Maternal nutrient restriction and nonhuman primate fetal skeletal muscle developm

描述（由申请方提供）：意义：人类妊娠中的胎儿营养限制（FNR）有多个来源，对器官发育产生不利影响，对后代健康产生长期影响，包括易患肥胖症和2型糖尿病（T2 D）。根本机制仍然不明确。依据：绵羊和大鼠研究表明，FNR影响胎儿骨骼肌（SM）发育，并对成年SM特性产生持久影响。由于SM是葡萄糖和脂肪酸利用的主要场所，以及力的产生，SM特性的变化对后代胰岛素抵抗具有长期影响。迄今为止，这一领域的工作仅限于大鼠和绵羊。使用非人灵长类动物（NHP）的妊娠研究对于确定大鼠和绵羊结果的相关性并允许外推至人类妊娠至关重要。为了支持我们的假设，我们提供了初步的数据，证明下调的哺乳动物雷帕霉素（mTOR）系统的目标在胎儿SM在母体营养限制（MNR）狒狒。假设：FNR通过下调生长信号通路诱导MNR，这通过减少肌纤维数量、改变纤维类型组成和降低线粒体活性来损害NHP中的胎儿SM发育。具体目标：我们将使用我们的FNR狒狒模型来1）分析由30%全局MNR诱导的胎儿SM的结构和组成变化; 2）探索MNR对胎儿SM发育至关重要的信号通路的影响。方法：我们的目标是了解在NHP模型中MNR如何改变胎儿SM的发育和性质。将妊娠狒狒随机分配到对照组（CTR -随意饲喂）和MNR限制组（饲喂70%的CTR）。在妊娠0.9时，对胎儿腓肠肌和比目鱼肌进行取样用于分析。目的：总体目标不仅是确认，而且还将我们对MNR绵羊SM发展的观察扩展到NHP模型;例如，我们包括新的研究，以测试MNR狒狒FSM中的氧化能力和胰岛素敏感性是否改变。创新：这些研究的新奇在于目前完全缺乏关于MNR和胎儿SM发育的NHP数据。工作环境：PI在胎儿SM发育方面具有经验和主要研究兴趣，并发表了大量文章，因此所有所需技术均在进行中。肌肉组织可从NIH P01免费获得。成功完成该项目的所有要求都已到位。影响：所鉴定的组分将为预防和治疗干预提供靶点，以预防FNR诱导的胎儿SM胰岛素抵抗增加。此外，预计这些发现将促进我们对胎儿SM发育如何影响成人SM功能的理解，这将在预防和治疗FNR导致的成人肥胖和T2 D方面具有重要的应用。 公共卫生相关性：胎儿营养缺乏症是由许多妊娠条件引起的，例如母体营养不良、胎盘效率降低、青春期妊娠和妊娠间隔过密。美国农业部经济研究服务局2002年的一项研究表明，11.1%的美国家庭（1200万家庭）经历过粮食不安全或饥饿。很明显，尽管营养限制不引人注目，但它是一个重要的和日益严重的问题，影响到人口，包括当今美国的育龄妇女。此外，母体子宫供血不良、母体应激等并发症也会诱发胎儿营养缺乏。绵羊和大鼠的研究表明，胎儿营养缺乏会影响胎儿骨骼肌的发育，并对成人骨骼肌的特性产生长期影响。由于骨骼肌是葡萄糖和脂肪酸利用的主要场所，以及力的产生，骨骼肌特性的变化对后代的健康有长期的影响。然而，大鼠和绵羊的胎儿发育数据不能自动外推到人类，因为这些动物模型和人类之间存在许多妊娠差异。使用非人灵长类动物的妊娠研究对于确定大鼠和绵羊结果的相关性并允许外推至人类妊娠至关重要。利用从NIH P01项目获得的胎儿肌肉，我们的目标是了解在非人灵长类动物模型中母体营养限制如何改变胎儿骨骼肌的发育和特性。所鉴定的组分将为预防和治疗干预提供靶点，以预防由胎儿营养缺乏诱导的胎儿骨骼肌胰岛素抵抗增加。此外，预计这些结果将促进我们对胎儿骨骼肌发育改变如何影响成人骨骼肌功能的理解，这将在预防和治疗由胎儿营养缺乏引起的成人肥胖和糖尿病方面具有重要的应用。

DESCRIPTION (provided by applicant): SIGNIFICANCE: Fetal nutrient restriction (FNR) in human pregnancy has multiple origins and adversely affects organ development with long-term consequences for offspring health, including pre-disposition to obesity and type2 diabetes (T2D). Underlying mechanisms remain undefined. RATIONALE: Sheep and rat studies indicate that FNR affects fetal skeletal muscle (SM) development with long-lasting effects on adult SM properties. Since SM is the main site of glucose and fatty acid utilization, as well as force generation, changes in SM properties have long-term effects on offspring insulin resistance. To date, work in this area has been exclusively in rats and sheep. Pregnancy studies using nonhuman primates (NHP) are vital to determine relevance of rat and sheep findings and permit extrapolation to human pregnancy. To support our hypothesis we provide preliminary data demonstrating down-regulation of the mammalian target of rapamycin (mTOR) system in fetal SM in maternal nutrient restriction (MNR) baboons. HYPOTHESIS: FNR induced MNR by down-regulates growth signaling pathways which impairs fetal SM development in NHP through decreased muscle fiber number, changed fiber type composition and reduced mitochondrial activity. SPECIFIC AIMS: We will use our baboon model of FNR to 1) analyze structural and compositional changes in fetal SM induced by 30% global MNR; 2) explore MNR effects on signaling pathways crucial for fetal SM development. APPROACH: Our goal is to understand how development and properties of fetal SM are altered by MNR in a NHP model. Pregnant baboons are randomly assigned to a control group (CTR - fed ad libitum) and a MNR restricted group (fed 70% of CTR). At 0.9 gestation, fetal gastrocnemius and