Cell stress molecules in the skeletal muscle of GNE myopathy

BMC Neurol. 2013 Mar 12;13:24. doi: 10.1186/1471-2377-13-24.


Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amyloid beta-Protein Precursor / metabolism
  • Arabidopsis Proteins / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Female
  • Gene Expression Regulation / genetics*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Intramolecular Transferases / metabolism
  • Male
  • Middle Aged
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscular Diseases / genetics*
  • Muscular Diseases / pathology*
  • Mutation / genetics
  • Neural Cell Adhesion Molecules / genetics
  • Neural Cell Adhesion Molecules / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Regression Analysis
  • Young Adult
  • alpha-Crystallin B Chain / genetics*
  • alpha-Crystallin B Chain / metabolism


  • Amyloid beta-Protein Precursor
  • Arabidopsis Proteins
  • Cytokines
  • Histocompatibility Antigens Class I
  • Neural Cell Adhesion Molecules
  • alpha-Crystallin B Chain
  • Nitric Oxide Synthase Type II
  • Phosphotransferases (Alcohol Group Acceptor)
  • N-acylmannosamine kinase
  • Intramolecular Transferases
  • marneral synthase, Arabidopsis