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Brain Advance Access published online on April 17, 2008
Brain, doi:10.1093/brain/awn053
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Published by Oxford University Press on behalf of the Guarantors of Brain (2008). The online version of this article has been published under an open access model. users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commerical purposes provided that: the original authorship is properly and fully attributed; the Journal and the Guarantors of Brain are attributed as the original place of publication with the correction citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

Interrelation of inflammation and APP in sIBM: IL-1β induces accumulation of β-amyloid in skeletal muscle

Jens Schmidt1,2, Konstanze Barthel2, Arne Wrede3, Mohammad Salajegheh1, Mathias Bähr2 and Marinos C. Dalakas1,4

1Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA, 2Department of Neurology and Department of Experimental and Clinical Neuroimmunology, 3Department of Neuropathology, University of Göttingen, Germany and 4Neuromuscular Division, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA

Correspondence to: Dr Jens Schmidt, Department of Neurology and Department of Experimental and Clinical Neuroimmunology, University of Göttingen, Waldweg 33, 37073 Göttingen, Germany, or Dr Marinos Dalakas, Neuromuscular Division, Thomas Jefferson University, 900 Walnut Street, Suite 200, Philadelphia, PA 19107, USA E-mail: j.schmidt{at}gmx.org or marinos.dalakas{at}jefferson.edu

Distinct interrelationships between inflammation and β-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN-{gamma}, TNF-{alpha} and IL-1β in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor protein (APP) significantly and consistently correlated with inflammation in the muscle and mRNA-levels of chemokines and IFN-{gamma}. Only in sIBM, immunohistochemical analysis revealed that inflammatory mediators including IL-1β co-localized to β-amyloid depositions within myofibres. In human myotubes, exposure to IL-1β caused upregulation of APP with subsequent intracellular aggregation of β-amyloid. Our data suggest that, in sIBM muscle, production of high amounts of pro-inflammatory mediators specifically induces β-amyloid-associated degeneration. The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle.

Key Words: muscle inflammation; protein aggregation; autoimmunity; β-amyloid; chemokines and cytokines

Abbreviations: APP, amyloid precursor protein; BACE-1, β-site of APP cleaving enzyme 1; DM, dermatomyositis; IFN-{gamma}, interferon-{gamma}; IL-1β, interleukin-1β; IL-6, interleukin-6; MHC class-I, major histocompatibility complex class I; NCAM, neural cell adhesion molecule; PM, polymyositis; sIBM, sporadic inclusion body myositis; TGF-β, transforming growth factor-β; TNF-{alpha}, tumour necrosis factor-{alpha}

Received October 27, 2007. Revised February 12, 2008. Accepted February 26, 2008.


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