Regulation of Neonatal Muscle Protein Synthesis

描述(由申请人提供)：骨骼肌块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物质和激素调节新生儿骨骼肌蛋白质沉积高比率的机制，目的是确定优化低出生体重儿营养管理的新策略。以前的工作表明，摄食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，并且是通过增强翻译起始激活来影响的。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，还是导致肌肉蛋白质合成的胰岛素和营养敏感性随着发育而丧失的细胞机制都没有阐明。这一建议验证了假设：1)仅餐后亮氨酸的升高可以通过调节翻译起始因子的活性来刺激新生儿肌肉蛋白质的合成；2)餐后葡萄糖的升高通过激活胰岛素/营养信号通路而增强了喂养诱导的新生儿肌肉蛋白质合成的刺激作用，而不依赖于胰岛素；以及3)胰岛素/营养信号通路的活性随着发育的下调削弱了肌肉蛋白质合成的营养和胰岛素敏感性。为了解决这些假设，我们提出了以下目标。在目标1中，将通过体内肌肉蛋白质合成的动力学测量和与40S核糖体亚基结合所需的翻译起始因子的活性的测定来确定亮氨酸生理性增加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以及胰岛素/营养信号蛋白和翻译启动因子的活性来评估生理性血糖升高对肌肉蛋白质合成和调节翻译启动的胰岛素/营养信号通路的活性的影响。在目标3中，将确定正信号调节因子和负信号调节因子在影响肌肉蛋白质合成对胰岛素和营养的敏感性发育性下降中的相对贡献。所有研究都将使用胰腺基质夹，并将在7日龄和26日龄的猪身上进行。

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.