Leucine stimulates protein synthesis in skeletal muscle of neonatal pigs by enhancing mTORC1 activation
Open Access
- 1 October 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Endocrinology and Metabolism
- Vol. 295 (4), E868-E875
- https://doi.org/10.1152/ajpendo.90314.2008
Abstract
Skeletal muscle in the neonate grows at a rapid rate due in part to an enhanced sensitivity to the postprandial rise in amino acids, particularly leucine. To elucidate the molecular mechanism by which leucine stimulates protein synthesis in neonatal muscle, overnight-fasted 7-day-old piglets were treated with rapamycin [an inhibitor of mammalian target of rapamycin (mTOR) complex (mTORC)1] for 1 h and then infused with leucine for 1 h. Fractional rates of protein synthesis and activation of signaling components that lead to mRNA translation were determined in skeletal muscle. Rapamycin completely blocked leucine-induced muscle protein synthesis. Rapamycin markedly reduced raptor-mTOR association, an indicator of mTORC1 activation. Rapamycin blocked the leucine-induced phosphorylation of mTOR, S6 kinase 1 (S6K1), and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1) and formation of the eIF4E·eIF4G complex and increased eIF4E·4E-BP1 complex abundance. Rapamycin had no effect on the association of mTOR with rictor, a crucial component for mTORC2 activation, or G protein β-subunit-like protein (GβL), a component of mTORC1 and mTORC2. Neither leucine nor rapamycin affected the phosphorylation of AMP-activated protein kinase (AMPK), PKB, or tuberous sclerosis complex (TSC)2, signaling components that reside upstream of mTOR. Eukaryotic elongation factor (eEF)2 phosphorylation was not affected by leucine or rapamycin, although current dogma indicates that eEF2 phosphorylation is mTOR dependent. Together, these in vivo data suggest that leucine stimulates muscle protein synthesis in neonates by enhancing mTORC1 activation and its downstream effectors.Keywords
This publication has 39 references indexed in Scilit:
- Rapamycin Limits Formation of Active Eukaryotic Initiation Factor 4F Complex Following Meal Feeding in Rat Hearts ,Journal of Nutrition, 2007
- Rapamycin blunts nutrient stimulation of eIF4G, but not PKCε phosphorylation, in skeletal muscleAmerican Journal of Physiology-Endocrinology and Metabolism, 2007
- Early, Aggressive Nutritional Management for Very Low Birth Weight Infants: What Is the Evidence?Seminars in Perinatology, 2007
- Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?Oncogene, 2006
- Developmental regulation of the activation of signaling components leading to translation initiation in skeletal muscle of neonatal pigsAmerican Journal of Physiology-Endocrinology and Metabolism, 2006
- Time course changes in signaling pathways and protein synthesis in C2C12myotubes following AMPK activation by AICARAmerican Journal of Physiology-Endocrinology and Metabolism, 2006
- Regulation of cardiac and skeletal muscle protein synthesis by individual branched-chain amino acids in neonatal pigsAmerican Journal of Physiology-Endocrinology and Metabolism, 2006
- Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKBMolecular Cell, 2006
- Dietary protein and lactose increase translation initiation factor activation and tissue protein synthesis in neonatal pigsAmerican Journal of Physiology-Endocrinology and Metabolism, 2006
- Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinaseProceedings of the National Academy of Sciences of the United States of America, 2005