Abstract
Intrauterine growth restricted (IUGR) fetuses are born with lower skeletal muscle mass, fewer proliferating myoblasts, and fewer myofibers compared to normally growing fetuses. Plasma concentrations of insulin, a myogenic growth factor, are lower in IUGR fetuses. We hypothesized that a two-week insulin infusion at 75% gestation would increase myoblast proliferation and fiber number in IUGR fetal sheep. Catheterized control fetuses received saline (CON-S, n=6), and the IUGR fetuses received either saline (IUGR-S, n=7) or insulin (IUGR-I, 0.014 ± 0.001 units/kg/hr, n=11) for 14 days. Fetal arterial blood gases and plasma amino acid levels were measured. Fetal skeletal muscles (biceps femoris, BF; and flexor digitorum superficialis, FDS) and pancreases were collected at necropsy (126 ± 2 dGA) for immunochemistry analysis, real-time qPCR, or flow cytometry. Insulin concentrations in IUGR-I and IUGR-S were lower vs. CON-S (P ≤ 0.05, group). Fetal arterial PaO2, O2 content, and glucose concentrations were lower in IUGR-I vs. CON-S (P ≤ 0.01) throughout the infusion period. IGF-1 concentrations tended to be higher in IUGR-I vs. IUGR-S (P=0.06), but both were lower vs. CON-S (P ≤ 0.0001, group). More myoblasts were in S/G2 cell cycle stage in IUGR-I vs. both IUGR-S and CON-S (145% and 113%, respectively, P ≤ 0.01). IUGR-I FDS muscle weighed 40% less and had 40% lower fiber number vs. CON-S (P ≤ 0.05) but were not different from IUGR-S. Myonuclear number per fiber and the mRNA expression levels of muscle regulatory factors were not different between groups. While the pancreatic β-cell mass was lower in both IUGR-I and IUGR-S compared to CON-S, the IUGR groups were not different from each other indicating that feedback inhibition by endogenous insulin did not reduce β-cell mass. A two-week insulin infusion at 75% gestation promoted myoblast proliferation in the IUGR fetus but did not increase fiber or myonuclear number. Myoblasts in the IUGR fetus retain the capacity to proliferate in response to mitogenic stimuli, but intrinsic defects in the fetal myoblast by 75% gestation may limit the capacity to restore fiber number.
Highlights
Intrauterine growth restriction (IUGR) due to placental insufficiency (PI) is a common condition during pregnancy that lowers the supply of both oxygen and nutrients to the developing fetus [1, 2]
IUGR-S and IUGR-I fetal heart weights were 28% and 22% less, the kidneys were 29% and 22% less, and the brains were 12% and 15% less, respectively, when compared to CON-S
After normalizing to body weight, only the ratio of brain:body weight of IUGR-S fetuses was greater compared to CON-S; no statistical differences were found between IUGR-I and CON-S
Summary
Intrauterine growth restriction (IUGR) due to placental insufficiency (PI) is a common condition during pregnancy that lowers the supply of both oxygen and nutrients to the developing fetus [1, 2]. Fetuses exposed to IUGR are born with smaller skeletal muscle mass compared to normally growing counterparts [3, 4]. The consequences of less lean muscle mass affect fetal weight, but persist beyond the perinatal period into adulthood [5, 6], resulting in lasting adverse metabolic health conditions [7,8,9,10]. PI-IUGR fetuses in an experimental fetal sheep model have lower skeletal muscle mass and myofiber number compared to normally growing fetuses [18]. These fetuses have reduced rates of myogenesis, or the capacity for the myoblast to proliferate and fuse into multinucleated myofibers by 90% of gestation [18]. Insulin plays an important role in fetal growth and development; the exact role of insulin in regulating fetal skeletal muscle growth is still being elucidated
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