4-hydroxy-2-nonenal and Myositis--Inclusion-Body

Rimmed vacuoles in sporadic inclusion body myositis (s-IBM) contain nuclear remnants. We sought to determine if the nuclear degeneration seen in s-IBM is associated with DNA damage. In muscle biopsy specimens from ten patients with s-IBM and 50 controls, we immunolocalized 1) phosphorylated histone H2AX (γ-H2AX), which is a sensitive immunocytochemical marker of DNA double-strand breaks and 2) DNA-PK, which is an enzyme involved in double-strand break repair. In s-IBM, vacuolar peripheries often showed strong immunoreactivity to γ-H2AX and the three components of DNA-PK (DNA-PKcs, Ku70, and Ku80). A triple fluorescence study of Ku70, emerin, and DNA displayed nuclear breakdown and it suggested impaired nuclear incorporation of Ku70. The percentage of positive nuclei for γ-H2AX was significantly higher in vacuolated fibers than non-vacuolated fibers in s-IBM, or fibers in polymyosits. We hypothesize that a dysfunction of nuclear envelope may cause nuclear fragility, double-strand breaks and impaired nuclear transport in s-IBM.

Topics: Aged; Aged, 80 and over; Aldehydes; Antigens, Nuclear; DNA Breaks, Double-Stranded; DNA-Activated Protein Kinase; DNA-Binding Proteins; Female; Histones; Humans; Ku Autoantigen; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Male; Microscopy, Immunoelectron; Middle Aged; Muscle Fibers, Skeletal; Myositis, Inclusion Body; Nitric Oxide Synthase Type II