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Workshop W02: Muscle Disorders with Aberrant Protein Expression

Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathies (h-IBM) are progressive degenerative muscle diseases. s-IBM is the most common muscle disease of older patients. It causes severe weakness but no dementia. h-IBMs have different genetic transmissions and thus probably different genetic defects. In s-IBM, muscle fibers are vacuolated, have intrafiber congophilia and mitochondrial abnormalities, and are associated with mononuclear cell inflammation. In neither s-IBM nor the h-IBMs are the sequential steps of the pathogenic cascade understood . Because sand h-IBMs have a number of pathologic features in common (except for lack of lymphocytic inflammation in h-IBMs), we postulate that their different causes trigger the same upstream aberration leading to a similar downstream cascade of pathogenic events, which are ultimately responsible for the characteristic muscle –fiber degeneration. Intriguingly, our studies have demonstrated that the IBM muscle pathologic phenotype is strikingly similar to that of AD brain. Amyloid(A ), amyloidprecursor protein (A PP), A PP-mRNA, and typical paired helical filaments (PHFs) containing phosphorylated t are accumulated within IBM muscle fibers. Moreover, t in IBM-PHFs is phosphorylated on the same epitopes and probably by the same kinases as in AD brain, since IBM-PHFs contain activated ERK and cdk5. Similarly to AD, IBM-PHFs contain bound RNA. Other “AD characteristic” proteins, including presenilin-1, apolipoprotein E, and markers of oxidative stress, are accumulated within IBM muscle fibers. EMabnormal synapses on IBM muscle fibers have been recently demonstrated by us. In the pathogenic cascade leading to IBM, the accumulation of A PP, A PPmRNA, and Ab appears to precede other abnormalities. Overexpression of the A PP gene, via adenovirus, introduced into cultured normal human muscle fibers leads to their developing several aspects of the IBM phenotype. We therefore hypothesized that overexpression of A PP might be upstream to other cellular abnormalities we have demonstrated, including oxidative stress and mitochondrial abnormalities. Our most recent studies suggest an important pathogenic role of aberrant signal transduction. Conclusions: Since in both s-IBM and AD very similar phenotypes develop in postmitotic aging cells, muscle fibers and neurons respectively, the pathogenic mechanisms initially triggering and the ensuing cascades might be very similar, with the tissue involved being determined, at least partially, by different genetic backgrounds, and/or the etiologic “agent.”