soleus muscles are sampled for analyses. OBJECTIVE: The overall goal is not just to confirm but also to extend our observations of SM development in MNR sheep to the NHP model; for example we include new studies testing whether oxidative capacity and insulin sensitivity are altered in FSM of MNR baboons. INNOVATION: The novelty of these studies lies in the complete current lack of NHP data on MNR and fetal SM development. ENVIRONMENT: The PI has experience and major research interest in fetal SM development, and has published extensively so all the required techniques are on-going. Muscle tissues are available at no cost from a funded NIH P01. All requirements for successful completion of this project are in place. IMPACT: The identified components will provide targets for preventive and therapeutic interventions to prevent increased fetal SM insulin resistance induced by FNR. In addition, it is expected that findings will advance our understanding of how altered fetal SM development affects functions of adult SM, which will have important applications in prevention and treatment of adult onset obesity and T2D resulting from FNR. PUBLIC HEALTH RELEVANCE: Fetal nutrient deficiency results from many conditions in pregnancy, e.g. maternal malnutrition, reduced placenta efficiency, adolescence pregnancy, and closely spaced pregnancy. A 2002 study by the Economic Research Service of the United States Department of Agriculture, 11.1 percent of US households (12 million households) experienced either food insecurity or hunger. Clearly in spite of its low profile, nutrient restriction is an important and growing problem that affects the population, including women of child bearing age in the United States today. In addition, poor maternal blood supply to the uterus, maternal stress and other complications will also induce fetal nutrient deficiency. Sheep and rat studies indicate that fetal nutrient deficiency affects fetal skeletal muscle development with long-lasting effects on adult skeletal muscle properties. Since skeletal muscle is the main site of glucose and fatty acid utilization, as well as force generation, changes in skeletal muscle properties have long-term effects on offspring health. However, fetal developmental data from rats and sheep cannot automatically be extrapolated to humans, due to the existence of many differences in pregnancy between those animal models and humans. Pregnancy studies using nonhuman primates are vital to determine relevance of rat and sheep findings and permit extrapolation to human pregnancy. Using the fetal muscle obtained from a funded NIH P01 project, our goal of this project is to understand how development and properties of fetal skeletal muscle are altered by maternal nutrient restriction in a nonhuman primate model. The identified components will provide targets for preventive and therapeutic interventions to prevent increased fetal skeletal muscle insulin resistance induced by fetal nutrient deficiency. In addition, it is expected that the results will advance our understanding of how altered fetal skeletal muscle development affects functions of adult skeletal muscle, which will have important applications in the prevention and treatment of adult onset obesity and diabetes resulting from fetal nutrient deficiency.