Skeletal muscle protein accretion rates and hindlimb growth are reduced in late gestation intrauterine growth‐restricted fetal sheep

Abstract

Reduced skeletal muscle mass in the fetus with intrauterine growth restriction (IUGR) persists into adulthood and may contribute to increased metabolic disease risk. To determine how placental insufficiency with reduced oxygen and nutrient supply to the fetus affects hindlimb blood flow, substrate uptake and protein accretion rates in skeletal muscle, late gestation control (CON) (n = 8) and IUGR (n = 13) fetal sheep were catheterized with aortic and femoral catheters and a flow transducer around the external iliac artery. Muscle protein kinetic rates were measured using isotopic tracers. Hindlimb weight, linear growth rate, muscle protein accretion rate and fractional synthetic rate were lower in IUGR compared to CON (P < 0.05). Absolute hindlimb blood flow was reduced in IUGR (IUGR: 32.9 ± 5.6 ml min^-1 ; CON: 60.9 ± 6.5 ml min^-1 ; P < 0.005), although flow normalized to hindlimb weight was similar between groups. Hindlimb oxygen consumption rate was lower in IUGR (IUGR: 10.4 ± 1.4 μmol min^-1 100 g^-1 ; CON: 14.7 ± 1.3 μmol min^-1 100 g^-1 ; P < 0.05). Hindlimb glucose uptake and lactate output rates were similar between groups, whereas amino acid uptake was lower in IUGR (IUGR: 1.3 ± 0.5 μmol min^-1 100 g^-1 ; CON: 2.9 ± 0.2 μmol min^-1 100 g^-1 ; P < 0.05). Blood O₂ saturation (r² = 0.80, P < 0.0001) and plasma glucose (r² = 0.68, P < 0.0001), insulin (r² = 0.40, P < 0.005) and insulin-like growth factor (IGF)-1 (r² = 0.80, P < 0.0001) were positively associated and norepinephrine (r² = 0.59, P < 0.0001) was negatively associated with hindlimb weight. Slower hindlimb linear growth and muscle protein synthesis rates match reduced hindlimb blood flow and oxygen consumption rates in the IUGR fetus. Metabolic adaptations to slow hindlimb growth are probably hormonally-mediated by mechanisms that include increased fetal norepinephrine and reduced IGF-1 and insulin.