Most premature infants have experienced extrauterine growth restriction by hospital discharge. Many remain small to adulthood and incur short- and long-term costs to their metabolic health, including an increased risk for obesity. Our long-term goal is to identify strategies to optimize the nutritional management of premature infants. The objective of this application is to determine whether prematurity limits the anabolic response to feeding and if this is mitigated by optimizing feeding strategies to enhance the efficiency of nutrient use for anabolic processes. The central hypothesis is that prematurity reduces lean growth, particularly in small for gestational age (SGA) neonates, but lean growth can be improved by cyclical stimulation of mammalian target of rapamycin signaling imparted by either feeding on an intermittent bolus schedule, rather than continuously, or by ad- ministration of intermittent leucine pulses when continuous feeding must be prescribed. The hypothesis is based on data from the applicants' laboratories. The rationale is that understanding the fundamental mechanisms by which different modes of feeding modulate lean mass in early life has the potential to translate into practices that will improve lean growth of preterm infants. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine if prematurity alters the protein synthetic response of muscle to feeding by blunting insulin- and amino acid-induced translation initiation; 2) Determine if lean growth is reduced in the preterm, particularly SGA, but is improved by intermittent bolus feeding rather than continuous feeding delivered either parenterally or enterally; and 3) Determine if intermittent leucine pulses enhance lean growth by stimulating protein synthesis and myonuclear accretion and reducing degradation in pre- term continuously fed neonates. We will determine body composition, growth rate, and muscle protein synthesis and degradation, satellite cell abundance and proliferation, amino acid and insulin signaling, metabolite and whole transcriptome profiles, and insulin and amino acid sensitivity in SGA preterm, appropriate for gestational age (AGA) preterm, and term pigs fed on an intermittent bolus schedule or continuously, either parenterally or enterally, and in those provided intermittent leucine pulses when continuously fed. The methods are established in the applicants' laboratories. The approach is innovative because it will examine in the preterm piglet model the coordinated response of muscle protein synthesis, degradation, myonuclear accretion, amino acid and insulin signaling, and metabolite and transcript profiles that regulate lean growth. The proposed work is unique because it is the first to comprehensively examine in a relevant preterm model the effectiveness of different feeding modalities including a novel leucine supplementation approach on component processes that determine muscle growth. The proposed research is significant because it is expected to advance our under- standing of how prematurity impacts the anabolic response to nutrition. The results will provide important novel information required for the optimization of the nutritional management of preterm infants.
The proposed research is relevant to public health because the discovery of the mechanisms by which prematurity alters muscle growth and the identification of nutritional paradigms that improve lean growth brings basic research closer to the translational level of improving the nutritional support of preterm infants. Thus, the proposed research that will use the preterm piglet as a model of the human preterm infant is relevant to the mission of the NIH as it will provide fundamental new knowledge on how the nutritional management of preterm infants can be optimized to improve both their short- and long-term health.
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