Lower Metabolic Capacity in Skeletal Muscle Mitochondria From Intrauterine Growth Restricted Sheep Fetuses

Abstract

Placental insufficiency (PI) induced intrauterine growth restriction (IUGR) increases the risk of mortality and morbidity in both newborns and adults. PI causes a progressive, chronic, and severe decline in the maternal-fetal nutrient transport starting in mid-gestation, which results in fetal hypoxemia and hypoglycemia. Unfortunately, the decline in nutrient availability occurs concurrently with critical myogenic windows in fetal development establishing the proper complement of skeletal muscle mass in utero. Thus, IUGR fetuses are also afflicted with sarcopenia that persists into adulthood and predisposes offspring to metabolic diseases. Recent evidence indicates that the metabolic capacity of the skeletal muscle of IUGR fetuses is lowered in response to low nutrient availability. IUGR skeletal muscle adaptations to low nutrient availability includes lower protein synthesis rates as well as lower fractional glucose oxidation and amino acid oxidation rates. In the current studies, we test the hypothesis that mitochondria isolated from IUGR fetal sheep skeletal muscle have defects in both nutrient oxidation and energy production. Previous findings have linked hypoglycemia and hypoxemia to lower glucose oxidation rates in the IUGR fetus. It was postulated that pyruvate oxidation was hindered in IUGR skeletal muscle mitochondria due to the inhibition pyruvate dehydrogenase (PDH), the first step in pyruvate metabolism. However, we show PDH activity is 67% higher in IUGR skeletal muscle. Moreover, the abundance of Mitochondrial Pyruvate Carrier 2 (MPC2), the primary mitochondrial pyruvate transporter, as well as the abundances of rate-limiting Tricarboxylic Acid Cycle (TCA) enzymes, isocitrate dehydrogenase and oxoglutarate dehydrogenase, are lower in IUGR mitochondria compared to controls (P<0.05). The lower abundances of enzymes involved in substrate oxidation in IUGR fetuses are accompanied by a 47% lower complex-I mediated oxygen consumption rate (OCR) and 18% lower Complex I activity, both of which indicate impaired electron transport chain (ETC) function. Reduced pyruvate oxidation in IUGR fetal skeletal muscle is the result of concomitant decreases in pyruvate transport, TCA cycle function, and ETC function. Fetal adaptations to nutrient restriction program metabolic dysfunction in postnatal skeletal muscle in IUGR individuals. We hypothesized that mitochondria isolated from myotubes which are differentiated from 30-day old IUGR lamb satellite cells have a 44% lower complex-I mediated OCR compared to controls. The lower OCR in IUGR myotube mitochondria is associated with lower abundances of ETC Complex III and IV subunit abundances. Although the mitochondrial metabolic changes observed in IUGR myotubes differ from the metabolic changes observed in IUGR fetal skeletal muscle mitochondria, these results show the persistence of skeletal muscle mitochondrial dysfunction in IUGR individuals from birth into postnatal life.