Oxidative stress and predominant Aβ42(43) deposition in myopathies with rimmed vacuoles

This study was undertaken to determine the C terminus of amyloid β protein (Aβ), accumulated in vacuolated muscle fibers, and compare these findings to the level of oxidative stress. Eight patients with myopathies characterized by rimmed vacuoles (RVs) were analyzed. Monoclonal antibodies specific to Aβ40 or Aβ42(43) revealed that the Aβ42(43) immunoreactivity was solely distributed in the vacuolated muscle fibers, and that only a part was also immunopositive for anti-Aβ40. Quantitative analyses in four specimens, in which eight or more vacuolated muscle fibers were observed, revealed that the mean incidence of Aβ42(43)-positive muscle fibers was 79.5±6.2% in total vacuolated muscle fibers, whereas that of the Aβ40-positive fibers was 42.9±12.6%. The predominance of Aβ42(43) deposition was statistically significant (P<0.05). Aβ deposition was then compared with the distribution of oxidative nucleic acid damage in muscle fibers using a monoclonal antibody against 8-hydroxy-2′-deoxyguanosine and 8-hydroxyguanosine (8OHdG&G). The cytoplasmic staining for anti-8OHdG&G was found not only in vacuolated muscle fibers, but also in other muscle fibers including morphologically normal ones. Positive staining was completely abolished by RNase pretreatment and, thus, was suggested to reflect an increase of cellular RNA oxidation. The distribution of 8OHdG&G was much broader than the Aβ deposition. These data suggest that Aβ42(43) is predominantly involved in the pathogenesis of muscle fiber degeneration with RVs, and that oxidative damage may precede Aβ deposition in muscle fibers and play a key role in the pathomechanism of myopathies with RVs.