title: Muscle atrophy in Limb Girdle Muscular Dystrophy 2A: a morphometric and molecular study.
abstract: OBJECTIVE
  The peculiar clinical features and the pathogenic mechanism related to calpain-3 deficiency (impaired sarcomere remodelling) suggest that the ubiquitin-proteasome degradation pathway may have a crucial role in Limb Girdle Muscular Dystrophy 2A (LGMD2A). We therefore investigated muscle atrophy and the role of the ubiquitin-proteasome and lysosomal-autophagic degradation pathways.
  
  
  METHODS
  We selected 25 adult male LGMD2A patients (and seven controls), classified them using clinical severity score, analysed muscle fibre size by morphometry and protein and/or transcriptional expression levels of the most important atrophy- and autophagy-related genes (MuRF1, atrogin1, LC3, p62, Bnip3).
  
  
  RESULTS
  Muscle fibre size was significantly lower in LGMD2A than in controls and it was significantly correlated with patients' clinical disability score recorded at the time of biopsy, suggesting that functional and structural muscle impairment are dependent. The large majority of atrophic fibres originate from a mechanism different from regeneration, as assessed by neonatal myosin immunolabelling. As compared with controls, LGMD2A muscles have higher MuRF1 (but not atrogin1) protein and MuRF1 gene expression levels, and MuRF1 protein levels significantly correlated with both muscle fibre size and clinical disability score. LGMD2A muscles have slightly increased levels of LC3-II and p62 proteins and a significant up-regulation of p62 and Bnip3 gene expression.
  
  
  CONCLUSIONS
  In LGMD2A muscles the activation of the atrophy programme appeared to depend mainly upon induction of the ubiquitin-proteasome system and, to a lesser extent, the autophagic-lysosomal degradation pathway.
authors: Department of Neurosciences, University of Padova, Padova, Italy.
authors: M
authors: M
authors: Fanin
authors: A C
authors: AC
authors: Nascimbeni
authors: C
authors: C
authors: Angelini
mesh_terms: D000293:Adolescent; D000328:Adult; D002154:Calpain / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012038:Regeneration / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; D025801:Ubiquitin; C105884:CAPN3 protein, human; D002154:Calpain; D046988:Proteasome Endopeptidase Complex
keywords: autophagic-lysosomal degradation; calpain-3; limb girdle muscular dystrophy; muscle atrophy; ubiquitin-proteasome system