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.

抽象的大多数过早婴儿的出于不清楚并且处于in- 产生了肥胖和2型糖尿病的终身风险。我们的长期目标是确定降低的机制早产儿的瘦长生长和改变对营养的代谢反应；这些发现将为开发提供信息 - 新的营养策略来改善预后。本应用的目的是确定是否过早出生后，合成代谢抗性的耐药性会损害瘦肉的生长和特定的氨基补充酸可改善瘦质量积聚。中心假设是早产限制精益通过钝化氨基酸和胰岛素诱导的蛋白质合成和肌核积累的生长骨骼肌，但可以通过靶向促进机械靶标的氨基酸补充来改善雷帕霉素复合物1（MTORC1）依赖性细胞过程。该假设基于来自AP-的数据培训者的实验室，并得到文献的支持。理由是了解基本的机甲早产来改变合成代谢对营养的反应对于告知和修改饲料至关重要的障碍至关重要早产婴儿出生后瘦质量的增长率的实践。假设将通过追求两个具体目的来测试：1）确定急性蛋白合成代谢抗性是否对进食早产是长期的，导致肌肉和瘦质量积聚减少。 2）确定是否用亮氨酸和/或精氨酸前体补充，瓜氨酸可以通过上调增强瘦肉的生长 MTORC1依赖性肌肉蛋白合成和肌核积累。猪出生的早产和学期到达等于人类晚期或后期的年龄，我们将确定身体成分，生长速率，能量消耗，荷花质，底物和代谢物谱以及骨骼肌蛋白合成和DEG- 辐射速率，血流，氨基酸，胰岛素和eNOS信号传导，代谢组和转录谱以及卫星细胞抽象和增殖，以响应喂养，胰腺夹夹和补充用亮氨酸和/或瓜氨酸来进行。这些方法是在申请人的实验室中建立的。方法是创新性是因为它将使用全面的方法，这些方法将同时检查体内响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，和肌核积聚，以及这些过程如何应对针对促进Anab-的饮食干预措施的反应橄榄症。拟议的研究之所以独特，是因为它们在相关的早产模型中全面检查为早产的合成代谢抗性的基础的机制限制了精益生长并检查靶向氨基酸在调节骨骼肌生长的过程中的有效性。拟议的研究很重要，因为它将促进我们对早产如何影响的理解骨骼肌对营养的合成代谢反应。结果将提供新的信息以优化营养早产儿的统治管理，以改善其长期代谢健康和成长。

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。