Regulation of Neonatal Muscle Protein Synthesis

新生儿肌肉蛋白合成的调节

• 批准号: 6679891
• 负责人: TERESA A DAVIS
• 金额: $ 33.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-20 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6679891
• 关键词: SDS polyacrylamide gel electrophoresis; biological signal transduction; genetic translation; glucose; high performance liquid chromatography; hormone regulation /control mechanism; immunoprecipitation; insulin; insulin receptor; leucine; messenger RNA; muscle proteins; newborn animals; nutrient intake activity; protein biosynthesis; striated muscles; swine; western blottings

DESCRIPTION (provided by applicant): The accretion of skeletal muscle mass is a dominant component of neonatal growth. The long-term objective is to define the mechanisms by which nutrients and hormones mediate the high rate of skeletal muscle protein deposition in neonates, with the goal of identifying new strategies to optimize the nutritional management of low birth weight infants. Previous work showed that the feeding-induced stimulation of muscle protein synthesis is mediated independently by insulin and amino acids and is effected by enhanced activation of translation initiation. The insulin response is associated with a heightened responsiveness of the insulin signaling pathway in immature muscle. However, neither the contribution of individual amino acids and glucose to the feeding response, nor the cellular mechanisms responsible for the loss in the insulin and nutrient sensitivity of muscle protein synthesis with development have been elucidated. This proposal tests the hypotheses that: 1) The postprandial rise in leucine alone can stimulate muscle protein synthesis in neonates by modulating translation initiation factor activity; 2) The postprandial rise in glucose enhances the feeding-induced stimulation of muscle protein synthesis in neonates by activating the insulin/nutrient signaling pathway, independently of insulin; and 3) Down-regulation in the activity of the insulin/nutrient signaling pathway with development blunts the nutrient and insulin sensitivity of muscle protein synthesis. The following aims are proposed to address these hypotheses. In Aim 1, the effect of a physiological rise in leucine on muscle protein synthesis and translation initiation factor activity will be determined using in vivo kinetic measurement of muscle protein synthesis and determination of the activity of the translation initiation factors required for mRNA binding to the 40S ribosomal subunit. In Aim 2, the effect of a physiological rise in glucose on muscle protein synthesis and the activity of the insulin/nutrient signaling pathway that regulates translation initiation will be assessed from measurements of muscle protein synthesis and the activities of insulin/nutrient signaling proteins and translation initiation factors. In Aim 3,the relative contributions of positive versus negative signaling regulators in effecting the developmental decline in the sensitivity of muscle protein synthesis to insulin and nutrients will be determined. All studies will use pancreatic-substrate clamps and will be performed in 7- and 26-day-old pigs.

描述（由申请人提供）：骨骼肌质量的增加是新生儿生长的主要组成部分。长期目标是确定营养素和激素介导新生儿骨骼肌蛋白沉积率高的机制，目的是确定优化低出生体重儿营养管理的新策略。先前的工作表明，喂养诱导的肌肉蛋白质合成的刺激是由胰岛素和氨基酸独立介导的，并受到增强的翻译起始激活的影响。胰岛素反应与未成熟肌肉中胰岛素信号通路的反应性升高相关。然而，既没有个别氨基酸和葡萄糖的贡献，也没有细胞机制负责的损失，在胰岛素和营养敏感性的肌肉蛋白质合成与发展已经阐明。该提案检验了以下假设：1）单独的亮氨酸餐后升高可以通过调节翻译起始因子活性来刺激新生儿肌肉蛋白质合成; 2）葡萄糖餐后升高通过激活胰岛素/营养信号通路（独立于胰岛素）来增强新生儿肌肉蛋白质合成的喂养诱导的刺激;和3）随着发育，胰岛素/营养物信号传导途径活性的下调减弱了肌肉蛋白质合成的营养物和胰岛素敏感性。提出以下目标来解决这些假设。在目的1中，将使用肌肉蛋白质合成的体内动力学测量和mRNA与40 S核糖体亚基结合所需的翻译起始因子活性的测定来确定亮氨酸的生理性升高对肌肉蛋白质合成和翻译起始因子活性的影响。在目标2中，将通过测量肌肉蛋白质合成和胰岛素/营养信号蛋白和翻译起始因子的活性，评估葡萄糖生理性升高对肌肉蛋白质合成和调节翻译起始的胰岛素/营养信号通路活性的影响。在目标3中，将确定正信号调节剂与负信号调节剂在影响肌肉蛋白质合成对胰岛素和营养物的敏感性的发育下降中的相对贡献。所有研究将使用胰腺基质夹，并将在7天和26日龄猪中进行。