Regulation of Neonatal Muscle Protein Synthesis

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和激素介导新生儿骨骼肌蛋白沉积率高的机制，以确定优化低出生体重婴儿营养管理的新策略。先前的研究表明，摄食诱导的肌肉蛋白质合成刺激是由胰岛素和氨基酸独立介导的，并受翻译起始激活增强的影响。胰岛素反应与未成熟肌肉中胰岛素信号通路的高反应性有关。然而，无论是单个氨基酸和葡萄糖对摄食反应的贡献，还是与发育过程中肌肉蛋白质合成的胰岛素和营养敏感性损失有关的细胞机制都没有被阐明。本研究验证了以下假设：1)餐后单独增加亮氨酸可通过调节翻译起始因子活性刺激新生儿肌肉蛋白合成；2)餐后血糖升高通过激活独立于胰岛素的胰岛素/营养信号通路，增强了摄食对新生儿肌肉蛋白合成的刺激；3)随着发育，胰岛素/营养信号通路活性下调，使肌肉蛋白质合成的营养和胰岛素敏感性减弱。提出以下目标来解决这些假设。在Aim 1中，亮氨酸生理升高对肌肉蛋白合成和翻译起始因子活性的影响将通过肌肉蛋白合成的体内动力学测量和mRNA结合到40S核糖体亚基所需的翻译起始因子活性的测定来确定。在Aim 2中，葡萄糖的生理升高对肌肉蛋白合成和调节翻译起始的胰岛素/营养信号通路活性的影响将通过测量肌肉蛋白合成、胰岛素/营养信号蛋白和翻译起始因子的活性来评估。在Aim 3中，将确定阳性和阴性信号调节因子在影响肌肉蛋白合成对胰岛素和营养物质敏感性的发育下降中的相对贡献。所有的研究都将使用胰底物夹钳，并将在7日龄和26日龄的猪中进行。

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.