Vacuolated muscle fibers in muscle biopsies of 8 out of 8 inclusion body myositis (IBM) patients, including 2 hereditary patients, manifested increased mRNA for the beta-amyloid precursor protein (beta APP) that contains Kunitz-type protease inhibitor motif. In affected fibers, increased beta APP-mRNA correspond to abnormally accumulated beta APP immunoreactivity (including beta-amyloid protein epitope). In normal human muscle fibers increased beta APP-mRNA was present only at the neuromuscular junctions. Our study (a) suggests that abnormally accumulated beta APP in IBM vacuolated fibers results, at least partly, from increased beta APP generation, and (b) provides the first demonstration of up-regulated beta APP-mRNA in pathologic human tissue other than brain of Alzheimer's disease and Down's syndrome.