Mitochondrial DNA depletion in sporadic inclusion body myositis

Abstract

Sporadic inclusion body myositis (sIBM) is a late onset disorder of unkown aetiology. Mitochondrial changes such as cytochrome oxidase deficient fibres are a well recognised feature and mitochondrial DNA (mtDNA) deletions have also been reported, but not consistently. Since mtDNA deletions are not present in all cases, we investigated whether other types of mtDNA abnormality were responsible for the mitochondrial changes. We studied 9 patients with sIBM. To control for fibre loss or replacement with inflammatory cells, we compared sIBM patients with necrotising myopathy (n = 4) as well as with healthy controls. Qualitative anlysis for mtDNA deletions and quantitative measurement of mtDNA copy number showed that muscle from patients with sIBM contained on average 67% less mtDNA than healthy controls (P = 0.001). The level of mtDNA was also significantly depleted in sIBM when compared to necrotising myopathy. No significant difference in copy number was seen in patients with necrotising myopathy compared to controls. Deletions of mtDNA were present in 4 patients with sIBM, but not all. Our findings suggest that mtDNA depletion is a more consistent finding in sIBM, and one that may be implicated in the pathogenesis of the disease.

Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

“…Recently, it was reported that mtDNA deletion [33] and mitochondrial DNA rearrangements occur in sIBM [8]. To further identify the molecular mechanism of sIBM, we amplified whole mitochondrial DNA (mtDNA) from myoblasts from normal controls and 3 sIBM patients.…”

The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

“…Apart from mtDNA point mutations, single large deletion in mtDNA at high levels cause multisystem diseases in children and NMDs associated with chronic progressive external ophthalmoplegia in adults and proximal myopathy [ 76 , 79 ]. Other NMDs with mtDNA deletions are sporadic inclusion body myositis (sIBM) (reported in 67% of sIBM patients) [ 108 , 109 ] and giant axonal neuropathy (GAN). These deletions are generally spontaneously acquired [ 105 ], probably as accidents during mtDNA replication in the oocyte, in the early embryo or later on, along lifetime.…”

“…In particular, most of the muscular dystrophies (MD) have some MRC complexes with impaired or decreased function ( Table 1 ): complex I in Becker MD (BMD), complexes III and IV in DMD, and complexes I and V in oculopharyngeal (OPMD) and in distal MD (DD). Other NMDs with MRC alterations are myofibrillar myopathies (complexes I and IV) ( Table 2 ), ALS (CIV subunit I) ( Table 3 ), SMA (complexes I and IV) ( Table 3 ), GAN (complexes I and IV) ( Table 4 ), and sIBM (complex IV) [ 108 ]. Impaired MRC function promotes mitochondrial dysfunction, eventually leading to progressive weakness and muscle wasting.…”

Mitochondrial Dysfunction: A Common Hallmark Underlying Comorbidity between sIBM and Other Degenerative and Age-Related Diseases

“…Despite the fact that pathological mitochondrial evidence is frequently observed in muscle biopsies from sIBM patients, mitochondrial abnormalities in this disease have scarcely been assessed at a molecular level [10,11]. Our group described, for the first time, mitochondrial DNA alterations in sIBM muscle.…”