Decreased
glucose transfer to the fetus is characteristic of pregnancies complicated by maternal under nutrition and
placental insufficiency. Chronic experimental restriction of
glucose transfer to the sheep fetus for the final 40% of gestation with a maternal
insulin infusion (HG fetuses) results in fetal
hypoglycemia, hypoinsulinemia, and decreased rates of fetal growth and
protein accretion compared to controls (CON). Lower rates of fetal
protein accretion are due to increased fetal
protein breakdown and not decreased
protein synthesis. However, the specific skeletal muscle pathways responsible for increased
protein breakdown have not been determined. Nor has it been determined if low fetal
glucose or
insulin concentrations are more important for regulating these skeletal muscle
protein breakdown pathways. We tested whether chronic restriction of
glucose transfer to the fetus increased the
ubiquitin-proteosome pathway or autophagy-lysosome pathway in fetal sheep skeletal muscle and found no evidence for an increase in the autophagy-lysosome pathway. However, HG fetuses had increase
mRNA expression of MaFBx1 (twofold, P < 0.01) and a trend for increased
mRNA expression of MuRF1 (P = 0.08) compared to CON. A subset of chronically
hypoglycemic fetuses received an isoglycemic
insulin infusion for the final 7 days of the maternal
insulin infusion (HG + INS fetuses) and had MaFBx1 and MuRF1
mRNA concentrations similar to CON fetuses. These results demonstrate that fetuses exposed to sustained
hypoglycemia have decreased
protein accretion due to activation of the skeletal muscle
ubiquitin-proteosome pathway and that a fetal hyperinsulinemic clamp can suppress this pathway even in the context of continued
hypoglycemia.