title: Impaired regeneration in LGMD2A supported by increased PAX7-positive satellite cell content and muscle-specific microrna dysregulation.
abstract: BACKGROUND
  Recent in vitro studies suggest that CAPN3 deficiency leads initially to accelerated myofiber formation followed by depletion of satellite cells (SC). In normal muscle, up-regulation of miR-1 and miR-206 facilitates transition from proliferating SCs to differentiating myogenic progenitors.
  
  
  METHODS
  We examined the histopathological stages, Pax7 SC content, and muscle-specific microRNA expression in biopsy specimens from well-characterized LGMD 2A patients to gain insight into disease pathogenesis.
  
  
  RESULTS
  Three distinct stages of pathological changes were identified that represented the continuum of the dystrophic process from prominent inflammation with necrosis and regeneration to prominent fibrosis, which correlated with age and disease duration. Pax7-positive SCs were highest in the fibrotic group and correlated with down-regulation of miR-1, miR-133a, and miR-206.
  
  
  CONCLUSIONS
  These observations, and other published reports, are consistent with microRNA dysregulation leading to inability of Pax7-positive SCs to transit from proliferation to differentiation. This results in impaired regeneration and fibrosis.
authors.affiliation: Neuromuscular Center at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Xiomara Q
authors.initials: XQ
authors.lastname: Rosales
authors.forename: Vinod
authors.initials: V
authors.lastname: Malik
authors.forename: Amita
authors.initials: A
authors.lastname: Sneh
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Sarah
authors.initials: S
authors.lastname: Lewis
authors.forename: Janaiah
authors.initials: J
authors.lastname: Kota
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.forename: Caroline
authors.initials: C
authors.lastname: Astbury
authors.forename: Rob
authors.initials: R
authors.lastname: Pyatt
authors.forename: Shalini
authors.initials: S
authors.lastname: Reshmi
authors.forename: Louise R
authors.initials: LR
authors.lastname: Rodino-Klapac
authors.forename: K Reed
authors.initials: KR
authors.lastname: Clark
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Zarife
authors.initials: Z
authors.lastname: Sahenk
mesh_terms: D000293:Adolescent; D000328:Adult; D002454:Cell Differentiation; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D051763:PAX7 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism* / Q000473:pathology
chemical_list: D035683:MicroRNAs; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human
references.citation: J Med Genet. 2005 Sep;42(9):686-93
references.pmid: 16141003
references.citation: Hum Mol Genet. 2011 Sep 1;20(17):3331-45
references.pmid: 21624972
references.citation: Cell Metab. 2010 Oct 6;12(4):341-351
references.pmid: 20727829
references.citation: Cell Struct Funct. 2008;33(2):163-9
references.pmid: 18827405
references.citation: Neuromuscul Disord. 2008 Dec;18(12):913-21
references.pmid: 18974005
references.citation: J Clin Invest. 2011 Aug;121(8):3258-68
references.pmid: 21737882
references.citation: Trends Genet. 2008 Apr;24(4):159-66
references.pmid: 18325627
references.citation: Ann Neurol. 2006 Jun;59(6):905-11
references.pmid: 16607617
references.citation: Muscle Nerve. 2009 Sep;40(3):455-65
references.pmid: 19705426
references.citation: J Neurol Sci. 1983 Dec;62(1-3):303-14
references.pmid: 6668477
references.citation: Nat Med. 1999 May;5(5):503-11
references.pmid: 10229226
references.citation: FASEB J. 2009 Oct;23(10):3335-46
references.pmid: 19528256
references.citation: J Neurol Sci. 1999 Dec 1;171(1):31-7
references.pmid: 10567047
references.citation: Hum Mol Genet. 2008 Jun 15;17(12):1855-66
references.pmid: 18334579
references.citation: Neurosci Res. 2007 Apr;57(4):513-21
references.pmid: 17258832
references.citation: Neuromuscul Disord. 2005 Mar;15(3):218-24
references.pmid: 15725583
references.citation: Hum Mol Genet. 2008 Nov 1;17(21):3271-80
references.pmid: 18676612
references.citation: Mol Cell Biol. 2011 Jan;31(1):203-14
references.pmid: 21041476
references.citation: Am J Hum Genet. 1997 May;60(5):1128-38
references.pmid: 9150160
references.citation: J Neurol Sci. 1984 May;64(2):149-60
references.pmid: 6747662
references.citation: Hum Mol Genet. 2005 Aug 1;14(15):2125-34
references.pmid: 15961411
references.citation: Genes Dev. 2009 Mar 1;23(5):619-32
references.pmid: 19240126
references.citation: J Neuropathol Exp Neurol. 2006 Oct;65(10):995-1003
references.pmid: 17021404
references.citation: J Mol Biol. 2011 Apr 1;407(3):439-49
references.pmid: 21295580
references.citation: J Neurol Sci. 1973 Jan;18(1):111-29
references.pmid: 4120482
references.citation: J Cell Biol. 2010 Sep 6;190(5):867-79
references.pmid: 20819939
references.citation: Tissue Eng Part A. 2012 May;18(9-10):889-98
references.pmid: 22070522
references.citation: Cell Tissue Res. 2010 Jun;340(3):541-8
references.pmid: 20467789
references.citation: J Clin Invest. 2012 Jun;122(6):2054-65
references.pmid: 22546853
references.citation: J Biol Chem. 2010 Apr 23;285(17):12670-83
references.pmid: 20139084
references.citation: Nat Genet. 2006 Feb;38(2):228-33
references.pmid: 16380711
references.citation: Braz J Med Biol Res. 2002 Jun;35(6):691-5
references.pmid: 12045834
references.citation: Muscle Nerve. 2006 Mar;33(3):424-32
references.pmid: 16372320