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Amino Acids and Muscle Protein Synthesis

氨基酸和肌肉蛋白质合成

基本信息

批准号：
7112898
负责人：
ROBERT R WOLFE
金额：
$ 40.83万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2008-06-30
项目状态：
已结题

项目摘要

The initiation phase of mRNA translation is a key target for the regulation of protein synthesis in skeletal muscle. Translation initiation is mediated by a number of factors which are collectively referred to as eukaryotic initiation factors (eIF). Our general hypothesis is that the factors governing translational control of muscle protein synthesis are responsive not only to the prevailing plasma concentrations of amino acids, but also to the direction in which concentration of leucine changes. The specific mechanism whereby amino acids affect the rate of muscle protein synthesis in vivo is governed by the interplay of the various initiation factors. We propose that a sufficient amount of amino acids are required to repress the phosphorylation state of eIF2alpha (which reflects charging of tRNA) and to maintain the activity of eukaryotic initiation factor (eIF)2B for the basal rate of muscle protein synthesis to be maintained. Further, responses to potential activation of other pathways will be inadequate to result in increased muscle protein synthesis unless there is sufficient charging of tRNA and activity of eIF2B. We propose that in the circumstance of an adequate basal amount of amino acids the transient stimulation of muscle protein synthesis by an increase in amino acid availability is mediated via an mTOR-dependent signaling pathway resulting in an increased phosphorylation of the eIF4E binding protein 1 (4E-BP1) and the 70KDa ribosomal protein S6 kinase (S6K1). In addition, leucine has a specific stimulatory effect on synthesis by activating an mTOR-independent (ie, rapamycin- insensitive) signaling pathway resulting in an increased phosphorylation of eIF4G. We will investigate a series of specific hypotheses related to these general proposals using a porcine model that enable us to make frequent, rapid measurements of both muscle protein synthesis and the various initiation factors. The results will clarify the mechanisms whereby amino acids regulate muscle protein synthesis, and the ultimate benefit of this information will be in terms of designing appropriate nutritional support in a variety of clinical settings.

mRNA 翻译的起始阶段是骨骼肌蛋白质合成调节的关键目标。翻译起始由许多因素介导，这些因素统称为真核起始因子（eIF）。我们的一般假设是，控制肌肉蛋白质合成翻译控制的因素不仅对氨基酸的主要血浆浓度有反应，而且对亮氨酸浓度变化的方向也有反应。氨基酸影响体内肌肉蛋白质合成速率的具体机制是由各种起始因子的相互作用控制的。我们建议需要足够量的氨基酸来抑制 eIF2α 的磷酸化状态（反映 tRNA 的充电）并维持真核起始因子 (eIF)2B 的活性，以维持肌肉蛋白质合成的基础速率。此外，除非有足够的 tRNA 充电和 eIF2B 活性，否则对其他途径的潜在激活的反应将不足以导致肌肉蛋白质合成增加。我们认为，在氨基酸基础量充足的情况下，氨基酸可用性增加对肌肉蛋白合成的短暂刺激是通过 mTOR 依赖性信号通路介导的，导致 eIF4E 结合蛋白 1 (4E-BP1) 和 70KDa 核糖体蛋白 S6 激酶 (S6K1) 磷酸化增加。此外，亮氨酸通过激活不依赖于mTOR（即雷帕霉素不敏感）的信号通路，导致eIF4G磷酸化增加，从而对合成具有特定的刺激作用。我们将使用猪模型研究与这些一般建议相关的一系列具体假设，使我们能够频繁、快速地测量肌肉蛋白质合成和各种起始因子。结果将阐明氨基酸调节肌肉蛋白质合成的机制，这些信息的最终好处将在于在各种临床环境中设计适当的营养支持。