Key pointsr To investigate loss of skeletal muscle mass in intrauterine growth-restricted (IUGR) fetuses near term, which may result from myoblast dysfunction, we examined semitendinosus myofibre and myoblast morphology in placental insufficiency-induced IUGR sheep fetuses; we also isolated and cultured IUGR fetal myoblasts to determine whether reduced rates of proliferation were due to intrinsic cellular defects or extrinsic factors associated with serum.r Using tests for myogenin and pax7 to identify differentiated and undifferentiated fetal myoblasts, respectively, we found that myofibre area and percentage of myogenin-positive nuclei were less in IUGR fetal semitendinosus muscles than in controls, but myofibre density and percentage of pax7-positive nuclei were not different.r The percentage of pax7-positive cells that expressed proliferating cellular nuclear antigen was less in IUGR semitendinosus muscles than in controls, while in myoblasts isolated from fetal sheep and replicated and differentiated in culture, IUGR fetal myoblasts proliferated at slower rates than control myoblasts, under identical culture conditions, but the ability to differentiate was similar between treatments.r Media supplemented with IUGR serum decreased replication rates in both IUGR and control myoblasts compared to media supplemented with control fetal serum.r These findings show that myoblasts proliferate at slower rates in IUGR fetuses due to a combination of intrinsic cellular characteristics and extrinsic serum factors; the intrinsic defects may explain reduced skeletal muscle mass observed in IUGR newborn children and adults.Abstract Intrauterine growth restriction (IUGR) reduces skeletal muscle mass in fetuses and offspring. Our objective was to determine whether myoblast dysfunction due to intrinsic cellular deficiencies or serum factors reduces myofibre hypertrophy in IUGR fetal sheep. At 134 days, IUGR fetuses weighed 67% less (P < 0.05) than controls and had smaller (P < 0.05) carcasses and semitendinosus myofibre areas. IUGR semitendinosus muscles had similar percentages of pax7-positive nuclei and pax7 mRNA but lower (P < 0.05) percentages of myogenin-positive nuclei (7 ± 2% and 13 ± 2%), less myoD and myogenin mRNA, and fewer (P < 0.05) proliferating myoblasts (PNCA-positive-pax7-positive) than controls (44 ± 2% vs. 52 ± 1%). Primary myoblasts were isolated from hindlimb muscles, and after 3 days in growth media (20% fetal bovine serum, FBS), myoblasts from IUGR fetuses had 34% fewer (P < 0.05) myoD-positive cells than controls and replicated 20% less (P < 0.05) during a 2 h BrdU pulse. IUGR myoblasts also replicated less (P < 0.05) than controls during a BrdU pulse after 3 days in media containing 10% control or IUGR fetal sheep serum (FSS). Both myoblast types replicated less (P < 0.05) with IUGR FSS-supplemented media compared to control FSS-supplemented media. In differentiation-promoting media (2% FBS), IUGR and control myoblasts had similar percentages of myogenin-positive nuclei after 5 days and formed similar...
Fetal adaptations to placental insufficiency alter postnatal metabolic homeostasis in skeletal muscle by reducing glucose oxidation rates, impairing insulin action, and lowering the proportion of oxidative fibers. In animal models of intrauterine growth restriction (IUGR), skeletal muscle fibers have less myonuclei at birth. This means that myoblasts, the sole source for myonuclei accumulation in fibers, are compromised. Fetal hypoglycemia and hypoxemia are complications that result from placental insufficiency. Hypoxemia elevates circulating catecholamines, and chronic hypercatecholaminemia has been shown to reduce fetal muscle development and growth. We have found evidence for adaptations in adrenergic receptor expression profiles in myoblasts and skeletal muscle of IUGR sheep fetuses with placental insufficiency. The relationship of β-adrenergic receptors shifts in IUGR fetuses because Adrβ2 expression levels decline and Adrβ1 expression levels are unaffected in myofibers and increased in myoblasts. This adaptive response would suppress insulin signaling, myoblast incorporation, fiber hypertrophy, and glucose oxidation. Furthermore, this β-adrenergic receptor expression profile persists for at least the first month in IUGR lambs and lowers their fatty acid mobilization. Developmental programming of skeletal muscle adrenergic receptors partially explains metabolic and endocrine differences in IUGR offspring, and the impact on metabolism may result in differential nutrient utilization.
