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

Abstract

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- γ, TNF-α 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- γ. 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.

Journal

Journal ID (nlm-ta): Brain

Journal ID (publisher-id): brainj

Journal ID (hwp): brain

Title: Brain

Publisher: Oxford University Press

ISSN (Print): 0006-8950

ISSN (Electronic): 1460-2156

Publication date (Print): May 2008

Publication date (Electronic): 17 April 2008

Publication date PMC-release: 17 April 2008

Volume: 131

Issue: 5

Pages: 1228-1240

Affiliations

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

Author notes

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@ 123456gmx.org or marinos.dalakas@ 123456jefferson.edu

Article

Publisher ID: awn053

DOI: 10.1093/brain/awn053

PMC ID: 2367696

PubMed ID: 18420712

Copyright statement: Published by Oxford University Press on behalf of the Guarantors of Brain (2008).

License:

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Categories

Subject: Original Articles