Evaluation of Cardiac and Skeletal Muscle Progenitor Cell Dynamics in Growth Restricted Fetuses
Loading...
Date
2025-02-24
Authors
Barooni, Neeka
Journal Title
Journal ISSN
Volume Title
Publisher
University of Oregon
Abstract
Fetal growth restriction (FGR) increases the risk of cardiometabolic disease due in part to deficits in cardiac and skeletal muscle growth that are not fully compensated for after birth. Deficits in fetal cardiomyocyte number and maturity are thought to mediate lifelong cardiac dysfunction in FGR offspring. Similarly, the total number of skeletal muscle myofibers is set in utero. Thus, reductions in fetal myofiber number and hypertrophic enlargement limit skeletal muscle growth and metabolic function throughout the lifespan. Previous studies identify decreased cell cycle activity in cardiac and skeletal muscle of FGR fetuses. Additionally, reductions in myogenic regulator factor (MRF) expression and in the frequency of binucleated cardiomyocytes imply impairments in terminal differentiation and maturation in FGR muscle. Due to limitations in current techniques, whether cardiac and skeletal muscle progenitor cells of FGR fetuses exhibit decreased proliferation and/or myogenic capacity in vivo remains a critical gap in knowledge.
Using an ovine model of placental insufficiency and FGR, this dissertation aimed to identify the cellular origins of dysregulated cardiac and skeletal muscle development in FGR fetuses. We hypothesized that intrauterine stress exposure disrupts proliferation and differentiation programs in muscle progenitor cells of FGR fetuses, thereby limiting cardiac and skeletal muscle growth and function both in utero and throughout postnatal life. To test this hypothesis, we developed a novel flow cytometry approach to evaluate cardiomyocyte and skeletal myoblast development in late-gestation FGR and CON fetuses.
We identified impairments in cardiomyocyte development in FGR hearts, with distinct phenotypes specific to the left and right ventricles (LV, RV). Cardiomyocyte endocycling was upregulated in both ventricles of FGR fetuses. However, this increase appeared to compromise LV cardiomyocyte differentiation and maturity, while RV cardiomyocyte proliferation was notably reduced in FGR hearts. In the skeletal muscle of FGR fetuses, we observed decreased rates of myoblast proliferation and fewer myoblasts in the early stages of myogenesis. The proportion of unfused, late-differentiation myoblasts was increased in FGR, but this is likely due to impairments in myoblast fusion, as indicated by decreased Myomaker abundance in FGR skeletal muscle. Both cardiomyocyte and skeletal myoblast dynamics correlated with fetal IGF-1 concentrations. Our findings suggest that exogenous growth factor stimulation may be necessary or sufficient to restore fetal cardiac and skeletal muscle growth, potentially reducing the risk of cardiometabolic disease in offspring with prior FGR.