Abstract
Dysferlinopathies are caused by mutations in the DYSF gene and patients may present with proximal or distal myopathy. Dysferlin is responsible for membrane resealing, and mutations may result in a defect in membrane repair following mechanical or chemical stress, causing an influx of Ca(2+). Since mitochondria are involved in Ca(2+) buffering, we hypothesised that mitochondrial defects may be present in skeletal muscle biopsies from patients with mutations in this gene. The aim was to characterise mitochondrial defects in muscle from patients with dysferlinopathies. Here, we analysed skeletal muscle biopsies for eight patients by quadruple immunofluorescent assay to assess oxidative phosphorylation protein abundance. Long-range PCR in single muscle fibres was used to look for presence of clonally expanded large-scale mitochondrial DNA rearrangements in patients' skeletal muscle (n = 3). Immunofluorescence demonstrated that the percentage of complex I- and complex IV-deficient fibres was higher in patients with DYSF mutations than in age-matched controls. No clonally expanded mtDNA deletions were detected using long-range PCR in any of the analysed muscle fibres. We conclude that complex I and complex IV deficiency is higher in patients than age matched controls but patients do not have rearrangements of the mtDNA. We hypothesise that respiratory chain deficiency may be the results of an increased cytosolic Ca(2+) concentration (due to a membrane resealing defect) causing mitochondrial aberrations.