35 Trainee Award: Regulators of branched-chain amino acid catabolism and activators of muscle protein synthesis are reduced in skeletal muscle of fetal growth-restricted sheep

Abstract Abstract: Introduction In a sheep model of placental insufficiency and fetal growth restriction (FGR), rates of branched-chain amino acid (BCAA) uptake into fetal hindlimb muscle and BCAA incorporation into muscle protein synthesis (MPS) were lower compared to normal controls. However, intracellular BCAA concentrations were higher in FGR muscle. Objective Test the hypothesis that molecular pathways regulating BCAA catabolism and MPS are downregulated in FGR muscle. Methods Pregnant ewes were housed in elevated temperatures to induce placental insufficiency and FGR and compared to controls (CON; n = 15/group). At 0.9 gestation, protein was isolated from fetal biceps femoris muscle and analyzed by Western Blot for regulators of BCAA catabolism (BCAT2, BCKDH, BCKDK, KLF15, PPM1K) and MPS (AKT, mTOR, RPS6, 4E-BP1). Student’s t-test was used (P<0.05 was significant). Results In the BCAA catabolism pathway, protein expression of BCAT2 was 37% lower (P<0.01); phosphorylated and total BCKDH were 31% and 27% lower, respectively (P<0.05); and KLF15, an activator of BCKDH, was 15% lower (P<0.05) in FGR vs. CON. In the MPS pathway, total AKT was 20% lower (P<0.05) and the ratio of phosphorylated to total RPS6 was 41% lower (P<0.05) in FGR vs. CON. Conclusion Molecular regulators of BCAA catabolism and MPS were reduced in FGR muscle, indicating less BCAA flux into catabolic pathways and decreased incorporation of BCAA into protein. We speculate that elevated intramuscular BCAAs are the result of decreased utilization by muscle and are instead used to promote fetal survival during FGR pregnancies. (Supported by NIH R01HD079404)