title: Muscle atrophy, ubiquitin-proteasome, and autophagic pathways in dysferlinopathy.
abstract: BACKGROUND
  Muscle fiber atrophy and the molecular pathways underlying this process have not been investigated in dysferlinopathy patients.
  
  
  METHODS
  In 22 muscles from dysferlinopathy patients we investigated fiber atrophy by morphometry and ubiquitin-proteasome and autophagic pathways using protein and/or transcriptional analysis of atrophy- and autophagy-related genes (MuRF1, atrogin1, LC3, p62, Bnip3).
  
  
  RESULTS
  Dysferlinopathy showed significant fiber atrophy and higher MuRF-1 protein and mRNA levels, which correlated with fiber size, suggesting activation of the atrophy program by proteasome induction.
  
  
  CONCLUSIONS
  Some of the MuRF-1 upregulation and proteasome induction may be attributed to the prominent regeneration found. A potential role of impaired autophagy was suggested by p62-positive protein aggregates in atrophic fibers and significantly higher levels of LC3-II and p62 proteins and overexpression of p62 and Bnip3 mRNA. Damaged muscle fibers and prominent inflammatory changes may also enhance autophagy due to the insufficient level of proteasomal degradation of mutant dysferlin.
authors.affiliation: Department of Neurosciences, University of Padova, Biomedical Campus "Pietro d'Abano," via Giuseppe Orus 2B, 35129, Padova, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Fanin
authors.forename: Anna C
authors.initials: AC
authors.lastname: Nascimbeni
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
mesh_terms: D000293:Adolescent; D000328:Adult; D001343:Autophagy / Q000235:genetics* / Q000502:physiology*; D015153:Blotting, Western; D000073939:Dysferlin; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology; D009133:Muscular Atrophy / Q000473:pathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D025801:Ubiquitin / Q000235:genetics* / Q000502:physiology*; D055815:Young Adult
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: LGMD2B; autophagic-lysosomal degradation; dysferlin; dysferlinopathy; limb-girdle muscular dystrophy; muscle atrophy; ubiquitin-proteasome system