Cytochrome c oxidase-intermediate fibres: importance in understanding the pathogenesis and treatment of mitochondrial myopathy.

An important diagnostic muscle biopsy finding in patients with mitochondrial DNA disease is the presence of respiratory-chain deficient fibres. These fibres are detected as cytochrome c oxidase-deficient following a sequential cytochrome c oxidase-succinate dehydrogenase reaction, often in a mosaic pattern within a population of cytochrome c oxidase-normal fibres. Detailed analysis of muscle biopsies from patients with various mitochondrial DNA defects shows that a spectrum of deficiency exists, as there are a large number of fibres which do not correspond to being either completely cytochrome c oxidase-normal (brown staining) or cytochrome c oxidase-deficient (blue staining). We have used a combination of histochemical and immunocytochemical techniques to show that a population of cytochrome c oxidase-intermediate reacting fibres are a gradation between normal and deficient fibres. We show that cytochrome c oxidase-intermediate fibres also have different genetic characteristics in terms of amount of mutated and wild-type mtDNA, and as such, may represent an important transition between respiratory normal and deficient fibres. Assessing changes in intermediate fibres will be crucial to evaluating the responses to treatment and in particular to exercise training regimes in patients with mitochondrial DNA disease.