Impact of fetal inflammatory adaptations on metabolic outcomes in intrauterine growth restricted offspring

University Of Nebraska Lincoln, Lincoln NE

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Abstract

PROJECT SUMMARY/ABSTRACT Intrauterine growth restriction (IUGR) results from fetal stress and impairs lifelong muscle growth and metabolic health. Fetal adaptations that reduce myoblast function and muscle glucose oxidation mediate these pathologies, but the underlying molecular mechanisms of these adaptations are unknown, which is a barrier to developing preventative treatments. Recent preliminary findings indicate that potential mechanisms include enhancement of TNF? Receptor 1 (TNFR1) and Toll-Like Receptor 4 (TLR4) signaling pathways in muscle via greater gene expression for key pathway components, stabilization of TRAF6 via upregulated USP25, and reduced content of the NF?B inactivator I?B?. Because inflammatory pathways regulate muscle growth and metabolism, they represent ideal potential targets for therapies to improve IUGR outcomes. Based on this premise, the proposed study aims to test if the use of the nutraceutical curcumin ? which is known to reduce TNFR1 and TLR4 pathways ? can be used to overcome in utero enhancement of these pathways. Findings in this project will contribute to Dr. Yates' long-term goal of improving muscle growth and metabolism in IUGR fetuses and offspring by identifying and targeting underlying fetal adaptations. The experiments in this application will use a well- characterized ovine model to test the hypothesis that maternofetal supplementation with the food-borne biomolecule curcumin will improve muscle glucose oxidation and myoblast function in IUGR-born neonates by mitigating the effects of enhanced inflammatory pathways. This hypothesis will be tested through two specific aims (SAs), which are to determine the extent to which suppressing enhanced inflammatory pathways improves glucose oxidation (SA1) and myoblast function and hypertrophic growth (SA2) in IUGR skeletal muscle. In vivo and ex vivo experiments in SA1 will determine insulin-stimulated glucose uptake and oxidation in muscle of controls, IUGR lambs, and IUGR lambs born to curcumin-supplemented ewes. Metabolic phenotypes will be determined in major muscle groups by staining for fiber type ratios, and gene/protein expression of key TNFR1 and TLR4 pathway components will be measured. Experiments in SA2 will determine functional capacity in cultured IUGR myoblasts, which can then be compared to myoblast population dynamics determined by muscle staining. Fiber size, number, and density will indicate hypertrophic muscle growth, and serial ultrasound and bioimpedance measures will estimate muscle accretion, fat deposition, and body composition. The expected results will indicate whether mitigating the effects of enhanced inflammatory signaling in IUGR fetuses improves postnatal metabolic health by: 1) improving insulin responsiveness and glucose oxidation in IUGR muscle and 2) abolishing intrinsic functional deficits in myoblasts and restoring muscle growth. Data from the study will determine if these signaling pathways are appropriate targets for prenatal therapies to improve IUGR metabolic outcomes, which coincides with the Nebraska Center for the Prevention of Obesity through Dietary Molecules (NPOD)'s theme of identifying food-borne bio-signals to prevent, treat, and cure obesity-related diseases.