Mitochondrial and inflammatory changes in sporadic inclusion body myositis
Version of Record online: 4 MAR 2015
© 2014 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Neuropathology and Applied Neurobiology
Volume 41, Issue 3, pages 288–303, April 2015
How to Cite
Rygiel, K. A., Miller, J., Grady, J. P., Rocha, M. C., Taylor, R. W. and Turnbull, D. M. (2015), Mitochondrial and inflammatory changes in sporadic inclusion body myositis. Neuropathology and Applied Neurobiology, 41: 288–303. doi: 10.1111/nan.12149
- Issue online: 4 MAR 2015
- Version of Record online: 4 MAR 2015
- Accepted manuscript online: 18 APR 2014 03:14AM EST
- Manuscript Accepted: 24 MAR 2014
- Manuscript Received: 13 DEC 2013
- Newcastle University Centre for Brain Ageing and Vitality
- Biotechnology and Biological Sciences Research Council
- Engineering and Physical Sciences Research Council
- Economic and Social Research Council
- Medical Research Council. Grant Number: G0700718
- UK NIHR Biomedical Research Centre in Age and Age Related Diseases
- Newcastle upon Tyne Hospitals NHS Foundation Trust
- MRC Centre for Neuromuscular Disease. Grant Number: G000608-1
- The Wellcome Trust Centre for Mitochondrial Research. Grant Number: 096919/Z/11/Z
- The Lily Foundation
- UK NHS Highly Specialised ‘Rare Mitochondrial Disorders of Adults and Children’ Service
- complex I;
- mitochondrial deletions;
Sporadic inclusion body myositis (sIBM) is the most common late onset muscle disease causing progressive weakness. In light of the lack of effective treatment, we investigated potential causes underlying muscle wasting. We hypothesized that accumulation of mitochondrial respiratory deficiency in muscle fibres may lead to fibre atrophy and degeneration, contributing to muscle mass reduction.
Histochemical and immunohistochemical analyses were performed on muscle biopsies from 16 sIBM patients to detect activity of mitochondrial enzymes and expression of mitochondrial respiratory chain proteins along with inflammatory markers respectively. Mitochondrial DNA mutations were assessed in single muscle fibres using real-time PCR.
We identified respiratory-deficient fibres at different stages of mitochondrial dysfunction, with downregulated expression of complex I of mitochondrial respiratory chain being the initial feature. We detected mitochondrial DNA rearrangements in the majority of individual respiratory-deficient muscle fibres. There was a strong correlation between number of T lymphocytes and macrophages residing in muscle tissue and the abundance of respiratory-deficient fibres. Moreover, we found that respiratory-deficient muscle fibres were more likely to be atrophic compared with respiratory-normal counterparts.
Our findings suggest that mitochondrial dysfunction has a role in sIBM progression. A strong correlation between the severity of inflammation, degree of mitochondrial changes and atrophy implicated existence of a mechanistic link between these three parameters. We propose a role for inflammatory cells in the initiation of mitochondrial DNA damage, which when accumulated, causes respiratory dysfunction, fibre atrophy and ultimately degeneration of muscle fibres.