Vary Thomas C, Deiter Gina, Lynch Christopher J
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
J Nutr. 2007 Aug;137(8):1857-62. doi: 10.1093/jn/137.8.1857.
Feeding promotes protein synthesis in cardiac muscle through a stimulation of the messenger RNA translation initiation phase of protein synthesis by enhancing assembly of active eukaryotic initiation factor (eIF)4F complex. The experiments reported herein examined the potential role for a rapamycin-sensitive signaling pathway in increasing formation of active eIF4G-eIF4E complex during meal feeding. Hearts from male Sprague-Dawley rats fed a meal consisting of rat nonpurified diet were sampled prior to and 3 h following the meal in the presence or absence of treatment with rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) complex 1. Rapamycin prevented the meal feeding-induced stimulation of myocardial protein synthesis. Inhibition of mTOR with rapamycin decreased the association of rapamycin-associated TOR protein with mTOR and prevented the feeding-induced assembly of eIF4G-eIF4E complex. In contrast, the abundance of eIF4E binding protein-1 (4E-BP1)-eIF4E complex was unaffected by either meal feeding or rapamycin. Pretreatment with rapamycin completely prevented the feeding-induced phosphorylation of eIF4G(Ser(1108)), whereas the inhibitor only partially attenuated meal feeding-induced 70-kDa ribosomal protein S6 kinase1(Thr(389)) phosphorylation and extent of 4E-BP1 in the gamma-form. Meal feeding-induced phosphorylation of protein kinase B on either Ser(473) or Thr(308) was unaffected by rapamycin. These findings suggest the extent of phosphorylation of eIF4G following meal feeding occurs by a rapamycin-sensitive mechanism in cardiac muscle. Furthermore, the rapamycin-sensitive reductions in phosphorylation of eIF4G may also lead to decreased formation of active eIF4G-eIF4E complex.
进食通过增强活性真核生物起始因子（eIF）4F复合物的组装，刺激蛋白质合成的信使核糖核酸翻译起始阶段，从而促进心肌中的蛋白质合成。本文报道的实验研究了雷帕霉素敏感信号通路在进食期间增加活性eIF4G - eIF4E复合物形成中的潜在作用。在有或没有用雷帕霉素（一种哺乳动物雷帕霉素靶蛋白（mTOR）复合物1的抑制剂）处理的情况下，对喂食大鼠非纯化饮食的雄性Sprague - Dawley大鼠的心脏在进食前和进食后3小时进行取样。雷帕霉素阻止了进食诱导的心肌蛋白质合成刺激。用雷帕霉素抑制mTOR可减少雷帕霉素相关的TOR蛋白与mTOR的结合，并阻止进食诱导的eIF4G - eIF4E复合物的组装。相比之下，eIF4E结合蛋白-1（4E - BP1）- eIF4E复合物的丰度不受进食或雷帕霉素的影响。雷帕霉素预处理完全阻止了进食诱导的eIF4G（Ser（1108））磷酸化，而该抑制剂仅部分减弱了进食诱导的70 kDa核糖体蛋白S6激酶1（Thr（389））磷酸化以及γ形式的4E - BP1的程度。进食诱导的蛋白激酶B在Ser（473）或Thr（308）上的磷酸化不受雷帕霉素影响。这些发现表明，进食后eIF4G的磷酸化程度是通过心肌中雷帕霉素敏感的机制发生的。此外，雷帕霉素敏感的eIF4G磷酸化减少也可能导致活性eIF4G - eIF4E复合物的形成减少。
