Regulation of Neonatal Muscle Protein Synthesis

描述（由申请人提供）：骨骼肌质量的增加是新生儿生长的主要组成部分。本研究的长期目标是确定营养素和激素调节新生儿骨骼肌蛋白沉积高速率的机制，目的是确定优化低出生体重儿营养管理的新策略。我们以前的工作表明，新生儿肌肉蛋白质合成的高速率在很大程度上是由于餐后mRNA翻译的激活增强。这种增强的反应是由氨基酸和胰岛素介导的，并且是由于营养和胰岛素信号传导途径以及翻译起始因子的增强激活。口胃喂养，使用连续或间歇推注输送，是低出生体重婴儿吸吮、吞咽或呼吸受损的常见临床实践。对于哪种营养支持机制是最佳的，存在争议。有强有力的证据表明，间歇性大剂量喂养比连续喂养促进更大的体重增加和小肠生长，但这是否对骨骼肌生长是未知的。初步研究表明，与间歇性大剂量喂养相比，连续喂养期间氨基酸和胰岛素水平的适度增加可能不足以最大限度地刺激肌肉蛋白质合成，因为翻译起始激活不足。该提案测试了以下总体假设：间歇性大剂量喂食比连续喂食促进骨骼肌蛋白质合成和增长的速率更高，并且该反应由氨基酸和胰岛素及其激活氨基酸和胰岛素信号传导组分和翻译调节剂介导。为解决这一假设，提出了以下目标。在目的1中，将使用肌肉蛋白合成的体内动力学测量以及营养和胰岛素信号传导、翻译起始和延伸以及新生猪骨骼肌中核糖体蛋白翻译的指数的测定来确定间歇推注与连续饲喂对肌肉蛋白合成速率和细胞内调节蛋白活化的影响。在目标2中，氨基酸和胰岛素在介导肌肉蛋白质合成对间歇推注和连续喂养的反应中的作用将使用胰腺底物钳和蛋白质合成的测量以及营养和胰岛素信号蛋白和翻译调节剂的活化来评估。在目标3中，将确定间歇推注与连续饲喂对新生猪肌肉生长的长期影响，并确定调控机制。这项研究将为不同类型的营养支持影响新生儿生长的机制提供新的基础知识。这些研究的独特之处在于，它们使营养素和激素调节蛋白质合成的分子机制的基础研究更接近于改善低出生体重儿床边营养支持的转化水平。公共卫生相关性：管饲，无论是作为连续滴注或间歇推注输送，是低出生体重婴儿的常见临床实践，但这些不同的喂养方式对肌肉生长的影响尚不清楚。我们建议测试的假设，间歇性大剂量喂养促进骨骼肌蛋白质的合成速率比连续喂养，这种反应是由胰岛素和氨基酸介导的，通过激活细胞内信号成分，调节蛋白质的合成。这项工作将为不同类型的营养支持影响新生儿生长的机制提供新的基础知识，从而使基础研究更接近于改善低出生体重儿床边营养管理的转化水平。

DESCRIPTION (provided by applicant): The accretion of skeletal muscle mass is a dominant component of neonatal growth. The long-term objective of this research is to define the mechanisms by which nutrients and hormones regulate the high rate of skeletal muscle protein deposition in neonates, with the goal of identifying new strategies to optimize the nutritional management of low birth weight infants. Our previous work showed that the high rate of muscle protein synthesis in the neonate is due largely to an enhanced activation of mRNA translation after a meal. This heightened response is mediated by amino acids and insulin and is due to enhanced activation of nutrient and insulin signaling pathways and translation initiation factors. Orogastric feeding, using either continuous or intermittent bolus delivery, is a common clinical practice for low birth weight infants with impaired sucking, swallowing, or breathing. There is controversy as to which nutritional support mechanism is optimal. There is strong evidence that intermittent bolus feeding promotes greater weight gain and small intestinal growth than continuous feeding, but whether this is true for skeletal muscle growth is unknown. Preliminary studies suggest that the modest increase in amino acid and insulin levels during continuous feeding, compared to intermittent bolus feeding, may not be sufficient to maximally stimulate muscle protein synthesis due to inadequate activation of translation initiation. This proposal tests the overall hypothesis that intermittent bolus feeding promotes greater rates of skeletal muscle protein synthesis and accretion than continuous feeding and that this response is mediated by amino acids and insulin and their activation of amino acid and insulin signaling components and regulators of translation. The following aims are proposed to address this hypothesis. In Aim 1, the impact of intermittent bolus vs. continuous feeding on rates of muscle protein synthesis and activation of intracellular regulatory proteins will be determined using in vivo kinetic measurements of muscle protein synthesis and determination of indices of nutrient and insulin signaling, translation initiation and elongation, and ribosomal protein translation in skeletal muscle of neonatal pigs. In Aim 2, the role of amino acids and insulin in mediating the response of muscle protein synthesis to intermittent bolus and continuous feeding will be assessed using pancreatic-substrate clamps and measurements of protein synthesis and activation of nutrient and insulin signaling proteins and regulators of translation. In Aim 3, the long-term effects of intermittent bolus vs. continuous feeding on muscle growth in neonatal pigs will be determined and the regulatory mechanisms identified. This research will contribute fundamental new knowledge about the mechanism by which different types of nutritional support influence neonatal growth. The proposed studies are unique in that they bring basic research on the molecular mechanisms by which nutrients and hormones regulate protein synthesis closer to the translational level of improving the bedside nutritional support of low birth weight infants. PUBLIC HEALTH RELEVANCE: Tube feeding, either as a continuous drip or intermittent bolus delivery, is a common clinical practice for low birth weight infants, but the consequence of these different feeding modalities for muscle growth is unknown. We propose to test the hypothesis that intermittent bolus feeding promotes greater rates of synthesis of skeletal muscle proteins than continuous feeding, and that this response is mediated by insulin and amino acids through their activation of intracellular signaling components that regulate protein synthesis. The work will contribute fundamental new knowledge about the mechanism by which different types of nutritional support influence neonatal growth and in so doing brings basic research closer to the translational level of improving the bedside nutritional management of low birth weight infants.