title: Myoblast replication is reduced in the IUGR fetus despite maintained proliferative capacity in vitro.
abstract: Adults who were affected by intrauterine growth restriction (IUGR) suffer from reductions in muscle mass and insulin resistance, suggesting muscle growth may be restricted by molecular events that occur during fetal development. To explore the basis of restricted fetal muscle growth, we used a sheep model of progressive placental insufficiency-induced IUGR to assess myoblast proliferation within intact skeletal muscle in vivo and isolated myoblasts stimulated with insulin in vitro Gastrocnemius and soleus muscle weights were reduced by 25% in IUGR fetuses compared to those in controls (CON). The ratio of PAX7+ nuclei (a marker of myoblasts) to total nuclei was maintained in IUGR muscle compared to CON, but the fraction of PAX7+ myoblasts that also expressed Ki-67 (a marker of cellular proliferation) was reduced by 23%. Despite reduced proliferation in vivo, fetal myoblasts isolated from IUGR biceps femoris and cultured in enriched media in vitro responded robustly to insulin in a dose- and time-dependent manner to increase proliferation. Similarly, insulin stimulation of IUGR myoblasts upregulated key cell cycle genes and DNA replication. There were no differences in the expression of myogenic regulatory transcription factors that drive commitment to muscle differentiation between CON and IUGR groups. These results demonstrate that the molecular machinery necessary for transcriptional control of proliferation remains intact in IUGR fetal myoblasts, indicating that in vivo factors such as reduced insulin and IGF1, hypoxia and/or elevated counter-regulatory hormones may be inhibiting muscle growth in IUGR fetuses.
authors.affiliation: Department of PediatricsUniversity of Colorado School of Medicine, Perinatal Research Center, Aurora, Colorado, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Soto
authors.affiliation: Department of PediatricsUniversity of Colorado School of Medicine, Perinatal Research Center, Aurora, Colorado, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Blake
authors.affiliation: Department of PediatricsUniversity of Colorado School of Medicine, Perinatal Research Center, Aurora, Colorado, USA.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Wesolowski
authors.affiliation: Department of PediatricsUniversity of Colorado School of Medicine, Perinatal Research Center, Aurora, Colorado, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rozance
authors.affiliation: Department of MolecularCellular, and Developmental Biology, University of Colorado Boulder, BioFrontiers Institute, Boulder, Colorado, USA.
authors.forename: Kristen B
authors.initials: KB
authors.lastname: Barthel
authors.affiliation: Department of MedicineUniversity of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Bifeng
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Human PhysiologyUniversity of Oregon, Eugene, Oregon, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Hetrick
authors.affiliation: Department of Human PhysiologyUniversity of Oregon, Eugene, Oregon, USA.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: McCurdy
authors.affiliation: Department of PediatricsUniversity of Colorado School of Medicine, Perinatal Research Center, Aurora, Colorado, USA.
authors.forename: Natalia G
authors.initials: NG
authors.lastname: Garza
authors.affiliation: Department of PediatricsUniversity of Colorado School of Medicine, Perinatal Research Center, Aurora, Colorado, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Hay
authors.affiliation: Department of MolecularCellular, and Developmental Biology, University of Colorado Boulder, BioFrontiers Institute, Boulder, Colorado, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Leinwand
authors.affiliation: Department of PediatricsUniversity of Colorado School of Medicine, Perinatal Research Center, Aurora, Colorado, USA.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
authors.affiliation: Department of PediatricsUniversity of Colorado School of Medicine, Perinatal Research Center, Aurora, Colorado, USA Laura.Brown@ucdenver.edu.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Brown
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D005317:Fetal Growth Retardation / Q000473:pathology*; D007328:Insulin / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects; D011247:Pregnancy; D012756:Sheep
chemical_list: D007328:Insulin
keywords: fetal programming; muscle growth; myogenesis; skeletal muscle