title: The aromatic amino acid tryptophan stimulates skeletal muscle IGF1/p70s6k/mTor signaling in vivo and the expression of myogenic genes in vitro.
abstract: OBJECTIVE
  Nutrition plays a key role in the maintenance of muscle and bone mass, and dietary protein deficiency has in particular been associated with catabolism of both muscle and bone tissue. One mechanism thought to link protein deficiency with loss of muscle mass is deficiency in specific amino acids that play a role in muscle metabolism. The aim of this study was to test the hypothesis that the essential amino acid tryptophan, and its metabolite kynurenine, might directly affect muscle metabolism in the setting of protein deficiency.
  
  
  METHODS
  Adult mice (12 mo) were fed a normal diet (18% protein), as well as diets with low protein (8%) supplemented with increasing concentrations (50, 100, and 200 uM) of kynurenine (Kyn) or with tryptophan (Trp; 1.5 mM) for 8 weeks. Myoprogenitor cells were also treated with Trp and Kyn in vitro to determine their effects on cell proliferation and expression of myogenic differentiation markers.
  
  
  RESULTS
  All mice on the low-protein diets weighed less than the group fed normal protein (18%). Lean mass measured by dual-energy X-ray absorptiometry was lowest in mice on the high Kyn diet, whereas percent lean mass was highest in mice receiving Trp supplementation and percent body fat was lowest in mice receiving Trp. Enzyme-linked immunosorbent assays showed significant increases in skeletal muscle insulin-like growth factor-1, leptin, and the myostatin antagonist follistatin with Trp supplementation. mRNA microarray and gene pathway analysis performed on muscle samples demonstrate that mTor/eif4/p70s6k pathway molecules are significantly up-regulated in muscles from mice on Kyn and Trp supplementation. In vitro, neither amino acid affected proliferation of myoprogenitors, but Trp increased the expression of the myogenic markers MyoD, myogenin, and myosin heavy chain.
  
  
  CONCLUSIONS
  These findings suggest that dietary amino acids can directly affect molecular signaling in skeletal muscle, further indicating that dietary manipulation with specific amino acids could potentially attenuate muscle loss with dietary protein deficiency.
authors.affiliation: Georgia Regents University (Formerly Georgia Health Sciences University), Augusta, GA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Dukes
authors.affiliation: Georgia Regents University (Formerly Georgia Health Sciences University), Augusta, GA, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Davis
authors.affiliation: Georgia Regents University (Formerly Georgia Health Sciences University), Augusta, GA, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: El Refaey
authors.affiliation: Georgia Regents University (Formerly Georgia Health Sciences University), Augusta, GA, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Upadhyay
authors.affiliation: Georgia Regents University (Formerly Georgia Health Sciences University), Augusta, GA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mork
authors.affiliation: Georgia Regents University (Formerly Georgia Health Sciences University), Augusta, GA, USA.
authors.forename: Phonepasong
authors.initials: P
authors.lastname: Arounleut
authors.affiliation: Georgia Regents University (Formerly Georgia Health Sciences University), Augusta, GA, USA.
authors.forename: Maribeth H
authors.initials: MH
authors.lastname: Johnson
authors.affiliation: Georgia Regents University (Formerly Georgia Health Sciences University), Augusta, GA, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Hill
authors.affiliation: Georgia Regents University (Formerly Georgia Health Sciences University), Augusta, GA, USA.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Isales
authors.affiliation: Georgia Regents University (Formerly Georgia Health Sciences University), Augusta, GA, USA. Electronic address: Mhamrick@gru.edu.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Hamrick
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D024322:Amino Acids, Aromatic / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D038681:Follistatin / Q000378:metabolism; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007737:Kynurenine / Q000008:administration & dosage / Q000494:pharmacology; D020738:Leptin / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics; D018008:Myogenin / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics; D055435:Myostatin / Q000037:antagonists & inhibitors; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014364:Tryptophan / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D024322:Amino Acids, Aromatic; D038681:Follistatin; D020738:Leptin; D017570:MyoD Protein; D018008:Myogenin; D055435:Myostatin; D007737:Kynurenine; D007334:Insulin-Like Growth Factor I; D014364:Tryptophan; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D018995:Myosin Heavy Chains
keywords: Aging; C2 C12 cells; Muscle atrophy; Pathway analysis; Sarcopenia