Leucine and α-Ketoisocaproic Acid, but Not Norleucine, Stimulate Skeletal Muscle Protein Synthesis in Neonatal Pigs

• Published in: The Journal of nutrition Vol. 140; no. 8; pp. 1418 - 1424
• Main Authors: Escobar, Jeffery, Frank, Jason W, Suryawan, Agus, Nguyen, Hanh V, Van Horn, Cynthia G, Hutson, Susan M, Davis, Teresa A
• Format: Journal Article
• Language: English
• Published: United States American Society for Nutrition 01.08.2010
• Subjects: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) - metabolism; alpha-ketoisocaproic acid; amino acid metabolism; Amino Acids - analysis; Amino Acids - blood; animal models; animal proteins; Animals; Animals, Newborn - metabolism; binding proteins; biochemical pathways; blood chemistry; branched chain amino acids; chemical structure; Eukaryotic Initiation Factors - analysis; Eukaryotic Initiation Factors - metabolism; gene expression regulation; Insulin - blood; Keto Acids - pharmacology; leucine; Leucine - pharmacology; metabolites; Muscle Proteins - biosynthesis; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; neonates; norleucine; Norleucine - pharmacology; piglets; postprandial state; protein metabolism; protein synthesis; signal transduction; skeletal muscle; Swine - metabolism; translation (genetics); translation initiation factors
• ISSN: 0022-3166; 1541-6100
• DOI: 10.3945/jn.110.123042

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, α-ketoisocaproic acid (KIC), and norleucine infusion (0 or 400 μmol·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.