Abstract

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.