Skeletal muscle is a dynamic metabolic tissue that develops from a highly regulated population of myogenic precursor cells. Longitudinal studies in humans demonstrate that deficits in skeletal muscle mass during early life has lasting metabolic consequences. Fetuses with intrauterine growth restriction (IUGR) are born with inadequate muscle mass that never fully recovers, increasing their risk of developing disorders associated with the metabolic syndrome. Therefore, the intrauterine environment is a decisive period to achieve muscle mass over the life course of an individual, and necessitates restoration of muscle mass during the perinatal period. Our overall goal is to improve innate skeletal muscle growth in offspring with IUGR. Our central objective is to define the mechanisms that regulate slow muscle growth and that permanently disrupt transforming growth factor ? (TGF?) signaling in skeletal muscle stem cells (satellite cells) in cases with placental insufficiency and IUGR. Foundational experiments show aberrant TGF? signaling in satellite cells isolated from one-month old lambs with placental insufficiency and IUGR. The results indicate that there is precocious differentiation, cell fusion, and depletion of the myoblast pool, thus providing evidence that permanent dysregulation of TGF? signaling restricts muscle growth in offspring with IUGR. The inherent dysfunctions in TGF? signaling that are created in utero are retained in satellite cells isolated from lambs with IUGR because culture conditions are similar following isolation. We hypothesize that placental insufficiency attenuates TGF? signaling through transcriptional changes and dysregulation of SMAD4 signaling, and that this phenotype is propagated through epigenetic modifications in DNA methylation. We will investigate TGF? activity in a sheep model of placental insufficiency-induced IUGR (PI-IUGR) that represents complications seen in human IUGR, including defects in muscle-specific growth during the perinatal period.
In Aim 1, we will identify the transcriptional signatures that characterize reduced TGF? responsiveness in satellite cells isolated from lambs with PI-IUGR.
In Aim 2, we will evaluate post-translational modifications that influence the SMAD4 interactome in PI-IUGR satellite cells.
In Aim 3, we will define DNA methylation modifications that program TGF? signaling in satellite cells from IUGR lambs. This comprehensive investigation into fundamental factors that regulate postnatal skeletal muscle growth, and specifically the establishment of the skeletal muscle stem cells, is a prerequisite for designing new approaches to restore skeletal muscle mass in offspring with IUGR. This work is significant given no current interventions are available to treat IUGR prior to the onset of adaptations that permanently limit muscle growth and given poor muscle growth is linked to the development of diabetes and obesity. The knowledge gained from this proposal will set the stage for future efforts to preempt the complications of IUGR related to insufficient muscle mass.

Public Health Relevance

Fetal growth restriction causes poor skeletal muscle growth, which contributes to lifelong deficiencies in muscle mass increasing the risk for developing chronic metabolic diseases like diabetes. We show that intrinsic defects in growth factor responses are permanently disrupted in myogenic stem cells. The proposed work will define developmental programming aspects that promote precocious satellite cell differentiation in offspring with fetal growth restriction.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD101791-01
Application #
9957059
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Bremer, Andrew
Project Start
2020-03-10
Project End
2022-02-28
Budget Start
2020-03-10
Budget End
2021-02-28
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Arizona
Department
Veterinary Sciences
Type
Earth Sciences/Resources
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721