Respiratory chain dysfunction in perifascicular muscle fibres in patients with dermatomyositis is associated with mitochondrial DNA depletion

Abstract

Aims Patients with dermatomyositis (DM) suffer from reduced aerobic metabolism contributing to impaired muscle function, which has been linked to cytochrome c oxidase (COX) deficiency in muscle tissue. This mitochondrial respiratory chain dysfunction is typically seen in perifascicular regions, which also show the most intense inflammatory reaction along with capillary loss and muscle fibre atrophy. The objective of this study was to investigate the pathobiology of the oxidative phosphorylation deficiency in DM. Methods Muscle biopsy specimens with perifascicular COX deficiency from five juveniles and seven adults with DM were investigated. We combined immunohistochemical analyses of subunits in the respiratory chain including complex I (subunit NDUFB8), complex II (succinate dehydrogenase, subunit SDHB) and complex IV (COX, subunit MTCO1) with in situ hybridisation, next generation deep sequencing and quantitative polymerase chain reaction (PCR). Results There was a profound deficiency of complexes I and IV in the perifascicular regions with enzyme histochemical COX deficiency, whereas succinate dehydrogenase activity and complex II were preserved. In situ hybridisation of mitochondrial RNA showed depletion of mitochondrial DNA (mtDNA) transcripts in the perifascicular regions. Analysis of mtDNA by next generation deep sequencing and quantitative PCR in affected muscle regions showed an overall reduction of mtDNA copy number particularly in the perifascicular regions. Conclusion The respiratory chain dysfunction in DM muscle is associated with mtDNA depletion causing deficiency of complexes I and IV, which are partially encoded by mtDNA, whereas complex II, which is entirely encoded by nuclear DNA, is preserved. The depletion of mtDNA indicates a perturbed replication of mtDNA explaining the muscle pathology and the disturbed aerobic metabolism.

Disease spectrum of myopathies with elevated aldolase and normal creatine kinase

“…A previous study showed that perifascicular mitochondrial pathology occurred in 46.3% of dermatomyositis patients, but its correlation with CK level is unknown [27]. This mitochondrial dysfunction is thought to be a result of interferon‐beta induced reactive oxygen species leading to mitochondrial DNA depletion [28, 29]. Our observation of frequent perifascicular mitochondrial alterations in dermatomyositis patients with normal CK and elevated aldolase requires additional studies in a larger cohort of patients.…”

The Emerging Role of Mitochondrial Dysfunction in the Pathogenesis of Idiopathic Inflammatory Myopathies

“… 39 , 41 – 43 Contrary to IBM, very low numbers of large-scale mtDNA deletions have been reported in DM: less than 0.05% of DM muscle biopsies present this mutation, not differing from control subjects regarding this aspect. 44 …”

“…Even more, these reports provide evidence that respiratory chain dysfunction in DM is associated with mtDNA depletions. 44 , 50 , 51 Such COX-deficient fibers have also been associated with DM, lacking complex I and IV, while having preserved complex II activity. 44 …”

“… 44 , 50 , 51 Such COX-deficient fibers have also been associated with DM, lacking complex I and IV, while having preserved complex II activity. 44 …”

“…those having mitochondrial abnormalities) are associated with up-regulation of major histocompatibility complex class I and infiltration of T cells into muscle tissue in DM and IBM, respectively. 44 , 99 , 100 Currently, causality is not proven, and whether COX deficiency precedes inflammation or whether it is a consequence of the inflammation remains to be clarified. Inflammatory cytokines, including chemokine (C-X-C motif) ligand (CXCL)-8, interleukin-6, tumor necrosis factor-α, interleukin-1β, and monocyte chemoattractant protein-1, have been implicated in mitochondrial damage and mitochondria–muscle cross-talk.…”