title: Over-expression of PRAS40 enhances insulin sensitivity in skeletal muscle.
abstract: BACKGROUND
  Silencing proline-rich Akt substrate of 40-kDa (PRAS40) impairs insulin signalling in skeletal muscle.
  
  
  OBJECTIVE
  This study assessed the effects of over-expressing wild type or mutant AAA-PRAS40, in which the major phosphorylation sites and mTORC1-binding site were mutated, on insulin signalling in skeletal muscle.
  
  
  RESULTS
  Over-expression of WT-PRAS40, but not AAA-PRAS40, impaired the insulin-mediated activation of the mTORC1-pathway in human skeletal muscle cells (hSkMC). However, insulin-mediated Akt-phosphorylation was increased upon over-expression of WT-PRAS40 both in hSkMC and mouse skeletal muscle. Also over-expression of AAA-PRAS40 had an insulin-sensitizing effect, although to a lesser extent as WT-PRAS40. The insulin-sensitizing effect associated with increased IRS1 protein abundance and inhibition of proteasome activity. Finally, over-expression of WT-PRAS40 reversed hyperinsulinemia-induced insulin resistance.
  
  
  CONCLUSIONS
  This study identifies PRAS40 as a regulator of insulin sensitivity in hSkMC. In contrast to the mTORC1-pathway, the insulin-sensitizing action of PRAS40 occurs independent of binding of PRAS40 to the mTORC1-complex.
authors.affiliation: Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Centre , Auf'mHennekamp 65, D-40225 Düsseldorf , Germany .
authors.forename: Claudia
authors.initials: C
authors.lastname: Wiza
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chadt
authors.forename: Marcel
authors.initials: M
authors.lastname: Blumensatt
authors.forename: Timo
authors.initials: T
authors.lastname: Kanzleiter
authors.forename: Daniella
authors.initials: D
authors.lastname: Herzfeld De Wiza
authors.forename: Angelika
authors.initials: A
authors.lastname: Horrighs
authors.forename: Heidi
authors.initials: H
authors.lastname: Mueller
authors.forename: Emmani B M
authors.initials: EB
authors.lastname: Nascimento
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.forename: Hadi
authors.initials: H
authors.lastname: Al-Hasani
authors.forename: D Margriet
authors.initials: DM
authors.lastname: Ouwens
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D015870:Gene Expression; D006801:Humans; D006946:Hyperinsulinism / Q000503:physiopathology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D007328:Insulin; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex