Regulation of fetal skeletal muscle growth in IUGR

 描述(由申请人提供)：我们的长期研究目标是改善受宫内生长受限(IUGR)影响的胎儿、新生儿和成人的先天性骨骼肌生长和身体组成。IUGR导致的肌肉生长受损是肌肉质量终生减少(骨质疏松症)和代谢性疾病风险的主要原因，使围产期肌肉质量的恢复成为当务之急。我们的主要目标是确定胎儿氨基酸(AA)供应减少和胎儿胰岛素浓度降低与胎盘功能不全和肌肉生长减少之间的联系机制，并测试补充AA和/或胰岛素是否可以恢复IUGR胎儿的肌肉生长。我们已发表的和初步的数据已经确定了三个关键途径，这些途径有助于IUGR胎儿肌纤维数量减少和肌纤维肥大：抑制成肌细胞增殖，减少肌肉氨基酸(AA)摄取，以及增加蛋白质分解。我们假设，在肌肉发生的关键发育窗口期恢复胰岛素浓度和AA供应将恢复IUGR胎儿肌肉的增殖和肥大反应。我们将使用模拟人类IUGR的胎盘功能不全引起的IUGR的绵羊模型来测量体内和体外的肌肉特异性生长。在目标1中，我们将确定胎儿成肌细胞的增殖活性以及它们对恢复胰岛素浓度的反应。在目标2中，我们将确定肌纤维肥大失败的机制，以及增加AA供应是否促进肌纤维生长。最后，在概念验证目标3中，我们将在适当的发育窗口期纠正胰岛素和AA，以测试它们的组合是否需要恢复IUGR胎儿的骨骼肌量。IUGR导致的肌肉生长永久受损是糖尿病、肥胖症和其他在美国流行的严重慢性健康问题的重要因素。目前，在永久性限制肌肉生长的缺陷出现之前，没有可用的治疗方法来治疗IUGR。在生理、细胞和分子水平上全面研究调节胎儿肌肉生长的关键因素是设计新的恢复肌肉生长的方法的先决条件，为未来努力预防与低肌肉质量相关的IUGR并发症奠定基础。

 DESCRIPTION (provided by applicant): Our long term research goal is to improve innate skeletal muscle growth and body composition in the fetus, neonate, and adult affected by intrauterine growth restriction (IUGR). Impaired muscle growth as a result of IUGR is a major contributor to lifelong reductions in muscle mass (sarcopenia) and metabolic disease risk, making restoration of muscle mass during the perinatal period a high priority. Our overarching aim is to determine the mechanisms that link low fetal amino acid (AA) supply and decreased fetal insulin concentrations from placental insufficiency to decreased muscle growth, and to test whether supplemental AA and/or insulin could restore muscle growth in the IUGR fetus. Our published and preliminary data have identified three key pathways that contribute to reduced numbers of myofibers and decreased myofiber hypertrophy in the IUGR fetus: suppressed myoblast proliferation, reduced muscle amino acid (AA) uptake, and increased protein breakdown. We hypothesize that the restoration of insulin concentrations and AA supply during critical developmental windows of myogenesis will restore proliferative and hypertrophic responses in IUGR fetal muscle. We will use a sheep model of placental insufficiency-induced IUGR that mimics human IUGR to measure muscle-specific growth both in vivo and in vitro. In Aim 1, we will determine the proliferative activity of fetal myoblasts and their response to restoring insulin concentrations. In Aim 2, we will determine the mechanisms by which myofiber hypertrophy fails and whether increasing AA supply improves myofiber growth. Finally, in a proof-of-concept Aim 3, we will correct both insulin and AA during appropriate developmental windows to test whether their combination is required to restore skeletal muscle mass in the IUGR fetus. Permanently compromised muscle growth resulting from IUGR is an important contributor to diabetes, obesity, and other serious chronic health issues that are epidemic in the United States. Currently, no therapies are available to treat IUGR prior to the onset of deficits that permanently limit muscle growth. Comprehensive investigation into the key factors that regulate fetal muscle growth at a physiological, cellular, and molecular level is a prerequisite fo designing novel approaches to restore muscle growth, setting the stage for future efforts to preempt the complications of IUGR related to low muscle mass.