Myonuclear breakdown in sporadic inclusion body myositis is accompanied by DNA double strand breaks

Neuromuscul Disord. 2011 May;21(5):345-52. doi: 10.1016/j.nmd.2011.02.004. Epub 2011 Feb 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aldehydes / metabolism
  • Antigens, Nuclear / metabolism
  • DNA Breaks, Double-Stranded*
  • DNA-Activated Protein Kinase / metabolism
  • DNA-Binding Proteins / metabolism
  • Female
  • Histones / metabolism
  • Humans
  • Ku Autoantigen
  • Lysosomal Membrane Proteins / metabolism
  • Lysosomal-Associated Membrane Protein 2
  • Male
  • Microscopy, Immunoelectron / methods
  • Middle Aged
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology*
  • Muscle Fibers, Skeletal / ultrastructure
  • Myositis, Inclusion Body / genetics*
  • Myositis, Inclusion Body / pathology*
  • Nitric Oxide Synthase Type II / metabolism

Substances

  • Aldehydes
  • Antigens, Nuclear
  • DNA-Binding Proteins
  • H2AX protein, human
  • Histones
  • LAMP2 protein, human
  • Lysosomal-Associated Membrane Protein 2
  • Lysosomal Membrane Proteins
  • Nitric Oxide Synthase Type II
  • DNA-Activated Protein Kinase
  • Xrcc6 protein, human
  • Ku Autoantigen
  • 4-hydroxy-2-nonenal