Correction of Hypoxemia and Hypoglycemia Restores Muscle Mitochondrial Respiration and Remodels Mitochondrial Proteome in Growth-Restricted Sheep Fetuses.

Abstract

Placental insufficiency causes fetal hypoxemia and hypoglycemia and is a major driver of fetal growth restriction (FGR). In FGR skeletal muscle, mitochondrial respiration is reduced, partially due to altered mitochondrial protein abundance. We have shown that maternal oxygen and fetal glucose supplementation alleviates fetal hypoxemia and hypoglycemia and improves skeletal muscle satellite cell proliferation. However, its effects on muscle mitochondrial respiratory function and proteomic profiles remain unknown. Here, we tested whether correcting fetal hypoxemia and hypoglycemia restores mitochondrial oxidative phosphorylation and normalizes mitochondrial proteomic profiles in FGR sheep skeletal muscle. Placental insufficiency and FGR were induced by maternal hyperthermia during gestation. Near-term fetuses were chronically catheterized and received 7-10 days of maternal tracheal oxygen insufflation and fetal intravenous (IV) glucose infusion (FOG) or maternal air insufflation and fetal IV saline infusion (FAS). Both were compared to normally-grown control fetuses without supplementation (CON). Principal component analysis of the mitochondrial proteome indicated that FOG clustered closer to CON than to FAS. Abundances of 48 of 80 proteins that were differentially expressed in FAS vs CON returned to CON levels with FOG supplementation. Mitochondria isolated from CON and FOG muscle had similar glutamate/malate-driven state 3 (ADP stimulated) respiration, and both rates were greater than FAS mitochondria. Mitochondrial complex I activity was lower in FAS compared to CON, and FOG showed an intermediate level that was not different from either group. Together, these findings indicate that prenatal oxygen and glucose supplementation rescued mitochondrial respiratory dysfunction and partially normalized mitochondrial proteome in FGR skeletal muscle.