Abstract:
:Inclusion body myositis (IBM) is a late-onset inflammatory myopathy with distinctive clinical and histopathological features. The molecular basis for the disease remains unknown, but abnormal nuclear morphology and the accumulation of a protein that binds single-stranded DNA in a sequence-independent fashion suggest a nuclear defect. Evidence of mitochondrial respiratory chain dysfunction (ragged-red fibers, multiple mtDNA deletions) has been reported in IBM muscle. Here we have investigated the relationship of the mtDNA abnormalities in sporadic and familial IBM patients to the pathogenesis of the disease. In situ hybridization analysis with mtDNA probes revealed several different mtDNA abnormalities in cytochrome c oxidase-negative muscle fibers including large-scale mtDNA deletions and mtDNA depletion, but no evidence for nonspecific DNA binding. Contrary to previous reports, we did not observe mtDNA deletions on Southern blot analysis, consistent with the presence of multiple different deleted mtDNA species demonstrated by single fiber PCR. There was no consistent correlation between the mitochondrial abnormalities and markers of muscle regeneration, inflammation, or microscopically detectable pathological alterations of myonuclei in the same fibers. Thus, early molecular abnormalities in IBM may simply accelerate the accumulation of mtDNA abnormalities that occurs with natural aging.
journal_name
J Neuropathol Exp Neuroljournal_title
Journal of neuropathology and experimental neurologyauthors
Horvath R,Fu K,Johns T,Genge A,Karpati G,Shoubridge EAdoi
10.1097/00005072-199805000-00003subject
Has Abstractpub_date
1998-05-01 00:00:00pages
396-403issue
5eissn
0022-3069issn
1554-6578journal_volume
57pub_type
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journal_title:Journal of neuropathology and experimental neurology
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