Leucine and HMB Supplementation in Early Life to Promote Muscle Growth at the Expense of Adipose Deposition

摘要 婴儿期体重增加的成分和速度对饮食摄入量高度敏感。多余的脂肪组织 婴儿期早期增加易患儿童肥胖症，并增加成人肥胖的风险 在新陈代谢、健康和生产力方面会产生短期和长期成本。我们的长期目标是确定 可转化为高危人类婴儿和小猪种群的饮食策略以促进 饮食中使用氨基酸来支持肌肉生长，但代价是脂肪沉积。这样做的目的是 应用是为了确定补充完整的饮食(喂养以满足需要)是否含有亮氨酸 或其代谢产物β-羟基-β-甲基丁酸酯(HMB)将通过刺激提高蛋白质的利用效率 肌肉的合成代谢过程，从而加强饮食营养向瘦肉生长的分配， 同时减轻脂肪沉积。中心假设是在婴儿期，补充亮氨酸或HMB 刺激骨骼肌中调节蛋白质合成和卫星细胞复制的途径， 从而促进精益生长。当长期维持时，增加的代谢量总体上会减少 能量平衡和脂肪堆积。这一假设是基于申请者实验室的数据。这个 其基本原理是通过了解饮食成分影响肌肉生长的机制 并反过来影响饮食能量的利用，我们可以建立适当的饮食指南来 优化瘦体重的增长，同时减轻多余的脂肪沉积。在强劲的初步数据的指引下， 这一假设将通过追求两个具体目标来检验：1)确定是否喂养符合以下条件的完整饮食 蛋白质和能量需要量以及补充亮氨酸通过上调肌肉的生长来促进肌肉的生长 蛋白质合成和肌核增加，以及由此导致的代谢量变化是否减少 可用于脂肪积累的能量。2)确定完全饮食的HMB补充剂是否利用营养 与亮氨酸类似的感觉通路可以增强肌肉和瘦肉量的增加，并减轻脂肪沉积。 使用申请者实验室建立的方法，对生长速度、身体成分、 饲料蛋白质和能量利用效率对生长、能量消耗、蛋白质合成率、营养 信号、卫星细胞的丰度和增殖，以及激素、底物和代谢物的分布 在3周以上的幼猪身上进行测量。这种方法是创新的，因为它将识别细胞如何 肌肉对长期补充亮氨酸和HMB的反应影响全身蛋白质和能量 利用来影响生长和体重增加的构成。这项拟议的研究具有重要意义 因为它有望促进我们对亮氨酸及其代谢物在体内的作用的基本理解 早期生命中肌肉生长的调节，以及骨骼肌对整体能量和 生长有机体的蛋白质经济。将获得有关使用亮氨酸的潜力的新信息 和HMB补充剂，以促进婴儿的瘦肉生长和减轻脂肪积累，并用于猪肉生产。

ABSTRACT The composition and rate of weight gain in infancy are highly sensitive to dietary intake. Excess adipose tissue gain in early infancy predisposes to childhood obesity and increases the risk for developing adult obesity that incurs short- and long-term costs in terms of metabolic health and productivity. Our long-term goal is to identify dietary strategies that can be translated to populations of at risk human infants and young pigs to promote dietary amino acid use in support of muscle growth at the expense of adipose deposition. The objective of this application is to determine whether supplementation of a complete diet (fed to meet requirements) with leucine or its metabolite β-hydroxy-β-methylbutyrate (HMB) will improve efficiency of protein utilization by stimulating the muscle's anabolic processes and thereby enhance the partitioning of dietary nutrients toward lean growth, while mitigating fat deposition. The central hypothesis is that in infancy, leucine or HMB supplementation stimulates the pathways in skeletal muscle that regulate protein synthesis and satellite cell replication and, thereby, enhance lean growth. When sustained long-term, the increased metabolic mass diminishes overall energy balance and fat accretion. The hypothesis is based on data from the applicants' laboratories. The rationale is that by understanding the mechanisms by which dietary components can influence muscle growth in early infancy and, in turn, impact dietary energy utilization, we can establish appropriate dietary guidelines to optimize the growth of lean mass whilst mitigating excess fat deposition. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine if feeding a complete diet that meets protein and energy requirements and supplemented with leucine enhances muscle accretion by up-regulating protein synthesis and myonuclear accretion, and whether the resulting change in metabolic mass reduces energy available for fat accretion. 2) Determine if HMB supplementation of a complete diet utilizes nutrient sensing pathways similar to leucine to enhance muscle and lean mass accretion, and mitigate fat deposition. Using methods established in the applicants' laboratories, responses in growth rate, body composition, the efficiency of dietary protein and energy use for growth, energy expenditure, protein synthesis rates, nutrient signaling, satellite cell abundance and proliferation, and hormone, substrate, and metabolite profiles will be measured in young pigs over 3 weeks. The approach is innovative because it will identify how the cellular responses of muscle to long-term leucine and HMB supplementation impact whole body protein and energy utilization to influence growth and the composition of weight gain. The proposed research is significant because it is expected to advance our basic understanding of both the role of leucine and its metabolite in the regulation of muscle growth in early life, and the significance of skeletal muscle for the overall energy and protein economy of the growing organism. Novel information will be gained on the potential for using leucine and HMB supplementation to promote lean growth and mitigate fat accretion in infants and for pork production.