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REGULATION OF NEONATAL MUSCLE PROTEIN SYNTHESIS

新生儿肌肉蛋白合成的调节

基本信息

批准号：
10735768
负责人：
TERESA A DAVIS
金额：
$ 61.75万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735768
关键词：
Acute Age Amino Acids Anabolism Arginine Attenuated Basic Science Birth Blood flow Body Composition Cell physiology Childhood Citrulline Closure by clamp Complex Data Deposition Development Dietary Intervention Dietary Supplementation Dose Energy Metabolism FRAP1 gene Family suidae Fetal Growth Generations Goals Growth Health Hormones Human Impairment Infant Insulin Insulin Signaling Pathway Knowledge Laboratories Leucine Literature Liver Mediating Metabolic Methods Mission Modeling Muscle Muscle Proteins Neonatal Non-Insulin-Dependent Diabetes Mellitus Nutrient Nutrient availability Nutritional Nutritional Support Outcome Pancreas Peptide Initiation Factors Premature Birth Premature Infant Process Production Proliferating Protein Biosynthesis Proteins Public Health Publishing Regulation Research Resistance Signal Pathway Signal Transduction Skeletal Muscle Supplementation Term Birth Testing Thinness Translation Initiation United States United States National Institutes of Health Uterus Work cell type dietary effectiveness evaluation experience feeding improved improved outcome in vivo infancy innovation liver metabolism metabolome metabolomics neonate novel nutrition obesity risk postnatal premature protein degradation protein intake response satellite cell sensor skeletal muscle growth transcriptome transcriptomics

项目摘要

ABSTRACT Most premature infants experience extrauterine growth restriction for reasons that are unclear and are at in- creased lifelong risk for obesity and type 2 diabetes. Our long-term goal is to identify mechanisms that diminish lean growth and alter metabolic responses to nutrition in preterm infants; these findings will inform the develop- ment of new nutritional strategies to improve outcomes. The objective of this application is to determine if per- sistence of the anabolic resistance to feeding following premature birth impairs lean growth and if specific amino acid supplementation ameliorates lean mass accretion. The central hypothesis is that prematurity limits lean growth by blunting amino acid- and insulin-induced stimulation of protein synthesis and myonuclear accretion in skeletal muscle but can be improved by amino acid supplementation targeted to promote mechanistic target of rapamycin complex 1 (mTORC1)-dependent cellular processes. The hypothesis is based on data from the ap- plicants’ laboratories and supported by the literature. The rationale is that understanding the fundamental mech- anisms by which prematurity alters the anabolic response to nutrition is essential to inform and modify feeding practices for preterm infants to sustain intrauterine growth rates of lean mass after they are born. The hypothesis will be tested by pursuing two specific aims: 1) Determine if the acute protein anabolic resistance to feeding in the preterm is sustained long-term and results in reduced muscle and lean mass accretion; and 2) Determine if supplementation with leucine and/or the arginine precursor, citrulline enhances lean growth by upregulating mTORC1-dependent muscle protein synthesis and myonuclear accretion. When pigs born preterm and term reach ages equivalent to human late-infancy or late-childhood, we will determine body composition, growth rate, energy expenditure, hormone, substrate and metabolite profiles, and skeletal muscle protein synthesis and deg- radation rates, blood flow, amino acid, insulin and eNOS signaling, metabolomic and transcriptomic profiles, and satellite cell abundance and proliferation in response to feeding, pancreatic-substrate clamps, and supplemen- tation with leucine and/or citrulline. The methods are established in the applicants’ laboratories. The approach is innovative because it will use comprehensive approaches that will examine concurrently in vivo responses to preterm birth of the principal processes that regulate muscle growth, i.e., protein synthesis, protein degradation, and myonuclear accretion, and how these processes respond to dietary interventions targeted to promote anab- olism. The proposed studies are unique because they comprehensively examine in a relevant preterm model the mechanisms that underlie the anabolic resistance of the premature which limits lean growth and examine the effectiveness of targeted amino acid supplementation on processes that regulate skeletal muscle growth. The proposed research is significant because it will advance our understanding of how prematurity impacts the anabolic response of skeletal muscle to nutrition. The results will provide novel information to optimize the nutri- tional management of preterm infants to improve their long-term metabolic health and growth.

