title: Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids.
abstract: The relationship between mammalian target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis during instances of amino acid surplus in humans is based solely on correlational data. Therefore, the goal of this study was to use a mechanistic approach specifically designed to determine whether increased mTORC1 activation is requisite for the stimulation of muscle protein synthesis following L-essential amino acid (EAA) ingestion in humans. Examination of muscle protein synthesis and signaling were performed on vastus lateralis muscle biopsies obtained from 8 young (25 ± 2 y) individuals who were studied prior to and following ingestion of 10 g of EAA during 2 separate trials in a randomized, counterbalanced design. The trials were identical except during 1 trial, participants were administered a single oral dose of a potent mTORC1 inhibitor (rapamycin) prior to EAA ingestion. In response to EAA ingestion, an ~60% increase in muscle protein synthesis was observed during the control trial, concomitant with increased phosphorylation of mTOR (Ser(2448)), ribosomal S6 kinase 1 (Thr(389)), and eukaryotic initiation factor 4E binding protein 1 (Thr(37/46)). In contrast, prior administration of rapamycin completely blocked the increase in muscle protein synthesis and blocked or attenuated activation of mTORC1-signaling proteins. The inhibition of muscle protein synthesis and signaling was not due to differences in either extracellular or intracellular amino acid availability, because these variables were similar between trials. These data support a fundamental role for mTORC1 activation as a key regulator of human muscle protein synthesis in response to increased EAA availability. This information will be useful in the development of evidence-based nutritional therapies targeting mTORC1 to counteract muscle wasting associated with numerous clinical conditions.
authors: Division of Rehabilitation Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Jared M
authors: JM
authors: Dickinson
authors: Christopher S
authors: CS
authors: Fry
authors: Micah J
authors: MJ
authors: Drummond
authors: David M
authors: DM
authors: Gundermann
authors: Dillon K
authors: DK
authors: Walker
authors: Erin L
authors: EL
authors: Glynn
authors: Kyle L
authors: KL
authors: Timmerman
authors: Shaheen
authors: S
authors: Dhanani
authors: Elena
authors: E
authors: Volpi
authors: Blake B
authors: BB
authors: Rasmussen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000601:Amino Acids, Essential / Q000097:blood / Q000378:metabolism*; D001707:Biopsy, Needle; D018797:Cell Cycle Proteins; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D052097:Quadriceps Muscle / Q000187:drug effects / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000601:Amino Acids, Essential; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011506:Proteins; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus