Regulation of Neonatal Muscle Protein Synthesis

 描述(申请人提供)：大多数早产儿因出院而经历过宫外生长受限。许多人到成年还很小，并对他们的新陈代谢健康造成了短期和长期的成本，包括肥胖风险的增加。我们的长期目标是确定优化早产儿营养管理的策略。这项应用的目的是确定早产是否限制了对喂养的合成代谢反应，以及是否通过优化喂养策略来提高合成代谢过程中养分的使用效率来缓解这种反应。中心假说是，早产会减少瘦肉生长，特别是在小于胎龄(SGA)的新生儿中，但通过周期性刺激哺乳动物靶标雷帕霉素信号，可以改善瘦肉生长，方法是按间歇性给药而不是连续喂养，或在必须连续喂养的情况下给予间歇性亮氨酸脉冲。这一假设是基于申请者实验室的数据。其基本原理是，了解不同喂养方式在早期调节瘦肉质量的基本机制，有可能转化为改善早产儿瘦肉生长的实践。以强劲的初步数据为指导，将通过追求三个特定目标来检验这一假说：1)确定早产是否通过钝化胰岛素和氨基酸诱导的翻译启动来改变肌肉对喂养的蛋白质合成反应；2)确定早产时瘦肉生长是否会减少，尤其是SGA，但可以通过间歇喂饲而不是肠外或肠道内持续喂养来改善这一假说；以及3)确定间歇亮氨酸脉冲是否通过刺激蛋白质合成和肌核增殖以及减少早产持续喂养新生儿的降解来促进瘦肉生长。我们将测定SGA早产猪的身体成分、生长速度、肌肉蛋白质合成和降解、卫星细胞丰度和增殖、氨基酸和胰岛素信号、代谢物和整个转录组图谱，以及胰岛素和氨基酸敏感性，适合于胎龄(AGA)早产猪、按间歇给药计划饲喂或连续饲喂的足月猪，以及在连续饲喂时提供间歇亮氨酸脉冲的猪。这些方法是在申请者的实验室中建立的。该方法具有创新性，因为它将在早产仔猪模型中检查肌肉蛋白质合成、降解、肌核增加、氨基酸和胰岛素信号以及调节瘦肉生长的代谢物和转录物的协调反应。这项拟议的工作是独一无二的，因为它是第一次在相关的早产模型中全面检查不同喂养方式的有效性，包括一种新的亮氨酸补充方法，用于决定肌肉生长的组成部分过程。这项拟议的研究具有重要意义，因为它有望促进我们对早产如何影响营养的合成代谢反应的理解。研究结果将为优化早产儿营养管理提供重要的新信息。

 DESCRIPTION (provided by applicant): Most premature infants have experienced extrauterine growth restriction by hospital discharge. Many remain small to adulthood and incur short- and long-term costs to their metabolic health, including an increased risk for obesity. Our long-term goal is to identify strategies to optimize the nutritional management of premature infants. The objective of this application is to determine whether prematurity limits the anabolic response to feeding and if this is mitigated by optimizing feeding strategies to enhance the efficiency of nutrient use for anabolic processes. The central hypothesis is that prematurity reduces lean growth, particularly in small for gestational age (SGA) neonates, but lean growth can be improved by cyclical stimulation of mammalian target of rapamycin signaling imparted by either feeding on an intermittent bolus schedule, rather than continuously, or by ad- ministration of intermittent leucine pulses when continuous feeding must be prescribed. The hypothesis is based on data from the applicants' laboratories. The rationale is that understanding the fundamental mechanisms by which different modes of feeding modulate lean mass in early life has the potential to translate into practices that will improve lean growth of preterm infants. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine if prematurity alters the protein synthetic response of muscle to feeding by blunting insulin- and amino acid-induced translation initiation; 2) Determine if lean growth is reduced in the preterm, particularly SGA, but is improved by intermittent bolus feeding rather than continuous feeding delivered either parenterally or enterally; and 3) Determine if intermittent leucine pulses enhance lean growth by stimulating protein synthesis and myonuclear accretion and reducing degradation in pre- term continuously fed neonates. We will determine body composition, growth rate, and muscle protein synthesis and degradation, satellite cell abundance and proliferation, amino acid and insulin signaling, metabolite and whole transcriptome profiles, and insulin and amino acid sensitivity in SGA preterm, appropriate for gestational age (AGA) preterm, and term pigs fed on an intermittent bolus schedule or continuously, either parenterally or enterally, and in those provided intermittent leucine pulses when continuously fed. The methods are established in the applicants' laboratories. The approach is innovative because it will examine in the preterm piglet model the coordinated response of muscle protein synthesis, degradation, myonuclear accretion, amino acid and insulin signaling, and metabolite and transcript profiles that regulate lean growth. The proposed work is unique because it is the first to comprehensively examine in a relevant preterm model the effectiveness of different feeding modalities including a novel leucine supplementation approach on component processes that determine muscle growth. The proposed research is significant because it is expected to advance our under- standing of how prematurity impacts the anabolic response to nutrition. The results will provide important novel information required for the optimization of the nutritional management of preterm infants.