Leucine Supplementation to Promote Lean Growth in Early Life

描述(申请人提供)：尽管低出生体重婴儿和早期断奶的猪的营养管理有所改善，但许多人的生长发育迟缓，这可能会在代谢健康和生产力方面招致短期和长期的成本。我们的长期目标是确定战略，以优化人类婴儿和生长受到损害的小猪的营养管理。这项应用的目的是确定在蛋白质和/或能量摄入量微乎其微的情况下，口服亮氨酸补充剂是否可以用于促进早期生活中的瘦肉生长。中心假设是，补充亮氨酸刺激了调节蛋白质合成和卫星细胞复制的信号通路，并在生命早期抑制蛋白质降解。 而这些效应在长期持续时会增强精益增长。这一假设是基于申请者实验室的数据。其基本原理是，了解亮氨酸在早期调节瘦身质量的基本机制，有可能转化为实践，从而改善低出生体重儿和 早期断奶的小猪。在强大的初步数据的指导下，这一假说将通过追求两个具体目标来检验：1)确定长期补充边缘蛋白质饮食的亮氨酸是否通过上调蛋白质合成和肌核增加以及下调蛋白质降解来增强瘦肉量，并确定这种反应是否需要添加其他支链氨基酸；2)确定在蛋白质和能量都略有限制的日粮中补充亮氨酸或亮氨酸和额外的支链氨基酸是否会增加瘦肉量，并确定相关机制。我们将测定添加了10 d亮氨酸或支链氨基酸的仔猪的体成分、生长速度、饲料效率、蛋白质合成和降解率、卫星细胞丰度和增殖能力、氨基酸信号转译、降解信号和氨基酸氧化，这些饲料中的蛋白质(目标1)或蛋白质和能量(目标2)略受限制。这些方法在申请者的实验室中得到了很好的验证。这种方法是创新的，因为它将检查肌肉蛋白质合成、蛋白质降解和肌核增加对早期生活中长期补充亮氨酸的协调反应，并确定对瘦肉生长的影响。这项拟议的工作是独一无二的，因为它是第一个全面研究决定肌肉生长的所有组成部分过程的协调调节。这项拟议的研究意义重大，因为它有望促进我们对亮氨酸在调节早期瘦肉生长中的作用的理解。这一结果将为使用亮氨酸补充剂优化低出生体重儿的营养管理以及提高猪肉生产中膳食营养素的利用效率提供重要的新信息。 公共卫生相关性：拟议的研究与公共健康相关，因为亮氨酸影响新生儿瘦肉生长的机制的发现有望使基础研究更接近于改善低出生体重儿营养支持以及猪肉生产中膳食营养利用效率的转换水平。因此，拟议的使用农业上重要的家养物种的研究与美国国家卫生研究院和美国农业部的任务相关，因为它将提供基本的新知识，对改善人类健康和食用动物生产具有双重好处。

DESCRIPTION (provided by applicant): Despite improvements in the nutritional management of low birth weight infants and early weaned pigs, many experience growth faltering and this can incur both short- and long-term costs in terms of metabolic health and productivity. Our long-term goal is to identify strategies to optimize the nutritional management of both the human infant and the young pig whose growth has been compromised. The objective of this application is to determine whether the use of an oral leucine supplement can be used to enhance lean growth in early life when the intakes of protein and/or energy are marginal. The central hypothesis is that leucine supplementation stimulates the signaling pathways that regulate protein synthesis and satellite cell replication and inhibit protein degradation during early life, and these effects enhance lean growth when sustained over the long-term. The hypothesis is based on data from the applicants' laboratories. The rationale is that understanding the fundamental mechanisms by which leucine modulates lean body mass during early life has the potential to translate into practices that will improve lean growth of low birth weight infants and early weaned piglets. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine whether prolonged leucine supplementation of a marginal protein diet enhances lean mass by up-regulating protein synthesis and myonuclear accretion and down-regulating protein degradation, and also determine whether this response requires the addition of other branched-chain amino acids; and 2) Determine if supplementation with leucine, or leucine and additional branched chain amino acids, of a diet that is marginally restricted in both protein and energy will enhance lean mass accretion, and to identify the mechanisms involved. We will determine body composition, growth rate, feed efficiency, protein synthesis and degradation rates, satellite cell abundance and proliferative capacity, amino acid signaling to translation, degradation signaling, and amino acid oxidation in young pigs fed for 10 d leucine or branched-chain amino acid supplemented diets that are marginally (80%) restricted in protein (Aim 1) or protein and energy (Aim 2). The methods are well-established in the applicants' laboratories. The approach is innovative, because it will examine the coordinated response of muscle protein synthesis, protein degradation, and myonuclear accretion to long-term leucine supplementation during early life and determine the impact on lean growth. The proposed work is unique because it is the first to comprehensively examine the coordinated regulation of all the component processes that determine muscle growth. The proposed research is significant, because it is expected to advance our understanding of the role of leucine in the regulation of lean growth in early life. The results will provide important novel information on the potential for using leucine supplementation to optimize the nutritional management of low birth weight infants, and to improve the efficiency of utilization of dietary nutrients for pork production. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the discovery of the mechanisms by which leucine influences lean growth in neonates is expected to bring basic research closer to the translational level of improving the nutritional support of low birth weight infants as well as the efficiency of utilization of dietary nutrients fr pork production. Thus, the proposed research using an agriculturally important domestic species is relevant to the missions of the NIH and USDA as it will provide fundamental new knowledge that has dual benefits relevant for the improvement of human health and food animal production.