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.
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.
| Du, Min; Yan, Xu; Tong, Jun F et al. (2010) Maternal obesity, inflammation, and fetal skeletal muscle development. Biol Reprod 82:4-12 |
| Zhao, Junxing; Yue, Wanfu; Zhu, Mei J et al. (2010) AMP-activated protein kinase (AMPK) cross-talks with canonical Wnt signaling via phosphorylation of beta-catenin at Ser 552. Biochem Biophys Res Commun 395:146-51 |
