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Supplement

Signaling Pathways Involved in Translational Control of Protein Synthesis in Skeletal Muscle by Leucine¹

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033

²To whom correspondence should be addressed at The Pennsylvania State University College of Medicine, Department of Cellular and Molecular Physiology, P.O. Box 850, Hershey, PA 17033. E-mail: jjefferson{at}psu.edu.

Numerous reports established that in skeletal muscle the indispensable branched-chain amino acid leucine is unique in its ability to initiate signal transduction pathways that modulate translation initiation. Oral administration of leucine stimulates protein synthesis in association with hyperphosphorylation of the translational repressor, eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1), resulting in enhanced availability of the mRNA cap-binding protein eIF4E, for binding eIF4G and forming the active eIF4F complex. In addition, leucine enhances phosphorylation of the 70-kDa ribosomal protein S6 kinase (S6K1). These results suggest that leucine upregulates protein synthesis in skeletal muscle by enhancing both the activity and synthesis of proteins involved in mRNA translation. The stimulatory effects of leucine on translation initiation are mediated in part through the protein kinase mammalian target of rapamycin (mTOR), where both insulin signaling and leucine signaling converge to promote a maximal response.

KEY WORDS: • leucine • insulin • translation initiation • protein synthesis • skeletal muscle