title: Absence of hyperplasia in Gasp-1 overexpressing mice is dependent on myostatin up-regulation.
abstract: OBJECTIVE
  Overexpression of Gasp-1, an inhibitor of myostatin, leads to a hypermuscular phenotype due to hypertrophy rather than hyperplasia in mice. However to date, the cellular and molecular mechanisms underlying this phenotype are not investigated.
  
  
  METHODS
  Skeletal muscles of overexpressing Gasp-1 mice, called Tg(Gasp-1) mice, were analyzed by histological methods. Satellite cell-derived myoblasts from these mice were used to investigate the molecular mechanisms.
  
  
  RESULTS
  We demonstrated that hypertrophy in Tg(Gasp-1) mice was related to a myonuclear accretion during the first 3 postnatal weeks and an activation of the pro-hypertrophic Akt/mTORC/p70S6K signaling. In accordance with these results, we showed that overexpressing Gasp-1 primary myoblasts proliferated faster and myonuclei average per myotube was increased during differentiation. Molecular analysis revealed that Gasp-1 overexpression resulted in increased myostatin expression related to its auto-regulation. Despite its inhibition, myostatin led to Pax7 deregulation through its non-canonical Erk1/2 signaling pathway. Consistent with this, inhibition of Erk1/2 signaling pathway as well as neutralization of secreted myostatin rescue the Pax7 expression in overexpressing Gasp-1 myoblasts.
  
  
  CONCLUSIONS
  Our study shows that myostatin is able to act independently of its canonical pathway to regulate the Pax7 expression. Altogether, our results indicate that myostatin could regulate muscle development despite its protein inhibition.
authors.affiliation: INRA, UMR 1061 Génétique Moléculaire Animale, Université de Limoges, FR 3503 GEIST, Faculté des Sciences et Techniques, Limoges, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Brun
authors.forename: Luce
authors.initials: L
authors.lastname: Périé
authors.forename: Fabienne
authors.initials: F
authors.lastname: Baraige
authors.forename: Barbara
authors.initials: B
authors.lastname: Vernus
authors.forename: Anne
authors.initials: A
authors.lastname: Bonnieu
authors.forename: Véronique
authors.initials: V
authors.lastname: Blanquet
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D006965:Hyperplasia / Q000196:embryology / Q000235:genetics*; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D055435:Myostatin / Q000235:genetics*; D051763:PAX7 Transcription Factor / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C479636:Gprasp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C525912:Mstn protein, mouse; D055435:Myostatin; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases