Maternal nutrient restriction and nonhuman primate fetal skeletal muscle developm

描述（由申请人提供）：意义：人类妊娠中胎儿营养限制（FNR）有多种原因，对器官发育有不利影响，对后代健康有长期影响，包括易患肥胖和2型糖尿病（T2D）。潜在的机制仍未明确。理由：绵羊和大鼠的研究表明，FNR会影响胎儿骨骼肌（SM）的发育，并对成年骨骼肌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部位，因此SM特性的改变对后代胰岛素抵抗有长期影响。迄今为止，这一领域的研究只在老鼠和绵羊身上进行。使用非人类灵长类动物（NHP）进行妊娠研究对于确定大鼠和绵羊研究结果的相关性以及允许外推人类妊娠至关重要。为了支持我们的假设，我们提供了初步数据，证明母体营养限制（MNR）狒狒胎儿SM中雷帕霉素（mTOR）系统的哺乳动物靶点下调。假设：FNR通过下调生长信号通路诱导MNR，通过减少肌纤维数量、改变纤维类型组成、降低线粒体活性等途径损害NHP胎儿SM发育。具体目的：我们将利用我们的狒狒FNR模型，1)分析30%全球MNR诱导的胎儿SM的结构和成分变化；2)探讨MNR对胎儿SM发育关键信号通路的影响。方法：我们的目标是了解在NHP模型中，MNR如何改变胎儿SM的发育和特性。将怀孕的狒狒随机分为对照组（CTR随意饲喂）和MNR限制组（CTR饲喂70%）。在妊娠0.9时，取样胎儿腓肠肌和比目鱼肌进行分析。目的：总体目标不仅是确认，而且要将我们对MNR羊SM发展的观察扩展到NHP模型；例如，我们纳入了新的研究，测试了MNR狒狒的FSM是否改变了氧化能力和胰岛素敏感性。创新：这些研究的新颖之处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，并发表了大量文章，因此所有所需的技术都在进行中。肌肉组织可以从NIH资助的P01中免费获得。成功完成该项目的所有要求都已到位。影响：确定的成分将为预防和治疗干预提供靶点，以防止FNR引起的胎儿SM胰岛素抵抗增加。此外，该研究结果有望促进我们对胎儿SM发育改变如何影响成人SM功能的理解，这将在预防和治疗FNR引起的成人发病肥胖和T2D方面具有重要应用。

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.