Open Access Open Badges Research article

Cell stress molecules in the skeletal muscle of GNE myopathy

Charlotte Fischer1, Konstanze Kleinschnitz12, Arne Wrede3, Ingrid Muth1, Niels Kruse23, Ichizo Nishino4 and Jens Schmidt12*

Author Affiliations

1 Department of Neurology, University Medical Center, Göttingen, Germany

2 Department of Neuroimmunology, Institute for Multiple Sclerosis Research and Hertie Foundation, University Medical Center, Göttingen, Germany

3 Department of Neuropathology, Prion and Dementia Research Unit, University Medical Center, Göttingen, Germany

4 Department of Neuromuscular Research, National Institute of Neuroscience, Tokyo, Japan

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BMC Neurology 2013, 13:24  doi:10.1186/1471-2377-13-24

Published: 12 March 2013



Mutations of the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine-kinase (GNE)-gene are causally related to GNE myopathy. Yet, underlying pathomechanisms of muscle fibre damage have remained elusive. In sporadic inclusion body myositis (sIBM), the pro-inflammatory cell-stress mediators αB-crystallin and inducible nitric oxide synthase (iNOS) are crucial markers of the disease pathology.


10 muscle biopsies from GNE myopathy patients were analyzed for mRNA-expression of markers of cell-stress, inflammation and β-amyloid and compared to non-myopathic controls. Using double-labeling immunohistochemistry, serial sections of skeletal muscle biopsies were stained for amyloid precursor protein (APP), major histocompatibility complex (MHC)-I, αB-crystallin, neural cell adhesion molecule (NCAM), interleukin (IL)-1β, β-amyloid, iNOS, and phosphorylated neurofilament (P-neurofilament) as well as hematoxylin/eosin histochemistry. Corresponding areas of all biopsies with a total of 2,817 muscle fibres were quantitatively assessed for all markers.


mRNA-expression of APP, NCAM, iNOS, TNF-α and TGF-β was higher in GNE myopathy compared to controls, yet this was not statistically significant. The mRNA-expression of APP and αB-crystallin significantly correlated with the expression of several pro-inflammatory and cell-stress-associated markers as NCAM, IL-1β, TGF-β, CCL-3, and CCL4. By immunohistochemistry, αB-crystallin and iNOS were co-upregulated and the number of fibres positive for αB-crystallin, NCAM, MHC-I and iNOS significantly correlated with each other. A large fraction of fibres positive for αB-crystallin were double positive for iNOS and vice-versa. Moreover, several fibres with structural abnormalities were positive for αB-crystallin and iNOS. Notably, particularly normal appearing fibres displayed an overexpression of these molecules.


The cell-stress molecules αB-crystallin and iNOS are overexpressed in GNE myopathy muscle and may identify early disease mechanisms. The data help to better understand the pathology of GNE myopathy.

Cell stress; Nitric oxide; αB-crystallin; Myopathy; Skeletal muscle pathology