title: Mitochondrial and inflammatory changes in sporadic inclusion body myositis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne, UK; Newcastle University Centre for Brain Ageing and Vitality, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Rygiel
authors.forename: James
authors.initials: J
authors.lastname: Miller
authors.forename: John P
authors.initials: JP
authors.lastname: Grady
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Rocha
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Doug M
authors.initials: DM
authors.lastname: Turnbull
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D008928:Mitochondria / Q000473:pathology*; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004272:DNA, Mitochondrial
keywords: atrophy; complex I; inflammation; mitochondria; mitochondrial deletions; sIBM
references.citation: J Neuropathol Exp Neurol. 1995 Jul;54(4):581-7
references.pmid: 7602331
references.citation: Nucleic Acids Res. 2001 Aug 1;29(15):E74-4
references.pmid: 11470889
references.citation: Anal Biochem. 2007 Nov 1;370(1):127-9
references.pmid: 17662684
references.citation: Aging Cell. 2009 Sep;8(5):566-72
references.pmid: 19624578
references.citation: Brain. 2008 Nov;131(Pt 11):2832-40
references.pmid: 18984605
references.citation: Neurology. 2006 Jan 24;66(2 Suppl 1):S49-55
references.pmid: 16432145
references.citation: Brain. 1993 Apr;116 ( Pt 2):325-36
references.pmid: 8384916
references.citation: Ann Neurol. 1986 Feb;19(2):112-25
references.pmid: 3008636
references.citation: Ann Neurol. 2011 Mar;69(3):481-92
references.pmid: 21446022
references.citation: Methods Mol Med. 2000;38:265-77
references.pmid: 22351281
references.citation: Histochem J. 1989 Sep-Oct;21(9-10):545-55
references.pmid: 2556354
references.citation: Br J Rheumatol. 1998 Oct;37(10):1047-53
references.pmid: 9825742
references.citation: Neuromuscul Disord. 2002 Nov;12(9):853-7
references.pmid: 12398837
references.citation: Ann Neurol. 1995 Jan;37(1):24-9
references.pmid: 7818253
references.citation: Curr Opin Rheumatol. 2002 Nov;14(6):653-7
references.pmid: 12410086
references.citation: Am J Hum Genet. 2001 Mar;68(3):802-6
references.pmid: 11179029
references.citation: J Neuroimmunol. 2010 Aug 25;225(1-2):137-42
references.pmid: 20537411
references.citation: J Gerontol A Biol Sci Med Sci. 2007 Mar;62(3):235-45
references.pmid: 17389720
references.citation: J Neurol Sci. 2006 Nov 15;249(2):158-65
references.pmid: 16887149
references.citation: J Neurol Sci. 2009 Mar 15;278(1-2):25-9
references.pmid: 19101700
references.citation: Brain. 2012 Mar;135(Pt 3):886-99
references.pmid: 22366799
references.citation: Neurology. 1998 Sep;51(3):655 and 17 pages following
references.pmid: 9748002
references.citation: Neuropathol Appl Neurobiol. 2011 Apr;37(3):226-42
references.pmid: 21155862
references.citation: Exp Gerontol. 2009 Mar;44(3):170-6
references.pmid: 18983905
references.citation: Nucleic Acids Res. 2002 Jul 15;30(14):e68
references.pmid: 12136116
references.citation: Neuromuscul Disord. 2012 Aug;22(8):690-8
references.pmid: 22647770
references.citation: Neuromuscul Disord. 2010 Feb;20(2):142-7
references.pmid: 20074951