Title: Nutritional regulation of mTOR signaling in skeletal muscle of neonates in vivo Authors
Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: June 25, 2008
Publication Date: July 20, 2008
Citation: Davis, T.A., Fiorotto, M.L. 2008. Nutritional regulation of mTOR signaling in skeletal muscle of neonates in vivo [abstract]. The Federation of American Societies for Experimental Biology Summer Research Conferences, "Molecular Mechanisms Involved in the Nutrient Control of Cellular Function", Session 4, "Nutrient Control of Signal Transduction Pathways", July 20-25, 2008, Carefree, Arizona. p. 20. Technical Abstract: The post-prandial rise in both amino acids and insulin independently stimulate protein synthesis in the rapidly growing skeletal muscle of the neonate. Leucine, in particular, is important in mediating the response to amino acids. We have shown that a physiological rise in leucine, but not isoleucine or valine, by parenteral infusion acutely stimulates protein synthesis in skeletal muscle of neonatal pigs and this response decreases with age. Leucine increases neonatal muscle protein synthesis by a mammalian target of rapamycin (mTOR)-dependent process that involves the phosphorylation of 70-kDa ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1) and eIF4F assembly which modulates translation initiation. However, leucine does not affect upstream activators of mTOR, i.e., phosphokinase B, AMP-activated protein kinase, and tuberous sclerosis complex 1/2, or a regulator of translation elongation, eukaryotic elongation factor 2. Despite continued activation of the mTOR signaling pathway, the acute leucine-induced stimulation of muscle protein synthesis is not maintained for prolonged periods because circulating concentrations of essential amino acids fall as they are utilized as substrates for protein synthesis. However, if circulating amino acids levels are maintained, the leucine-induced stimulation of muscle protein synthesis can be maintained for at least 24 h. The activation of the mTOR signaling pathway by leucine is not affected by the circulating levels of other amino acids. Thus, leucine acts as a nutrient signal to stimulate translation initiation but whether this translates into a sustained increase in protein synthesis depends on the availability of amino acids.