Dysferlinopathy: mitochondrial abnormalities in human skeletal muscle

Abstract

Purpose: Mitochondrial defects have been associated with a series of muscular diseases. Dysferlinopathy, however, has been rarely reported with mitochondrial dysfunction. Here we report a cohort of dysferlinopathy patients with mitochondrial abnormalities found in muscle. Methods: Clinical data and muscle pathologies of nine cases with dysferlinopathy were retrospectively studied. mtDNA copy number, protein levels and activities of mitochondrial enzyme complexes were assayed. Results: Nine patients were diagnosed as having dysferlinopathy by DYSF sequencing and quantification of dysferlin levels in muscle homogenates. Muscle biopsies exhibited dystrophic changes (n = 9), ragged-red fibers (n = 9) and cytochrome c oxidase-deficient fibers (n = 9). mtDNA copy number increased significantly in 56% (15/27) of fibers with mitochondrial histology. Protein levels of complex IV subunits II (n = 5), complex III subunit core 2 (n = 2) and complex I NDUFB1 (n = 1) decreased. Impaired activities of complexes I, III and IV were observed in 56%, 33% and 78% of subjects and the activities were reduced by 21%, 18% and 40%, respectively. Besides, loss activities of complexes I/IV and decreased ATP level were also found in fibroblasts from dysferlinopathy. Conclusion: Prominent mitochondrial abnormalities are common pathological findings in muscle from dysferlinopathy. Our data indicated that mitochondria may play a significant role in the progression of dysferlinopathy and also highlighted the potential of mitochondrial protective drugs in rescuing the symptoms of dysferlinopathy.

KEYWORDS:

• muscle biopsy
• mitochondrion
• ragged-red fibers
• CCO-deficient fibers
• dysferlinopathy
• muscular dystrophy

Acknowledgements

We thank Marco Onorati and Alice Giani for critical reading of the manuscript.

Declaration of interest

The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the paper