| pubmed-article:20616343 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:20616343 | lifeskim:mentions | umls-concept:C0027121 | lld:lifeskim |
| pubmed-article:20616343 | lifeskim:mentions | umls-concept:C0086418 | lld:lifeskim |
| pubmed-article:20616343 | lifeskim:mentions | umls-concept:C0010453 | lld:lifeskim |
| pubmed-article:20616343 | lifeskim:mentions | umls-concept:C0014239 | lld:lifeskim |
| pubmed-article:20616343 | lifeskim:mentions | umls-concept:C0004391 | lld:lifeskim |
| pubmed-article:20616343 | lifeskim:mentions | umls-concept:C0242697 | lld:lifeskim |
| pubmed-article:20616343 | lifeskim:mentions | umls-concept:C0221099 | lld:lifeskim |
| pubmed-article:20616343 | lifeskim:mentions | umls-concept:C0205422 | lld:lifeskim |
| pubmed-article:20616343 | pubmed:issue | 3 | lld:pubmed |
| pubmed-article:20616343 | pubmed:dateCreated | 2010-8-31 | lld:pubmed |
| pubmed-article:20616343 | pubmed:abstractText | 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. | lld:pubmed |
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| pubmed-article:20616343 | pubmed:language | eng | lld:pubmed |
| pubmed-article:20616343 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:20616343 | pubmed:citationSubset | AIM | lld:pubmed |
| pubmed-article:20616343 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:20616343 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:20616343 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:20616343 | pubmed:month | Sep | lld:pubmed |
| pubmed-article:20616343 | pubmed:issn | 1525-2191 | lld:pubmed |
| pubmed-article:20616343 | pubmed:author | pubmed-author:AskanasValeri... | lld:pubmed |
| pubmed-article:20616343 | pubmed:author | pubmed-author:EngelW KingWK | lld:pubmed |
| pubmed-article:20616343 | pubmed:author | pubmed-author:NogalskaAnnaA | lld:pubmed |
| pubmed-article:20616343 | pubmed:author | pubmed-author:D'AgostinoCar... | lld:pubmed |
| pubmed-article:20616343 | pubmed:author | pubmed-author:TerraccianoCh... | lld:pubmed |
| pubmed-article:20616343 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:20616343 | pubmed:volume | 177 | lld:pubmed |
| pubmed-article:20616343 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:20616343 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:20616343 | pubmed:pagination | 1377-87 | lld:pubmed |
| pubmed-article:20616343 | pubmed:dateRevised | 2011-9-13 | lld:pubmed |
| pubmed-article:20616343 | pubmed:meshHeading | pubmed-meshheading:20616343... | lld:pubmed |
| pubmed-article:20616343 | pubmed:meshHeading | pubmed-meshheading:20616343... | lld:pubmed |
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