Prolonged Maternofetal Inflammation in the Pregnant Ewe at Mid-Gestation Increases Subsequent Fetal Inflammatory Tone and Disrupts Skeletal Muscle Growth and Glucose Metabolism Near Term

Abstract Chronic maternofetal inflammation in late gestation (i.e., peak fetal growth) causes fetal intrauterine growth restriction (IUGR) in sheep, which was associated with deficits in growth, body composition, and metabolic function before and after birth. However, the impact of sustained maternofetal inflammation during mid-gestation (i.e., peak placental growth and development) has not been explored. Therefore, our objective was to determine the effects of sustained maternofetal inflammation during this critical window on subsequent fetal inflammatory tone, metabolism, and myoblast (i.e., muscle stem cell) function. Pregnant ewes were injected every 3rd day from the 50th to 65th d of gestational age (dGA; term = 150 dGA) with saline (control; n = 12) or bacterial lipopolysaccharide endotoxin to induce maternofetal inflammation and IUGR (MI-IUGR; n = 12). Fetuses were surgically catheterized on dGA 118 to collect blood samples, and a hyperinsulinemic-euglycemic clamp (HEC) was performed on dGA 123. Fetuses were necropsied on dGA 125 to collect semitendinosus muscle samples. Fetal plasma TNFα concentrations tended to be greater (P = 0.07) for MI-IUGR fetuses (440 ± 45 pg/m l) than for controls (348 ± 24 pg/mL). Fetal blood O2 partial pressures were 12% less (P < 0.05) and maternofetal O2 gradients tended to be 11% greater (P = 0.08) for MI-IUGR fetuses than for controls. Hindlimb-specific glucose uptake rates did not differ between fetal groups, but hindlimb-specific glucose oxidation rates were reduced (P < 0.05) by 15% under basal conditions and by 27% under hyperinsulinemic conditions for MI-IUGR fetuses compared with controls. Semitendinosus glycogen content and β2 adrenoceptor content did not differ between fetal groups, but semitendinosus content of the TNFα receptor, TNFR1, was 41% greater (P < 0.05) for MI-IUGR fetuses than for controls. Immunohistochemistry revealed 18% fewer (P < 0.05) proliferating myoblasts (pax7+/Ki67+) and 38% fewer (P < 0.05) differentiated myoblasts (myogenin+) in semitendinosus from MI-IUGR fetuses compared with controls, which coincided with 13% smaller (P < 0.05) muscle fibers. From these findings, we conclude that sustained maternofetal inflammation during peak placental development at mid-gestation resulted in enhanced fetal inflammatory tone near term, which in turn impaired myoblast function, muscle fiber hypertrophy, and muscle glucose metabolism.