title: Calpain 3 is important for muscle regeneration: evidence from patients with limb girdle muscular dystrophies.
abstract: BACKGROUND
  Limb girdle muscular dystrophy (LGMD) type 2A is caused by mutations in the CAPN3 gene and complete lack of functional calpain 3 leads to the most severe muscle wasting. Calpain 3 is suggested to be involved in maturation of contractile elements after muscle degeneration. The aim of this study was to investigate how mutations in the four functional domains of calpain 3 affect muscle regeneration.
  
  
  METHODS
  We studied muscle regeneration in 22 patients with LGMD2A with calpain 3 deficiency, in five patients with LGMD2I, with a secondary reduction in calpain 3, and in five patients with Becker muscular dystrophy (BMD) with normal calpain 3 levels. Regeneration was assessed by using the developmental markers neonatal myosin heavy chain (nMHC), vimentin, MyoD and myogenin and counting internally nucleated fibers.
  
  
  RESULTS
  We found that the recent regeneration as determined by the number of nMHC/vimentin-positive fibers was greatly diminished in severely affected LGMD2A patients compared to similarly affected patients with LGMD2I and BMD. Whorled fibers, a sign of aberrant regeneration, was highly elevated in patients with a complete lack of calpain 3 compared to patients with residual calpain 3. Regeneration is not affected by location of the mutation in the CAPN3 gene.
  
  
  CONCLUSIONS
  Our findings suggest that calpain 3 is needed for the regenerative process probably during sarcomere remodeling as the complete lack of functional calpain 3 leads to the most severe phenotypes.
authors.affiliation: Department of Neurology, Neuromuscular Research Unit, The Copenhagen Muscle Research Center, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Hauerslev
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Sveen
authors.forename: Morten
authors.initials: M
authors.lastname: Duno
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: John
authors.initials: J
authors.lastname: Vissing
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Krag
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D015153:Blotting, Western; D002154:Calpain / Q000032:analysis* / Q000235:genetics; D003718:Denmark; D016189:Dystrophin / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000032:analysis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000737:chemistry* / Q000473:pathology / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D017570:MyoD Protein / Q000032:analysis; D018008:Myogenin / Q000032:analysis; D018995:Myosin Heavy Chains / Q000032:analysis; D010430:Pentosyltransferases; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D012038:Regeneration / Q000235:genetics; D012720:Severity of Illness Index; D014746:Vimentin / Q000032:analysis; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016189:Dystrophin; C503799:MYOG protein, human; D009124:Muscle Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D018008:Myogenin; D011506:Proteins; D014746:Vimentin; C443107:FKRP protein, human; D010430:Pentosyltransferases; C105884:CAPN3 protein, human; D002154:Calpain; D018995:Myosin Heavy Chains