Maternal nutrient restriction and nonhuman primate fetal skeletal muscle developm

说明(申请人提供)：意义：人类妊娠中的胎儿营养限制(FNR)有多种来源，并对器官发育产生不利影响，对后代健康造成长期后果，包括肥胖和2型糖尿病(T2D)的易感性。潜在的机制仍不清楚。理论基础：绵羊和大鼠的研究表明，FNR影响胎儿骨骼肌(SM)的发育，并对成人SM的特性产生长期影响。由于SM是葡萄糖和脂肪酸利用以及力量产生的主要场所，SM属性的变化对后代胰岛素抵抗有长期影响。到目前为止，这一领域的研究仅限于老鼠和绵羊。使用非人类灵长类动物(NHP)进行怀孕研究对于确定老鼠和绵羊的发现的相关性并允许对人类怀孕进行外推至关重要。为了支持我们的假设，我们提供了初步的数据，证明在母体营养限制(MNR)的狒狒中，哺乳动物雷帕霉素靶标(MTOR)系统在胎儿SM中下调。假说：FNR通过下调生长信号通路，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中胎儿SM的发育，从而诱导MNR。具体目标：我们将使用我们的恒河猴FNR模型来1)分析30%全局MNR对胎儿SM结构和成分的影响；2)探讨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是如何改变胎儿SM的发育和性质的。将怀孕的狒狒随机分为对照组(自由采食CTR)和MNR限制组(饲喂70%的CTR)。在0.9孕龄时，取胎儿腓肠肌和比目鱼肌进行分析。目的：总体目标不仅是为了证实我们对MNR绵羊SM发育的观察，也是为了将我们对SM发育的观察扩展到NHP模型；例如，我们包括新的研究，测试MNR狒狒的FSM中的氧化能力和胰岛素敏感性是否发生改变。创新：这些研究的新颖性在于目前完全缺乏关于MNR和胎儿SM发育的NHP数据。环境：PI在胎儿SM发育方面有经验和主要研究兴趣，并已广泛发表，因此所有必要的技术都在进行中。肌肉组织可以从美国国立卫生研究院资助的P01免费获得。成功完成这一项目的所有要求都已到位。影响：已确定的成分将为预防和治疗干预提供目标，以防止FNR导致的胎儿SM胰岛素抵抗增加。此外，这些发现将有助于我们了解胎儿SM发育改变如何影响成人SM的功能，这将在预防和治疗成人发作性肥胖和FNR引起的T2D方面有重要应用。 公共卫生相关性：胎儿营养缺乏是孕期许多情况造成的，例如产妇营养不良、胎盘效率降低、青春期怀孕和近距离妊娠。美国农业部经济研究处2002年的一项研究显示，11.1%的美国家庭(1200万户)经历了粮食不安全或饥饿。显然，尽管营养限制很低调，但它是一个影响人口的重要且日益严重的问题，包括今天美国的育龄妇女。此外，母体子宫供血不畅、母体应激等并发症也会诱发胎儿营养缺乏症。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，并对成年骨骼肌的特性产生长期影响。由于骨骼肌是利用葡萄糖和脂肪酸以及产生力量的主要部位，骨骼肌特性的变化对后代的健康有长期影响。然而，老鼠和绵羊的胎儿发育数据不能自动推断到人类，因为这些动物模型和人类在怀孕方面存在许多差异。使用非人类灵长类动物进行怀孕研究对于确定老鼠和绵羊的发现的相关性并允许对人类怀孕进行外推至关重要。使用从NIH P01资助项目中获得的胎儿肌肉，我们这个项目的目标是在一个非人类灵长类动物模型中了解母体营养限制如何改变胎儿骨骼肌的发育和特性。已确定的成分将为预防和治疗干预提供目标，以防止因胎儿营养缺乏而导致的胎儿骨骼肌胰岛素抵抗增加。此外，这一结果将有助于我们进一步了解胎儿骨骼肌发育改变对成人骨骼肌功能的影响，这将在预防和治疗因胎儿营养缺乏而导致的成人发作性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.