Prolonged amino acid infusion into intrauterine growth-restricted fetal sheep increases leucine oxidation rates

Abstract

Overcoming impaired growth in an intrauterine growth restricted (IUGR) fetus has potential to improve neonatal morbidity, long-term growth, and metabolic health outcomes. The extent to which fetal anabolic capacity persists as the IUGR condition progresses is not known. We tested whether prolonged amino acid infusion would increase protein accretion in the IUGR fetus produced from chronic placental insufficiency. IUGR fetal sheep were infused for 10 days with either mixed amino acids providing ~2 g·kg·day (IUGR-AA) or saline (IUGR-Sal) during late gestation. At the end of the infusion, fetal plasma leucine, isoleucine, lysine, methionine, and arginine concentrations were higher in IUGR-AA vs. IUGR-Sal (P<0.05). Fetal plasma glucose, oxygen, insulin, IGF-1, cortisol, and norepinephrine concentrations were similar between IUGR groups, but glucagon concentrations were 4-fold higher in IUGR-AA (P<0.05). Net umbilical amino acid uptake rate did not differ between IUGR groups; thus, the total amino acid delivery rate (net umbilical amino acid uptake plus infusion rate) was higher in IUGR-AA (IUGR-AA 30 ± 4, IUGR-Sal 19 ± 1 μmol·kg·min, P<0.05). Net umbilical glucose, lactate, and oxygen uptake rates were similar between IUGR groups. Fetal leucine oxidation rate measured using a leucine tracer was higher in IUGR-AA (IUGR-AA 2.5 ± 0.3, IUGR-Sal 1.7 ± 0.3 μmol·kg·min, P<0.05). Fetal protein accretion rate was not statistically different between the IUGR groups due to variability in response to amino acids (IUGR-AA 1.6 ± 0.4, IUGR-Sal 0.8 ± 0.3 μmol·kg-1·min). Prolonged amino acid infusion into IUGR fetal sheep increased leucine oxidation rates with variable anabolic response.

Postnatal Nutrient Repartitioning due to Adaptive Developmental Programming

“…43 Increasing amino acid supply via direct fetal infusion did not increase protein accretion or synthesis rates, muscle size, or fetal mass but increased amino acid oxidation rates. 44 Thus, reduced protein uptake and accretion by IUGR skeletal muscle does not appear to be the direct result of reduced fetal protein availability. Rather, it may be a product of β adrenergic adaptations due to chronic hypercatecholaminemia, as hypercatecholaminemia was not mitigated by amino acid infusion in this study.…”

“…43 Moreover, the effects of IUGR on circulating amino acid concentrations vary widely among individual amino acids. 43,44 For example, tyrosine, arginine, and isoleucine concentrations were reduced in IUGR fetal blood; however, taurine, glycine, and alanine concentrations were increased. 43 Increasing amino acid supply via direct fetal infusion did not increase protein accretion or synthesis rates, muscle size, or fetal mass but increased amino acid oxidation rates.…”

Real supermodels wear wool: summarizing the impact of the pregnant sheep as an animal model for adaptive fetal programming

“…Interestingly, acute infusion of amino acids into PI-IUGR fetuses did not increase leucine oxidation as it did in control fetuses but instead increased protein accretion (Brown et al, 2012). However, when amino acid infusion into PI-IUGR fetal sheep was maintained for 10 d, the increase in protein accretion was diminished and a greater amount of leucine was instead oxidized (Wai et al, 2018).…”

Farm Animals are Important Biomedical Models

“…However, substantial reductions in the uptake and utilization of amino acids by PI-IUGR fetal muscle led to corresponding drops of up to 42% in protein synthesis and accretion rates (Rozance et al, 2018). Interestingly, differential changes in both placental amino acid transport systems and fetal utilization rates yielded varying effects on circulating concentrations of individual amino acids (Rozance et al, 2018;Wai et al, 2018). For example, tyrosine, arginine, and isoleucine were reduced in PI-IUGR fetal blood, but taurine, glycine, and alanine were increased (Rozance et al, 2018).…”

“…For example, tyrosine, arginine, and isoleucine were reduced in PI-IUGR fetal blood, but taurine, glycine, and alanine were increased (Rozance et al, 2018). Moreover, exogenous amino acids delivered directly to the sheep fetus via infusion failed to improve protein synthesis and accretion rates, muscle growth, and fetal size (Wai et al, 2018). Instead, the extra amino acids were oxidized by the fetus for energy.…”