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Respiratory chain dysfunction in perifascicular muscle fibres in patients with dermatomyositis is associated with mitochondrial DNA depletion.
Hedberg-Oldfors, Carola; Lindgren, Ulrika; Visuttijai, Kittichate; Lööf, Daniel; Roos, Sara; Thomsen, Christer; Oldfors, Anders.
Afiliación
  • Hedberg-Oldfors C; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Lindgren U; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Visuttijai K; Neuromuscular Center, Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
  • Lööf D; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Roos S; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Thomsen C; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Oldfors A; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Neuropathol Appl Neurobiol ; 48(7): e12841, 2022 12.
Article en En | MEDLINE | ID: mdl-35894812
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Deficiencia de Citocromo-c Oxidasa / Dermatomiositis Tipo de estudio: Risk_factors_studies Límite: Adult / Humans Idioma: En Revista: Neuropathol Appl Neurobiol Año: 2022 Tipo del documento: Article País de afiliación: Suecia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Deficiencia de Citocromo-c Oxidasa / Dermatomiositis Tipo de estudio: Risk_factors_studies Límite: Adult / Humans Idioma: En Revista: Neuropathol Appl Neurobiol Año: 2022 Tipo del documento: Article País de afiliación: Suecia