Mitochondrial dysfunction in myofibrillar myopathy

Neuromuscul Disord. 2016 Oct;26(10):691-701. doi: 10.1016/j.nmd.2016.08.004. Epub 2016 Aug 10.


Myofibrillar myopathies (MFM) are characterised by focal myofibrillar destruction and accumulation of myofibrillar elements as protein aggregates. They are caused by mutations in the DES, MYOT, CRYAB, FLNC, BAG3, DNAJB6 and ZASP genes as well as other as yet unidentified genes. Previous studies have reported changes in mitochondrial morphology and cellular positioning, as well as clonally-expanded, large-scale mitochondrial DNA (mtDNA) deletions and focal respiratory chain deficiency in muscle of MFM patients. Here we examine skeletal muscle from patients with desmin (n = 6), ZASP (n = 1) and myotilin (n = 2) mutations and MFM protein aggregates, to understand how mitochondrial dysfunction may contribute to the underlying mechanisms causing disease pathology. We have used a validated quantitative immunofluorescent assay to study respiratory chain protein levels, together with oxidative enzyme histochemistry and single cell mitochondrial DNA analysis, to examine mitochondrial changes. Results demonstrate a small number of clonally-expanded mitochondrial DNA deletions, which we conclude are due to both ageing and disease pathology. Further to this we report higher levels of respiratory chain complex I and IV deficiency compared to age matched controls, although overall levels of respiratory deficient muscle fibres in patient biopsies are low. More strikingly, a significantly higher percentage of myofibrillar myopathy patient muscle fibres have a low mitochondrial mass compared to controls. We concluded this is mechanistically unrelated to desmin and myotilin protein aggregates; however, correlation between mitochondrial mass and muscle fibre area is found. We suggest this may be due to reduced mitochondrial biogenesis in combination with muscle fibre hypertrophy.

Keywords: Cytochrome c oxidase deficiency; Histochemistry; Immunofluorescence; Mitochondria; Mitochondrial DNA deletion; Myofibrillar myopathy.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Aged
  • Cell Cycle Proteins / genetics
  • Cohort Studies
  • Connectin / genetics
  • DNA, Mitochondrial
  • Desmin / genetics
  • Female
  • Humans
  • LIM Domain Proteins / genetics
  • Male
  • Microfilament Proteins
  • Middle Aged
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Mutation
  • Myopathies, Structural, Congenital / genetics
  • Myopathies, Structural, Congenital / metabolism*
  • Myopathies, Structural, Congenital / pathology
  • Ribonucleotide Reductases / genetics


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Connectin
  • DNA, Mitochondrial
  • Desmin
  • LDB3 protein, human
  • LIM Domain Proteins
  • MYOT protein, human
  • Microfilament Proteins
  • RRM2B protein, human
  • Ribonucleotide Reductases

Supplementary concepts

  • Myofibrillar Myopathy