title: Myonuclear breakdown in sporadic inclusion body myositis is accompanied by DNA double strand breaks.
abstract: 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.
authors.affiliation: Department of Neurology and Brain Medical Research Center, Kansai Medical University, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishii
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakano
authors.forename: Seika
authors.initials: S
authors.lastname: Nakamura
authors.forename: Reika
authors.initials: R
authors.lastname: Wate
authors.forename: Akiyo
authors.initials: A
authors.lastname: Shinde
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kusaka
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000447:Aldehydes / Q000378:metabolism; D034961:Antigens, Nuclear / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D000072200:Ku Autoantigen; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008297:Male; D016253:Microscopy, Immunoelectron / Q000379:methods; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism
chemical_list: D000447:Aldehydes; D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D052247:Nitric Oxide Synthase Type II; D051747:DNA-Activated Protein Kinase; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; C027576:4-hydroxy-2-nonenal