CHARACTERIZATION OF THE MITOCHONDRIAL-DNA ABNORMALITIES IN THE SKELETAL-MUSCLE OF PATIENTS WITH INCLUSION-BODY MYOSITIS

Inclusion body myositis (IBM) is a late-onset inflammatory myopathy wi th 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 mi tochondrial respiratory chain dysfunction (ragged-red fibers, multiple mtDNA deletions) has been reported in IBM muscle. Here we have invest igated the relationship of the mtDNA abnormalities in sporadic and fam ilial IBM patients to the pathogenesis of the disease. In situ hybridi zation analysis with mtDNA probes revealed several different mtDNA abn ormalities in cytochrome c oxidase-negative muscle fibers including la rge-scale mtDNA deletions and mtDNA depletion, but no evidence for non specific DNA binding. Contrary to previous reports, we did not observe mtDNA deletions on Southern blot analysis, consistent with the presen ce of multiple different deleted mtDNA species demonstrated by single fiber PCR. There was no consistent correlation between the mitochondri al abnormalities and markers of muscle regeneration, inflammation, or microscopically detectable pathological alterations of myonuclei in th e same fibers. Thus, early molecular abnormalities in IBM may simply a ccelerate the accumulation of mtDNA abnormalities that occurs with nat ural aging.