Wednesday, January 15, 2025
1/15/2025
PROJECT ABSTRACT Our goal is to improve skeletal muscle growth and body composition in the fetus, neonate, and adult affected by intrauterine growth restriction (IUGR). Fetal skeletal muscle growth is profoundly limited as a result of placental insufficiency and leads to lifelong reductions in muscle mass (sarcopenia) and metabolic disease risk, making restoration of muscle mass during the perinatal period a high priority. During the previous project period, we found multiple defects in fetal skeletal muscle growth in a highly relevant sheep model of IUGR, including lower muscle protein synthesis (MPS) rates, lower muscle mass relative to brain and whole-body weights, smaller myofibers with lower myonuclear number, and fewer total myofibers compared to normally-growing controls. Based on our preliminary data, we have identified adaptations within branched-chain amino acid (BCAA) catabolism that result in lower MPS in the IUGR fetus. Weight-specific BCAA uptake rates by the IUGR hindlimb are reduced despite normal circulating BCAA concentrations, the likely result of lower Na+K+-ATPase activity to drive BCAA into the myocyte. Branched-chain aminotransferase (BCAT) protein expression is higher, which is the first step in BCAA catabolism and results in de novo alanine and glutamine synthesis to support gluconeogenesis, anapleurosis, and energy production. Despite our recent progress, however, critical knowledge gaps remain regarding the mechanisms by which placental insufficiency programs the IUGR myocyte to reduce BCAA uptake and increase BCAA catabolism. Furthermore, it is not known when during an IUGR gestation these mechanisms become intrinsic to the myocyte or how they may be prevented and/or reversed to improve muscle growth. We have assembled a research team of highly qualified experts in metabolism and state-of-the-art metabolomic and proteomic techniques to fill these knowledge gaps. We will test the hypothesis that lower Na+K+-ATPase and higher BCAT activity are intrinsic to the fetal myocyte to increase BCAA catabolism and limit MPS by the end of an IUGR gestation, but that a targeted therapy (L-alanyl-L-glutamine, AG) delivered during a critical developmental window will ameliorate these defects to increase MPS. In Aim 1, we will determine the cellular mechanisms that reduce MPS and test the extent to which these adaptations are intrinsic to the myocyte and/or induced by extrinsic circulating factors the IUGR fetus. In Aim 2, we will address when MPS becomes limited during the course of an IUGR pregnancy. This information is critical to inform the timing of therapies during pregnancy aimed to increase fetal growth. In Aim 3, we will test the capacity of an AG infusion into the IUGR fetus to activate Na+K+-ATPase, stimulate BCAA uptake, and reverse BCAA catabolism to increase intramuscular BCAA for MPS. In summary, this proposal will address gaps in knowledge about how BCAA utilization is regulated in the fetus exposed to placental insufficiency when myofibers are forming, myonuclei are accreting, and hypertrophy rates are some of the highest during the lifespan. These studies are a necessary prerequisite for designing novel approaches to restore muscle growth.
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