Regulation of Neonatal Muscle Protein Synthesis

 描述（由申请人提供）：大多数早产儿在出院时出现宫外生长受限。许多人在成年后仍然很小，并对其代谢健康产生短期和长期成本，包括肥胖风险增加。我们的长期目标是确定优化早产儿营养管理的策略。本申请的目的是确定早产是否限制了对喂养的合成代谢反应，以及是否可以通过优化喂养策略来减轻这种反应，以提高合成代谢过程中营养物质的使用效率。中心假设是早产降低了瘦肉生长，特别是在小于胎龄（SGA）的新生儿中，但是瘦肉生长可以通过周期性刺激哺乳动物雷帕霉素信号传导的靶标来改善，所述雷帕霉素信号传导是通过间歇性推注时间表而不是连续喂养来给予的，或者当必须规定连续喂养时通过施用间歇性亮氨酸脉冲来给予的。该假设基于申请人实验室的数据。其基本原理是，了解不同喂养模式在早期生活中调节瘦体重的基本机制，有可能转化为改善早产儿瘦体重生长的实践。在强有力的初步数据的指导下，将通过追求三个具体目标来检验这一假设：1）确定早产是否通过钝化胰岛素和氨基酸诱导的翻译起始来改变肌肉对喂养的蛋白质合成反应; 2）确定早产儿的瘦肉生长是否减少，特别是SGA，但通过间歇性推注喂养而不是胃肠外或肠内持续喂养来改善;和3）确定间歇性亮氨酸脉冲是否通过刺激蛋白质合成和肌纤维增生以及减少早产儿连续喂养的降解来增强瘦肉生长。我们将确定SGA早产、适合胎龄（阿加）早产和间歇性推注或连续（胃肠外或肠内）喂养的足月猪的身体组成、生长速率、肌肉蛋白合成和降解、卫星细胞丰度和增殖、氨基酸和胰岛素信号传导、代谢产物和全转录组谱以及胰岛素和氨基酸敏感性，并且在那些当连续喂食时提供间歇性亮氨酸脉冲的动物中。这些方法是在申请人的实验室建立的。该方法是创新的，因为它将在早产仔猪模型中检查肌肉蛋白质合成、降解、肌纤维增生、氨基酸和胰岛素信号传导以及调节瘦肉生长的代谢物和转录物谱的协调反应。这项工作是独一无二的，因为它是第一个在相关的早产模型中全面研究不同喂养方式的有效性的研究，包括一种新的亮氨酸补充方法对决定肌肉生长的组分过程的有效性。这项拟议中的研究意义重大，因为它有望促进我们对早产如何影响营养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.