Article ; Online: Impaired autophagy in sporadic inclusion-body myositis and in endoplasmic reticulum stress-provoked cultured human muscle fibers.
The American journal of pathology
2010 Volume 177, Issue 3, Page(s) 1377–1387
Abstract: ... 30 disease control and normal control muscle biopsy samples and our cultured human muscle fibers ... The hallmark pathologies of sporadic inclusion-body myositis (s-IBM) muscle fibers are autophagic ... phosphorylated tau in a beta-pleated sheet amyloid configuration. Endoplasmic reticulum stress (ERS) and 26S ...
| Abstract | The hallmark pathologies of sporadic inclusion-body myositis (s-IBM) muscle fibers are autophagic vacuoles and accumulation of ubiquitin-positive multiprotein aggregates that contain amyloid-beta or phosphorylated tau in a beta-pleated sheet amyloid configuration. Endoplasmic reticulum stress (ERS) and 26S proteasome inhibition, also associated with s-IBM, putatively aggrandize the accumulation of misfolded proteins. However, autophagosomal-lysosomal pathway formation and function, indicated by autophagosome maturation, have not been previously analyzed in this system. Here we studied the autophagosomal-lysosomal pathway using 14 s-IBM and 30 disease control and normal control muscle biopsy samples and our cultured human muscle fibers in a microenvironment modified to resemble aspects of s-IBM pathology. We report for the first time that in s-IBM, lysosomal enzyme activities of cathepsin D and B were decreased 60% (P < 0.01) and 40% (P < 0.05), respectively. We also detected two indicators of increased autophagosome maturation, the presence of LC3-II and decreased mammalian target of rapamycin-mediated phosphorylation of p70S6 kinase. Moreover, in cultured human muscle fibers, ERS induction significantly decreased activities of cathepsins D and B, increased levels of LC3-II, decreased phosphorylation of p70S6 kinase, and decreased expression of VMA21, a chaperone for assembly of lysosomal V-ATPase. We conclude that in s-IBM muscle, decreased lysosomal proteolytic activity might enhance accumulation of misfolded proteins, despite increased maturation of autophagosomes, and that ERS is a possible cause of s-IBM-impaired lysosomal function. Thus, unblocking protein degradation in s-IBM muscle fibers may be a desirable therapeutic strategy. |
|||||
|---|---|---|---|---|---|---|
| MeSH term(s) | Aged ; Autophagy/physiology ; Blotting, Western ; Cathepsin B/metabolism ; Cathepsin D/metabolism ; Cells, Cultured ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum/pathology ; Humans ; Immunohistochemistry ; Lysosomes/metabolism ; Lysosomes/pathology ; Middle Aged ; Muscle Fibers, Skeletal/metabolism ; Myositis, Inclusion Body/metabolism ; Myositis, Inclusion Body/pathology | |||||
| Chemical Substances | Cathepsin B (EC 3.4.22.1) ; Cathepsin D (EC 3.4.23.5) | |||||
| Language | English | |||||
| Publishing date | 2010-07-08 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 2943-9 | |||||
| ISSN | 1525-2191 ; 0002-9440 | |||||
| ISSN (online) | 1525-2191 | |||||
| ISSN | 0002-9440 | |||||
| DOI | 10.2353/ajpath.2010.100050 | |||||
| Shelf mark |
|
|||||
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Ud II Zs.76: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.