Background: In the pathology of sporadic inclusion body myositis (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 haematoxylin–eosin, trichrome and multi-immunohistochemistry for neural cell adhesion molecule (NCAM), αB-crystallin, amyloid precursor protein (APP), desmin, major histocompatibility complex I, β-amyloid and ubiquitin. Corresponding areas of all biopsies were quantitatively analysed for all markers. Primary myotube cultures were exposed to the proinflammatory cytokines interleukin (IL)-1β and interferon (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 with the accumulation of β-amyloid in atrophic fibres, a major part of fibres positive for APP or αB-crystallin showed no morphological abnormalities. Expression of APP and αB-crystallin significantly correlated with each other and most double positive fibres displayed accumulation 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 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 pathological changes and underscore the fact that a network of cell stress, inflammation and degeneration is relevant to sIBM.
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I E Muth and K Barthel contributed equally to this study.
Funding The study was supported by the Deutsche Forschungsgemeinschaft (DFG; Schm 1669/2-1) and the Association Française contre les Myopathies (AFM; AM/CP/2008-1175/13512) to JS and by the intramural program of NINDS (to MCD).
Competing interests None.
Ethics approval The study was approved the by the National Institutes of Health and the University of Göttingen.
Provenance and Peer review Not commissioned; externally peer reviewed.
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