This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SIGNIFICANCE: Fetal nutrient deficiency in human pregnancy occurs due to a variety of situations, which leads to fetal intrauterine growth restriction (IUGR) with long-term consequences for offspring postnatal health. Fetal stage is crucial for skeletal muscle development since no net increase in skeletal muscle occurs after birth. Our preliminary studies indicate that fetal nutrient deficiency affects fetal skeletal muscle development by down-regulating mTOR signaling and protein synthesis. However, the factors contributing to this down-regulation are unclear. HYPOTHESIS: We hypothesize that reduction in concentration of amino acids in fetal blood due to nutrient deficiency down-regulates mTOR signaling and protein synthesis in fetal muscle. APPROACH: To test our hypothesis, we will use our well-established model in which fetal nutrient deficiency will be induced by 50% nutrient restriction (NR) of ewes. Fetuses of NR ewes will be infused with an amino acid mixture, and mTOR signaling and protein synthesis will be compared with those of uninfused fetuses of NR ewes and controls. OBJECTIVE: The overall goal is to identify the mechanisms by which nutrient deficiency during early to middle gestation down-regulates mTOR signaling and protein synthesis in fetal skeletal muscle. INNOVATION: The proposed work is innovative, because the mechanisms associated with the down-regulation of mTOR signaling and protein synthesis in fetal skeletal muscle have not been studied in vivo in any animal model of NR using nutrient replacement. The identified components are expected to provide targets for preventive and therapeutic interventions that will facilitate fetal muscle development in situations of nutrient deficiency. These interventions will aid the large numbers of pregnant women in this country whose fetuses experienced nutrient deficiency. In addition, it is expected that the results will fundamentally advance our understanding of the interaction between fetal skeletal muscle growth and nutrients, an area poorly studied up to now.
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