title: Chronic Hyperinsulinemia Increases Myoblast Proliferation in Fetal Sheep Skeletal Muscle.
abstract: Insulin is an important fetal growth factor. However, chronic experimental hyperinsulinemia in the fetus fails to accelerate linear and lean mass growth beyond normal rates. Mechanisms preventing accelerated lean mass accretion during hyperinsulinemia are unknown. To address potential mechanisms, late-gestation fetal sheep were infused with iv insulin and glucose to produce euglycemic hyperinsulinemia (INS) or saline for 7-9 days. Fetal substrate uptake and protein metabolic rates were measured. INS fetuses had 1.5-fold higher insulin concentrations (P < .0001) and equivalent glucose concentrations. INS fetuses had 20% more Pax7(+) nuclei in the biceps femoris, which indicates the potential for hyperinsulinemia to increase the number of myoblasts within late-gestation fetal skeletal muscle. Additionally, the percentage of Pax7(+) myoblasts that expressed Ki-67 was 1.3-fold higher and expression of myogenic regulatory factors was 50% lower in INS fetuses (MYF5 and MYOG [myogenin], P < .005), which indicates a shift toward myoblast proliferation over differentiation. There were no differences for fetal body, organ, or muscle weights, although INS placentas weighed 28% less (P < .05). Protein synthesis and accretion rates did not change in INS fetuses, nor did fiber muscle size. Essential amino acid concentrations were lower in the INS group (P < .05) except for tryptophan. Umbilical blood flow, net total amino acids, and O2 uptakes rates did not differ between groups. Arterial O2 content was 33% lower (P < .005) and norepinephrine was 100% higher in the INS fetuses (P < .01), all of which are factors that may counteract fetal protein accretion during hyperinsulinemia despite an increase in myoblast proliferation.
authors.affiliation: Perinatal Research Center (L.D.B., S.R.W., J.K., S.B., A.W., W.W.H., P.J.R.), Department of Pediatrics, Center for Women's Health Research (L.D.B., S.R.W., P.J.R.), and Department of Obstetrics and Gynecology (S.E.A.), University of Colorado Denver School of Medicine, Aurora, Colorado 80045.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Brown
authors.affiliation: Perinatal Research Center (L.D.B., S.R.W., J.K., S.B., A.W., W.W.H., P.J.R.), Department of Pediatrics, Center for Women's Health Research (L.D.B., S.R.W., P.J.R.), and Department of Obstetrics and Gynecology (S.E.A.), University of Colorado Denver School of Medicine, Aurora, Colorado 80045.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Wesolowski
authors.affiliation: Perinatal Research Center (L.D.B., S.R.W., J.K., S.B., A.W., W.W.H., P.J.R.), Department of Pediatrics, Center for Women's Health Research (L.D.B., S.R.W., P.J.R.), and Department of Obstetrics and Gynecology (S.E.A.), University of Colorado Denver School of Medicine, Aurora, Colorado 80045.
authors.forename: Jenai
authors.initials: J
authors.lastname: Kailey
authors.affiliation: Perinatal Research Center (L.D.B., S.R.W., J.K., S.B., A.W., W.W.H., P.J.R.), Department of Pediatrics, Center for Women's Health Research (L.D.B., S.R.W., P.J.R.), and Department of Obstetrics and Gynecology (S.E.A.), University of Colorado Denver School of Medicine, Aurora, Colorado 80045.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bourque
authors.affiliation: Perinatal Research Center (L.D.B., S.R.W., J.K., S.B., A.W., W.W.H., P.J.R.), Department of Pediatrics, Center for Women's Health Research (L.D.B., S.R.W., P.J.R.), and Department of Obstetrics and Gynecology (S.E.A.), University of Colorado Denver School of Medicine, Aurora, Colorado 80045.
authors.forename: Averi
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Perinatal Research Center (L.D.B., S.R.W., J.K., S.B., A.W., W.W.H., P.J.R.), Department of Pediatrics, Center for Women's Health Research (L.D.B., S.R.W., P.J.R.), and Department of Obstetrics and Gynecology (S.E.A.), University of Colorado Denver School of Medicine, Aurora, Colorado 80045.
authors.forename: Sasha E
authors.initials: SE
authors.lastname: Andrews
authors.affiliation: Perinatal Research Center (L.D.B., S.R.W., J.K., S.B., A.W., W.W.H., P.J.R.), Department of Pediatrics, Center for Women's Health Research (L.D.B., S.R.W., P.J.R.), and Department of Obstetrics and Gynecology (S.E.A.), University of Colorado Denver School of Medicine, Aurora, Colorado 80045.
authors.forename: William W
authors.initials: WW
authors.lastname: Hay
authors.affiliation: Perinatal Research Center (L.D.B., S.R.W., J.K., S.B., A.W., W.W.H., P.J.R.), Department of Pediatrics, Center for Women's Health Research (L.D.B., S.R.W., P.J.R.), and Department of Obstetrics and Gynecology (S.E.A.), University of Colorado Denver School of Medicine, Aurora, Colorado 80045.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rozance
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D005333:Fetus / Q000378:metabolism / Q000473:pathology; D006946:Hyperinsulinism / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D012756:Sheep
chemical_list: D007328:Insulin