Chen X, Green AS, Macko AR, Yates DT, Kelly AC, Limesand SW. Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep. Am J Physiol Endocrinol Metab 306: E58 -E64, 2014. First published November 19, 2013 doi:10.1152/ajpendo.00517.2013.-Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and -cell dysfunction. Previously, we showed that acute adrenergic blockade revealed enhanced insulin secretion responsiveness in the IUGR fetus. To determine whether chronic exposure to NE alone enhances -cell responsiveness afterward, we continuously infused NE into fetal sheep for 7 days and, after terminating the infusion, evaluated glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-induced insulin secretion (GPAIS). During treatment, NE-infused fetuses had greater (P Ͻ 0.05) plasma NE concentrations and exhibited hyperglycemia (P Ͻ 0.01) and hypoinsulinemia (P Ͻ 0.01) compared with controls. GSIS during the NE infusion was also reduced (P Ͻ 0.05) compared with pretreatment values. GSIS and GPAIS were approximately fourfold greater (P Ͻ 0.01) in NE fetuses 3 h after the 7 days that NE infusion was discontinued compared with age-matched controls or pretreatment GSIS and GPAIS values of NE fetuses. In isolated pancreatic islets from NE fetuses, mRNA concentrations of adrenergic receptor isoforms (␣1D, ␣2A, ␣2C, and 1), G protein subunit-␣i-2, and uncoupling protein 2 were lower (P Ͻ 0.05) compared with controls, but -cell regulatory genes were not different. Our findings indicate that chronic exposure to elevated NE persistently suppresses insulin secretion. After removal, NE fetuses demonstrated a compensatory enhancement in insulin secretion that was associated with adrenergic desensitization and greater stimulus-secretion coupling in pancreatic islets. adrenergic receptor; -cell; intrauterine growth restriction; uncoupling protein 2; catecholamines SMALL-FOR-GESTATIONAL AGE or intrauterine growth-restricted (IUGR) infants are at greater risk for developing metabolic diseases such as type 2 diabetes mellitus (29,40,54). Impaired insulin secretion is associated with a diabetic phenotype indicating that in utero complications can permanently compromise -cell development and function (27,28). A fetal sheep model with placental insufficiency-induced intruterine growth restriction shares many similarities with human IUGR fetuses, such as asymmetric growth, hypoxemia, hypoglycemia, hypoinsulinemia, and hypercatecholaminemia [epinephrine and norepinephrine (NE)] (4, 16,18,22,23,32,41,47). Furthermore, glucose-stimulated insulin secretion (GSIS) and -cell mass are lower in IUGR sheep fetuses, which also replicate features in human IUGR fetuses (34 -36, 41, 53). Several characteristics of the fetal IUGR environment, including hypoglycemia, hypoxemia, and hypercatecholaminemia, are proposed to ...
Intrauterine growth restriction (IUGR) reduces muscle mass and insulin sensitivity in offspring. Insulin sensitivity varies among muscle fiber types, with Type I fibers being most sensitive. Differences in fiber-type ratios are associated with insulin resistance in adults, and thus we hypothesized that near-term IUGR sheep fetuses exhibit reduced size and proportions of Type I fibers. Placental insufficiency-induced IUGR fetuses were ∼54% smaller (P < 0.05) than controls and exhibited hypoxemia and hypoglycemia, which contributed to 6.9-fold greater (P < 0.05) plasma norepinephrine and ∼53% lower (P < 0.05) plasma insulin concentrations. IUGR semitendinosus muscles contained less (P < 0.05) myosin heavy chain-I protein (MyHC-I) and proportionally fewer (P < 0.05) Type I and Type I/IIa fibers than controls, but MyHC-II protein concentrations, Type II fibers, and Type IIx fibers were not different. IUGR biceps femoris muscles exhibited similar albeit less dramatic differences in fiber type proportions. Type I and IIa fibers are more responsive to adrenergic and insulin regulation than Type IIx and may be more profoundly impaired by the high catecholamines and low insulin in our IUGR fetuses, leading to their proportional reduction. In both muscles, fibers of each type were uniformly smaller (P < 0.05) in IUGR fetuses than controls, which indicates that fiber hypertrophy is not dependent on type but rather on other factors such as myoblast differentiation or protein synthesis. Together, our findings show that IUGR fetal muscles develop smaller fibers and have proportionally fewer Type I fibers, which is indicative of developmental adaptations that may help explain the link between IUGR and adulthood insulin resistance.
In pregnancies complicated by placental insufficiency (PI), fetal hypoglycemia and hypoxemia progressively worsen during the third trimester, which increases circulating norepinephrine (NE). Pharmacological adrenergic blockade (ADR-block) at 0.9 gestation revealed that NE inhibits insulin secretion and enhanced β-cell responsiveness in fetuses with PI-induced intrauterine growth restriction (IUGR). NE concentrations in PI fetuses at 0.7 gestation were 3-fold greater compared to age-matched controls but the levels were similar to near-term controls. Therefore, our objective was to determine whether elevations in plasma NE concentrations inhibit insulin secretion and produce compensatory β-cell responsiveness in PI fetuses at 0.7 gestation. Fetal insulin was measured under basal, glucose-stimulated (GSIS), and glucose potentiated arginine-stimulated (GPAIS) conditions in the absence and presence of an ADR-block. Placental weights were 38% lower (P<0.05) in PI fetus than in controls, but fetal weights were not different. PI fetuses had lower (P<0.05) basal blood oxygen content, plasma glucose, IGF-1, and insulin concentrations and greater plasma NE concentrations (891±211 vs. 292±65 pg/ml; P<0.05) than controls. GSIS was lower in PI fetuses than in controls (0.34±0.03 vs. 1.08±0.06 ng/ml; P<0.05). ADR-block increased GSIS in PI fetuses (1.19±0.11 ng/ml; P<0.05) but decreased GSIS in controls (0.86±0.02 ng/ml; P<0.05). Similarly, GPAIS was 44% lower (P<0.05) in PI fetuses than in controls, and ADR-block increased (P<0.05) GPAIS in PI fetuses but not in controls. Insulin content per islet was not different between treatments. We conclude that elevations in fetal plasma NE suppress insulin concentrations and that compensatory β-cells stimulus-secretion responsiveness is present before IUGR.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.