title: Nutrient signalling in the regulation of human muscle protein synthesis.
abstract: The mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) are important nutrient- and energy-sensing and signalling proteins in skeletal muscle. AMPK activation decreases muscle protein synthesis by inhibiting mTOR signalling to regulatory proteins associated with translation initiation and elongation. On the other hand, essential amino acids (leucine in particular) and insulin stimulate mTOR signalling and protein synthesis. We hypothesized that anabolic nutrients would be sensed by both AMPK and mTOR, resulting in an acute and potent stimulation of human skeletal muscle protein synthesis via enhanced translation initiation and elongation. We measured muscle protein synthesis and mTOR-associated upstream and downstream signalling proteins in young male subjects (n=14) using stable isotopic and immunoblotting techniques. Following a first muscle biopsy, subjects in the 'Nutrition' group ingested a leucine-enriched essential amino acid-carbohydrate mixture (EAC). Subjects in the Control group did not consume nutrients. A second biopsy was obtained 1 h later. Ingestion of EAC significantly increased muscle protein synthesis, modestly reduced AMPK phosphorylation, and increased Akt/PKB (protein kinase B) and mTOR phosphorylation (P<0.05). mTOR signalling to its downstream effectors (S6 kinase 1 (S6K1) and 4E-binding protein 1 (4E-BP1) phosphorylation status) was also increased (P<0.05). In addition, eukaryotic elongation factor 2 (eEF2) phosphorylation was significantly reduced (P<0.05). Protein synthesis and cell signalling (phosphorylation status) was unchanged in the control group (P>0.05). We conclude that anabolic nutrients alter the phosphorylation status of both AMPK- and mTOR-associated signalling proteins in human muscle, in association with an increase in protein synthesis not only via enhanced translation initiation but also through signalling promoting translation elongation.
authors.affiliation: University of Texas Medical Branch, Department of Internal Medicine, Galveston, TX 77555-1144, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujita
authors.forename: Hans C
authors.initials: HC
authors.lastname: Dreyer
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Drummond
authors.forename: Erin L
authors.initials: EL
authors.lastname: Glynn
authors.forename: Jerson G
authors.initials: JG
authors.lastname: Cadenas
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yoshizawa
authors.forename: Elena
authors.initials: E
authors.lastname: Volpi
authors.forename: Blake B
authors.initials: BB
authors.lastname: Rasmussen
mesh_terms: D055372:AMP-Activated Protein Kinases; D000284:Administration, Oral; D000328:Adult; D000596:Amino Acids / Q000378:metabolism; D000601:Amino Acids, Essential / Q000008:administration & dosage / Q000494:pharmacology; D002241:Carbohydrates / Q000008:administration & dosage / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D005502:Food; D005947:Glucose / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D007930:Leucine / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis*; D009747:Nutritional Physiological Phenomena; D010441:Peptide Chain Elongation, Translational / Q000502:physiology; D010649:Phenylalanine / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D000596:Amino Acids; D000601:Amino Acids, Essential; D002241:Carbohydrates; D007328:Insulin; D009097:Multienzyme Complexes; D009124:Muscle Proteins; D010649:Phenylalanine; D011494:Protein Kinases; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D007930:Leucine; D005947:Glucose