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Pro-inflammatory cell stress in sIBM muscle: overexpression of αB-crystallin is associated with APP and accumulation of β-amyloid
  1. Ingrid E Muth
  1. University Medicine Göttingen, Germany
    1. Konstanze Barthel
    1. University Medicine Göttingen, Germany
      1. Mathias Bähr
      1. University Medicine Göttingen, Germany
        1. Marinos C Dalakas
        1. Imperial College, United Kingdom
          1. Jens Schmidt ({at}
          1. University Medicine Göttingen, Germany


            Background: In the pathology of sIBM, the relevance of cell-stress molecules such as the heat-shock-protein αB-crystallin, particularly in healthy appearing muscle fibres, has remained elusive.

            Methods: 10 muscle biopsies from sIBM patients were serially stained for H&E, trichrome, and multi-immunohistochemistry for neural-cell-adhesion-molecule (NCAM), αB-crystallin, amyloid-precursor-protein (APP), desmin, major-histocompatibility-complex (MHC) I, β amyloid, ubiquitin. Corresponding areas of all biopsies were quantitatively analyzed for all markers. Primary myotube cultures were exposed to pro-inflammatory cytokines IL-1β+IFN-γ.

            Results: In human myotubes exposed to IL-1β+IFN-γ, overexpression of APP was accompanied by upregulation of αB-crystallin. In sIBM muscle biopsies, over 20% of all fibres displayed accumulation of β-amyloid or vacuoles/ inclusions. A clearly larger fraction of the fibres were positive for αB-crystallin or APP. In contrast to the accumulation of β-amyloid in atrophic fibres, a major part of fibres positive for APP or αB-crystallin showed no morphological abnormalities. The expression of APP and αB-crystallin significantly correlated with each other and most double-positive fibres displayed accumulations of β-amyloid, vacuoles or an atrophic morphology. In almost all of these fibres, other markers of degeneration/regeneration such as NCAM and desmin were evident as additional indicators of a cell-stress response. Some fibres double-positive for APP and αB-crystallin displayed an infiltration by inflammatory cells.

            Conclusion: Our results suggest that αB-crystallin is associated with overexpression of APP in sIBM muscle and that upregulation of αB-crystallin precedes accumulation of β-amyloid. The data help to better understand early pathologic changes and underscore that a network of cell-stress, inflammation and degeneration is relevant to sIBM.

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