S6K1.
复制标题
尽管 4E-BP1 和 S6K1 信号传导未受损，但胰岛素无法刺激脓毒症中的肌肉蛋白合成。
DOI：
10.1152/ajpendo.2001.281.5.e1045
复制
发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Kimball,SR
中科院分区：
文献类型：
--
作者：
Vary,TC;Jefferson,LS;Kimball,SR
大鼠脓毒症的诱导引起对胰岛素刺激作用有抵抗力的骨骼肌中蛋白质合成的抑制。为了更好地了解这种缺乏反应的潜在原因，本研究旨在研究脓毒症诱导的胰岛素信号对mRNA翻译调节成分的改变。实验在脓毒性脓肿诱导后5天的大鼠后肢灌注制剂中进行。脓毒症导致腓肠肌蛋白质合成减少50%。脓毒症大鼠肌肉中的蛋白质合成对胰岛素的刺激没有反应，而对照组没有。在脓毒症大鼠腓肠肌中，胰岛素诱导的翻译抑制蛋白4e结合蛋白1 （4E-BP1）和70-kDa S6激酶（S6K1）(1)的过度磷酸化反应（胰岛素作用于mRNA翻译的两个靶点）未受到损害。在对照组和脓毒症大鼠中，胰岛素对4E- bp1的过度磷酸化导致其与失活的真核起始因子（eIF）4E·4E- bp1复合物分离。然而，通过eIF4E与eIF4G的关联评估，活性eIF4F复合物的组装并没有遵循由4E-BP1磷酸化变化导致的eIF4E可用性增加所预测的模式。事实上，脓毒症在胰岛素存在或不存在的情况下导致eIF4G与eIF4E相关的量急剧减少。因此，在脓毒症期间，胰岛素无法刺激蛋白质合成可能与翻译起始步骤的信号缺陷有关，该步骤涉及活性eIF4F复合物的组装。
Induction of sepsis in rats causes an inhibition of protein synthesis in skeletal muscle that is resistant to the stimulatory actions of insulin. To gain a better understanding of the underlying reason for this lack of response, the present study was undertaken to investigate sepsis-induced alterations in insulin signaling to regulatory components of mRNA translation. Experiments were performed in perfused hindlimb preparations from rats 5 days after induction of a septic abscess. Sepsis resulted in a 50% reduction in protein synthesis in the gastrocnemius. Protein synthesis in muscles from septic rats, but not controls, was unresponsive to stimulation by insulin. The insulin-induced hyperphosphorylation response of the translation repressor protein 4E-binding protein 1 (4E-BP1) and of the 70-kDa S6 kinase (S6K1) (1), two targets of insulin action on mRNA translation, was unimpaired in gastrocnemius of septic rats. Hyperphosphorylation of 4E-BP1 in response to insulin resulted in its dissociation from the inactive eukaryotic initiation factor (eIF)4E · 4E-BP1 complex in both control and septic rats. However, assembly of the active eIF4F complex as assessed by the association of eIF4E with eIF4G did not follow the pattern predicted by the increased availability of eIF4E resulting from changes in the phosphorylation of 4E-BP1. Indeed, sepsis caused a dramatic reduction in the amount of eIF4G associated with eIF4E in the presence or absence of insulin. Thus the inability of insulin to stimulate protein synthesis during sepsis may be related to a defect in signaling to a step in translation initiation involved in assembly of an active eIF4F complex.