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Muscle atrophy in L imb G irdle M uscular D ystrophy 2 A : a morphometric and molecular study
Author(s) -
Fanin M.,
Nascimbeni A. C.,
Angelini C.
Publication year - 2013
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12034
Subject(s) - muscle atrophy , atrophy , proteasome , myosin , protein degradation , biology , medicine , autophagy , muscle biopsy , endocrinology , microbiology and biotechnology , biochemistry , biopsy , genetics , apoptosis
Aims 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 L imb G irdle M uscular D ystrophy 2 A ( LGMD 2 A ). We therefore investigated muscle atrophy and the role of the ubiquitin‐proteasome and lysosomal‐autophagic degradation pathways. Methods We selected 25 adult male LGMD 2 A 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 LGMD 2 A 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, LGMD 2 A muscles have higher MuRF 1 (but not atrogin1) protein and MuRF1 gene expression levels, and MuRF 1 protein levels significantly correlated with both muscle fibre size and clinical disability score. LGMD 2 A muscles have slightly increased levels of LC 3‐ II and p62 proteins and a significant up‐regulation of p62 and Bnip3 gene expression. Conclusions In LGMD 2 A 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.