? DESCRIPTION (provided by applicant): 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.

R01HD079404

2015-04-01

2027-02-28