title: Dysferlinopathy: mitochondrial abnormalities in human skeletal muscle.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Department of Neurology , Qilu Hospital of Shandong University , Jinan , China.|b Department of Neurobiology, Kavli Institute for Neuroscience , Yale University School of Medicine , New Haven , CT , USA.
authors.forename: Fuchen
authors.initials: F
authors.lastname: Liu
authors.affiliation: a Department of Neurology , Qilu Hospital of Shandong University , Jinan , China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Lou
authors.affiliation: a Department of Neurology , Qilu Hospital of Shandong University , Jinan , China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: a Department of Neurology , Qilu Hospital of Shandong University , Jinan , China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: a Department of Neurology , Qilu Hospital of Shandong University , Jinan , China.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: c Otolaryngology Lab, Qilu Hospital of Shandong University , Jinan , China.
authors.forename: Xiulian
authors.initials: X
authors.lastname: Sun
authors.affiliation: a Department of Neurology , Qilu Hospital of Shandong University , Jinan , China.|d Key Laboratory for Experimental Teratology of the Ministry of Education , School of Medicine, Shandong University , Jinan , China.|e Brain Science Research Institute , Shandong University , Jinan , China.
authors.forename: Chuanzhu
authors.initials: C
authors.lastname: Yan
keywords: CCO-deficient fibers; dysferlinopathy; mitochondrion; muscle biopsy; muscular dystrophy; ragged-red fibers