Amino Acids and Muscle Protein Synthesis

氨基酸和肌肉蛋白质合成

• 批准号: 6532048
• 负责人: ROBERT R WOLFE
• 金额: $ 38.28万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532048
• 关键词: aminoacid; biological signal transduction; biopsy; carbon; dietary aminoacid; genetic translation; leucine; messenger RNA; muscle proteins; nitrogen; nutrition related tag; phosphorylation; phosphotransferases; protein biosynthesis; protein degradation; radiotracer; stable isotope; striated muscles; swine; translation factor

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翻译的起始阶段是调节骨骼肌蛋白质合成的关键靶点。翻译起始由许多因子介导，这些因子统称为真核起始因子（eIF）。 我们的一般假设是，肌肉蛋白质合成的翻译控制的因素是响应不仅占主导地位的血浆浓度的氨基酸，但也亮氨酸的浓度变化的方向。 氨基酸影响体内肌肉蛋白质合成速率的具体机制受各种起始因子的相互作用支配。 我们提出，需要足够量的氨基酸来抑制eIF 2 α的磷酸化状态（这反映了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，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，除非有足够的tRNA和eIF 2B活性。 我们提出，在足够的基础量的氨基酸的情况下，通过增加氨基酸可用性的瞬时刺激肌肉蛋白质合成是通过mTOR依赖性信号通路介导的，导致eIF 4 E结合蛋白1（4 E-BP 1）和70 KDa核糖体蛋白S6激酶（S6 K1）的磷酸化增加。 此外，亮氨酸通过激活mTOR非依赖性（即雷帕霉素不敏感）信号传导途径对合成具有特异性刺激作用，导致eIF 4G磷酸化增加。 我们将使用猪模型研究与这些一般建议相关的一系列特定假设，这些模型使我们能够频繁，快速地测量肌肉蛋白质合成和各种起始因子。 这些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是在各种临床环境中设计适当的营养支持。