抽象的大多数早产儿都会经历宫外生长受限，原因尚不清楚，并且处于内部状态。增加肥胖和 2 型糖尿病的终生风险。我们的长期目标是找到减少促进早产儿生长并改变对营养的代谢反应；这些发现将为开发者提供信息制定新的营养策略以改善结果。该应用程序的目的是确定是否每早产后对喂养的合成代谢抵抗的持续会损害瘦肉生长，如果特定氨基酸补充酸可以改善瘦体重增加。核心假设是早产限制了瘦身通过减弱氨基酸和胰岛素诱导的蛋白质合成和肌核增生的刺激来促进生长骨骼肌，但可以通过补充氨基酸来改善，以促进骨骼肌的机械目标雷帕霉素复合物 1 (mTORC1) 依赖性细胞过程。该假设基于来自应用程序的数据申请人的实验室并有文献支持。其基本原理是了解基本机制早产改变对营养的合成代谢反应的现象对于告知和改变喂养至关重要早产儿出生后维持宫内瘦体重生长速度的做法。假设将通过追求两个具体目标进行测试：1）确定急性蛋白质合成代谢抵抗是否存在早产长期持续，导致肌肉减少和瘦体重增加； 2) 确定是否补充亮氨酸和/或精氨酸前体瓜氨酸通过上调增强瘦肉生长 mTORC1 依赖性肌肉蛋白合成和肌核增生。猪早产和足月出生时达到相当于人类婴儿晚期或儿童晚期的年龄，我们将确定身体成分、生长速度、能量消耗、激素、底物和代谢物概况以及骨骼肌蛋白质合成和脱氢辐射率、血流量、氨基酸、胰岛素和 eNOS 信号传导、代谢组学和转录组学概况，以及卫星细胞丰度和增殖响应喂养、胰底夹和补充亮氨酸和/或瓜氨酸。这些方法是在申请人的实验室中建立的。方法是创新是因为它将使用综合方法来同时检查体内反应调节肌肉生长的主要过程的早产，即蛋白质合成、蛋白质降解、和肌核增生，以及这些过程如何响应旨在促进减重的饮食干预措施奥利主义。拟议的研究是独一无二的，因为它们在相关的早产模型中进行了全面检查早产儿合成代谢抵抗的机制限制了瘦肉生长并检查定向氨基酸补充对调节骨骼肌生长过程的有效性。拟议的研究意义重大，因为它将增进我们对早产如何影响骨骼肌对营养的合成代谢反应。结果将为优化营养提供新的信息对早产儿进行全面管理，以改善其长期代谢健康和生长。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Critical Windows for the Programming Effects of Early-Life Nutrition on Skeletal Muscle Mass.

DOI：
10.1159/000486490
发表时间：
2018-01-01
期刊：
Nestle Nutrition Institute workshop series
影响因子：
0
作者：
Fiorotto, Marta L;Davis, Teresa A
通讯作者：
Davis, Teresa A

Nutrition and the Brain - Exploring Pathways for Optimal Brain Health Through Nutrition: A Call for Papers.

营养与大脑 - 通过营养探索最佳大脑健康的途径：征文。

DOI：
10.1016/j.tjnut.2023.10.026
发表时间：
2023
期刊：
The Journal of nutrition
影响因子：
0
作者：
Barbey,AronK;Davis,TeresaA
通讯作者：
Davis,TeresaA

Intermittent bolus feeding does not enhance protein synthesis, myonuclear accretion, or lean growth more than continuous feeding in a premature piglet model.

DOI：
10.1152/ajpendo.00236.2021
发表时间：
2021-12-01
期刊：
American journal of physiology. Endocrinology and metabolism
影响因子：
0
作者：
Rudar M;Naberhuis JK;Suryawan A;Nguyen HV;Stoll B;Style CC;Verla MA;Olutoye OO;Burrin DG;Fiorotto ML;Davis TA
通讯作者：
Davis TA

Upholding the Tradition of Excellence of TheJournal of Nutrition.

秉承《营养杂志》的卓越传统。