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Title: Leucine and alpha-Ketoisocaproic acid, but not norleucine, stimulate skeletal muscle protein synthesis in neonatal pigs

Author
item ESCOBAR, JEFFERY - Children'S Nutrition Research Center (CNRC)
item FRANK, JASON - Children'S Nutrition Research Center (CNRC)
item SURYAWAN, AGUS - Children'S Nutrition Research Center (CNRC)
item NGUYEN, HANH - Children'S Nutrition Research Center (CNRC)
item VAN HORN, CYNTHIA - Wake Forest University
item HUTSON, SUSAN - Wake Forest University
item DAVIS, TERESA - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/17/2010
Publication Date: 6/9/2010
Citation: Escobar, J., Frank, J.W., Suryawan, A., Nguyen, H.V., Van Horn, C.G., Hutson, S.M., Davis, T.A. 2010. Leucine and alpha-Ketoisocaproic acid, but not norleucine, stimulate skeletal muscle protein synthesis in neonatal pigs. Journal of Nutrition. 140(8):1418-1424.

Interpretive Summary: Leucine is an amino acid that can act as a nutrient signal to stimulate protein synthesis. However, the chemical structure responsible for the leucine effect is unknown. This study was conducted to determine the chemical structure responsible for the action of leucine as a nutrient signal. Only leucine and alpha-ketoisocaproic acid (KIC) (leucine's metabolite) promote protein synthesis and the activation of intracellular signaling. In summary, the ability of leucine to promote protein synthesis is specific to leucine and its metabolite, KIC. The results suggest that leucine potentially can be used to stimulate protein synthesis, and hence, growth of human neonates.

Technical Abstract: The branched-chain amino acid, leucine, acts as a nutrient signal to stimulate protein synthesis in skeletal muscle of young pigs. However, the chemical structure responsible for this effect has not been identified. We have shown that the other branched-chain amino acids, isoleucine and valine, are not able to stimulate protein synthesis when raised in plasma to levels within the postprandial range. In this study, we evaluated the effect of leucine, alpha-ketoisocaproic acid (KIC), and norleucine infusion (0 or 400 micromol/kg(1)/h(1) for 60 min) on protein synthesis and activation of translation initiation factors in piglets. Infusion of leucine, KIC, and norleucine raised plasma levels of each compound compared with controls. KIC also increased ("P",0.01) and norleucine reduced ("P",0.02) plasma levels of leucine compared with controls. Administration of leucine and KIC resulted in greater ("P" , 0.006) phosphorylation of eukaryotic initiation factor (eIF) 4E binding protein-1 (4E-BP1) and eIF4G, lower ("P" , 0.04) abundance of the inactive 4E-BP1/eIF4E complex, and greater ("P" , 0.05) active eIF4G/eIF4E complex formation in skeletal muscle compared with controls. Protein synthesis in skeletal muscle was greater ("P",0.02) in leucine- and KIC-infused pigs than in those in the control group. Norleucine infusion did not affect muscle protein synthesis or translation initiation factor activation. In liver, neither protein synthesis nor activation of translation initiation factors was affected by treatment. These results suggest that the ability of leucine to act as a nutrient signal to stimulate skeletal muscle protein synthesis is specific for leucine and/or its metabolite, KIC.