Muscle atrophy, ubiquitin-proteasome, and autophagic pathways in dysferlinopathy
Copyright © 2014 Wiley Periodicals, Inc., a Wiley company
- Accepted manuscript online: 7 JAN 2014 04:09AM EST
- Manuscript Accepted: 2 JAN 2014
- Manuscript Revised: 18 DEC 2013
- Manuscript Received: 7 JUL 2013
- Association Française contre les Myopathies. Grant Numbers: 13859, 14199, 14999, 15696
- Comitato Telethon Fondazione Onlus. Grant Number: GTB12001
- Cited By
- limb girdle muscular dystrophy;
- muscle atrophy;
- ubiquitin-proteasome system;
- autophagic-lysosomal degradation
Introduction. 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, higher MuRF-1 protein and mRNA levels, which correlated with fiber size, suggesting activation of atrophy program by proteasome induction.
Discussion. Part of MuRF-1 up-regulation and proteasome induction might 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 over-expression of p62 and Bnip3 mRNA. Damaged muscle fibers and prominent inflammatory changes might also enhance autophagy due to the insufficient level of proteasomal degradation of mutant dysferlin. © 2014 Wiley Periodicals, Inc.