Our long term research goal is to improve innate skeletal muscle growth and body composition in the fetus, neonate, and adult affected by intrauterine growth restriction (IUGR). Impaired muscle growth as a result of IUGR is a major contributor to lifelong reductions in muscle mass (sarcopenia) and metabolic disease risk, making restoration of muscle mass during the perinatal period a high priority. Our overarching aim is to determine the mechanisms that link low fetal amino acid (AA) supply and decreased fetal insulin concentrations from placental insufficiency to decreased muscle growth, and to test whether supplemental AA and/or insulin could restore muscle growth in the IUGR fetus. Our published and preliminary data have identified three key pathways that contribute to reduced numbers of myofibers and decreased myofiber hypertrophy in the IUGR fetus: suppressed myoblast proliferation, reduced muscle amino acid (AA) uptake, and increased protein breakdown. We hypothesize that the restoration of insulin concentrations and AA supply during critical developmental windows of myogenesis will restore proliferative and hypertrophic responses in IUGR fetal muscle. We will use a sheep model of placental insufficiency-induced IUGR that mimics human IUGR to measure muscle-specific growth both in vivo and in vitro.
In Aim 1, we will determine the proliferative activity of fetal myoblasts and their response to restoring insulin concentrations.
In Aim 2, we will determine the mechanisms by which myofiber hypertrophy fails and whether increasing AA supply improves myofiber growth. Finally, in a proof-of-concept Aim 3, we will correct both insulin and AA during appropriate developmental windows to test whether their combination is required to restore skeletal muscle mass in the IUGR fetus. Permanently compromised muscle growth resulting from IUGR is an important contributor to diabetes, obesity, and other serious chronic health issues that are epidemic in the United States. Currently, no therapies are available to treat IUGR prior to the onset of deficits that permanently limit muscle growth. Comprehensive investigation into the key factors that regulate fetal muscle growth at a physiological, cellular, and molecular level is a prerequisite fo designing novel approaches to restore muscle growth, setting the stage for future efforts to preempt the complications of IUGR related to low muscle mass.

Public Health Relevance

The incidence of metabolic diseases such as obesity and diabetes has risen to epidemic proportions. Poor muscle growth resulting from intrauterine growth restriction (IUGR) contributes to lifelong reductions in muscle mass (sarcopenia), obesity, and diabetes risk. This project will determine the molecular mechanisms responsible for reduced fetal skeletal muscle growth, so that nutritional strategies can be targeted to improve muscle growth in IUGR fetuses and neonates.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
Program Officer
Raiten, Daniel J
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University of Colorado Denver
Schools of Medicine
United States
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Boehmer, B H; Brown, L D; Wesolowski, S R et al. (2018) Pulsatile hyperglycemia increases insulin secretion but not pancreatic ?-cell mass in intrauterine growth-restricted fetal sheep. J Dev Orig Health Dis 9:492-499
Wai, Sandra G; Rozance, Paul J; Wesolowski, Stephanie R et al. (2018) Prolonged amino acid infusion into intrauterine growth restricted fetal sheep increases leucine oxidation rates. Am J Physiol Endocrinol Metab :
Jonker, Sonnet S; Kamna, Daniel; Loturco, Dan et al. (2018) IUGR impairs cardiomyocyte growth and maturation in fetal sheep. J Endocrinol :
Rozance, Paul J; Zastoupil, Laura; Wesolowski, Stephanie R et al. (2018) Skeletal muscle protein accretion rates and hindlimb growth are reduced in late gestation intrauterine growth-restricted fetal sheep. J Physiol 596:67-82
Soto, Susan M; Blake, Amy C; Wesolowski, Stephanie R et al. (2017) Myoblast replication is reduced in the IUGR fetus despite maintained proliferative capacity in vitro. J Endocrinol 232:475-491
Brown, Laura D; Kohn, Jaden R; Rozance, Paul J et al. (2017) Exogenous amino acids suppress glucose oxidation and potentiate hepatic glucose production in late gestation fetal sheep. Am J Physiol Regul Integr Comp Physiol 312:R654-R663
Benjamin, Joshua S; Culpepper, Christine B; Brown, Laura D et al. (2017) Chronic anemic hypoxemia attenuates glucose-stimulated insulin secretion in fetal sheep. Am J Physiol Regul Integr Comp Physiol 312:R492-R500
Culpepper, Christine; Wesolowski, Stephanie R; Benjamin, Joshua et al. (2016) Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep. Am J Physiol Regul Integr Comp Physiol 311:R200-8
Barry, James S; Rozance, Paul J; Brown, Laura D et al. (2016) Increased fetal myocardial sensitivity to insulin-stimulated glucose metabolism during ovine fetal growth restriction. Exp Biol Med (Maywood) 241:839-47
Brown, Laura D; Wesolowski, Stephanie R; Kailey, Jenai et al. (2016) Chronic Hyperinsulinemia Increases Myoblast Proliferation in Fetal Sheep Skeletal Muscle. Endocrinology 157:2447-60

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