REGULATION OF NEONATAL MUSCLE PROTEIN SYNTHESIS

摘要 大多数早产儿都会经历宫外生长受限，原因不明，而且处于- 增加了患肥胖症和2型糖尿病的终身风险。我们的长期目标是找出 早产儿的瘦身生长和改变对营养的代谢反应；这些发现将告知发育- 制定新的营养战略，以改善结果。此应用程序的目标是确定是否每个- 早产后对喂养的合成代谢抵抗持续损害瘦肉生长和特定的氨基酸 补充酸性物质可以改善瘦肉量的增加。中心假说是早产限制了瘦身。 钝化氨基酸和胰岛素诱导的蛋白质合成和肌核增生的生长 骨骼肌，但可以通过补充氨基酸来改善，以促进 雷帕霉素复合体1(MTORC1)依赖的细胞过程。这一假设是基于美联社的数据- 并得到文献的支持。其基本原理是，理解基本的机制- 早产儿改变对营养的合成代谢反应的失调症是提供信息和修改喂养的关键 早产儿出生后维持宫内瘦肉生长速度的做法。假说 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 早产是长期持续的，会导致肌肉减少和瘦体重增加；以及2)确定 补充亮氨酸和/或精氨酸前体，瓜氨酸通过上调表达促进瘦肉生长 依赖mTORC1的肌肉蛋白质合成和肌核增生。当猪早产和足月出生时 达到相当于人类婴儿期后期或儿童期后期的年龄，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，以及骨骼肌蛋白质的合成和分解。 辐射率、血流量、氨基酸、胰岛素和eNOS信号、代谢和转录谱，以及 摄食、胰腺底物钳夹和补充剂对卫星细胞丰度和增殖的响应 加入亮氨酸和/或瓜氨酸。这些方法是在申请者的实验室中建立的。方法是 创新，因为它将使用全面的方法，同时检查体内对 调节肌肉生长的主要过程，即蛋白质合成、蛋白质降解、 以及这些过程对旨在促进Anab的饮食干预有何反应。 唯我独尊。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的检查 早产儿合成代谢抵抗的基础机制限制了瘦肉生长和检查 靶向氨基酸补充剂对调节骨骼肌生长过程的有效性。 这项拟议的研究具有重要意义，因为它将促进我们对早产如何影响 骨骼肌对营养的合成代谢反应。研究结果将为纽崔斯的优化提供新的信息。 对早产儿的常规管理，以改善其长期代谢健康和生长。

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.