Regulation of Fetal Skeletal Muscle Growth in IUGR

IUGR 胎儿骨骼肌生长的调节

• 批准号: 10589783
• 负责人: Laura Davidson Brown
• 金额: $ 54.3万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589783
• 关键词: Adult; Affect; Alanine; Amino Acids; Animals; Body Composition; Body Weight; Brain; Branched-Chain Amino Acids; Catabolism; Cells; Citric Acid Cycle; Data; Defect; Development; Diabetes Mellitus; Dietary Intervention; Epidemic; Exposure to; Fatty acid glycerol esters; Fetal Growth; Fetal Growth Retardation; Fetal Reduction; Fetal Sheep; Fetal Skeleton; Fetus; Gluconeogenesis; Glutamine; Goals; Growth; Growth Factor; Harvest; Hindlimb; Human; Hypertrophy; Incidence; Incubated; Infusion procedures; Insulin; Insulin Resistance; Intramuscular; Isoleucine; Knowledge; Label; Leucine; Longevity; Metabolic Diseases; Metabolism; Molecular; Molecular Target; Muscle; Muscle Cells; Muscle Fibers; Muscle Proteins; Na(+)-K(+)-Exchanging ATPase; Nutrient; Nutritional; Obesity; Organ; Placental Insufficiency; Pregnancy; Production; Protein Biosynthesis; Proteins; Proteomics; Qualifying; Regulation; Research; Risk; Role; Sarcolemma; Serum; Signal Transduction; Starvation; Techniques; Testing; Time; Valine; Weight; amino acid metabolism; branched-chain-amino-acid transaminase; comparison control; design; diabetes risk; disorder risk; falls; fetal; improved; innovation; metabolomics; muscle form; neonate; novel strategies; obesity risk; perinatal period; prevent; programs; protein expression; reduced muscle mass; response; restoration; sarcopenia; sarcopenic obesity; sheep model; skeletal muscle growth; solute; targeted treatment; uptake

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.

项目摘要 我们的目标是改善胎儿、新生儿和成人的骨骼肌生长和身体组成。 宫内生长受限(IUGR)。胎盘严重限制了胎儿骨骼肌的生长 并导致终生肌肉质量减少(骨骼肌减少)和代谢性疾病风险，使 围产期恢复肌肉质量是当务之急。在之前的项目期间，我们 在高度相关的IUGR绵羊模型中发现胎儿骨骼肌生长存在多种缺陷，包括 肌肉蛋白质合成率(MPS)，相对于大脑和全身重量较低的肌肉质量，较小 与正常生长的对照组相比，肌纤维具有较少的肌核数量和较少的总肌纤维。 基于我们的初步数据，我们已经确定了支链氨基酸(BCAA)中的适应性 导致IUGR胎儿MPS降低的分解代谢。IUGR后肢特定体重的支链氨基酸摄取率 尽管循环中支链氨基酸浓度正常，但仍呈下降趋势，这可能是由于Na+K+-ATPase活性降低 驱使支链氨基酸进入心肌细胞。支链氨基转移酶(BCAT)蛋白表达较高，这是 支链氨基酸分解代谢的第一步，导致从头合成丙氨酸和谷氨酰胺以支持 糖异生、胸膜后垂和能量生产。尽管我们最近取得了进展，但关键是 关于胎盘功能不全编程IUGR肌细胞的机制仍然存在知识空白 减少支链氨基酸摄取，增加支链氨基酸分解代谢。此外，在IUGR期间，还不知道何时 这些机制成为心肌细胞固有的机制，或者如何防止和/或逆转这些机制 促进肌肉生长。我们已经组建了一支由高素质的新陈代谢和 最先进的新陈代谢和蛋白质组学技术来填补这些知识空白。我们将检验这一假设 较低的Na+K+-ATPase和较高的BCAT活性是胎儿心肌细胞增加支链氨基酸分解代谢的内在原因 并在IUGR妊娠结束时限制MPS，但靶向治疗(L-丙氨酰-L-谷氨酰胺，AG)交付 在关键的发育窗口期将改善这些缺陷以增加MPS。在目标1中，我们将确定 降低MPS并测试这些适应的内在程度的细胞机制 肌细胞和/或外源性循环因子诱导胎儿宫内发育迟缓。在目标2中，我们将讨论国会议员 在IUGR怀孕期间变得有限。这一信息对于确定 怀孕期间的治疗旨在促进胎儿生长。在目标3中，我们将测试AG输液的容量 进入IUGR胎儿体内激活Na+K+-ATPase，刺激BCAA摄取，逆转BCAA分解代谢增加 MPS的肌肉内支链动脉。总而言之，这项建议将解决关于BCAA如何 当肌纤维形成时，暴露于胎盘功能不全的胎儿的利用受到调节，肌核是 附着率和肥大率是寿命中最高的。这些研究是必要的 设计恢复肌肉生长的新方法的先决条件。