title: Selective vacuolar degeneration in dystrophin-deficient canine Purkinje fibers despite preservation of dystrophin-associated proteins with overexpression of Dp71.
abstract: BACKGROUND
  Respiratory support therapy significantly improves life span in patients with Duchenne muscular dystrophy; cardiac-related fatalities, including lethal arrhythmias, then become a crucial issue. It is therefore important to more thoroughly understand cardiac involvement, especially pathology of the conduction system, in the larger Duchenne muscular dystrophy animal models such as dystrophic dogs.
  
  
  RESULTS
  When 10 dogs with canine X-linked muscular dystrophy in Japan (CXMD(J)) were examined at the age of 1 to 13 months, dystrophic changes of the ventricular myocardium were not evident; however, Purkinje fibers showed remarkable vacuolar degeneration as early as 4 months of age. The degeneration of CXMD(J) Purkinje fibers was coincident with overexpression of Dp71 at the sarcolemma and translocation of mu-calpain to the cell periphery near the sarcolemma or in the vacuoles. Immunoblotting of the microdissected fraction showed that mu-calpain-sensitive proteins such as desmin and cardiac troponin-I or -T were selectively degraded in the CXMD(J) Purkinje fibers. Utrophin was highly upregulated in the earlier stage of CXMD(J) Purkinje fibers, but the expression was dislocated when vacuolar degeneration was recognized at 4 months of age. Nevertheless, the expression of dystrophin-associated proteins alpha-, beta-, gamma-, and delta-sarcoglycans and beta-dystroglycan was well maintained at the sarcolemma of Purkinje fibers.
  
  
  CONCLUSIONS
  Selective vacuolar degeneration of Purkinje fibers was found in the early stages of dystrophin deficiency. Dislocation of utrophin besides upregulation of Dp71 can be involved with this pathology. The degeneration of Purkinje fibers can be associated with the distinct deep Q waves in ECG and fatal arrhythmia seen in dystrophin deficiency.
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Urasawa
authors.forename: Michiko R
authors.initials: MR
authors.lastname: Wada
authors.forename: Noboru
authors.initials: N
authors.lastname: Machida
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yuasa
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Shimatsu
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Wakao
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yuasa
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sano
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.forename: Akinori
authors.initials: A
authors.lastname: Nakamura
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac; D004285:Dogs; D016189:Dystrophin / Q000172:deficiency* / Q000235:genetics; D049029:Dystrophin-Associated Proteins / Q000032:analysis*; D004562:Electrocardiography; D009137:Muscular Dystrophy, Animal / Q000473:pathology*; D011690:Purkinje Fibers / Q000473:pathology* / Q000648:ultrastructure; D015854:Up-Regulation; D049411:Utrophin / Q000378:metabolism*; D014617:Vacuoles / Q000473:pathology*
chemical_list: D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D049411:Utrophin; C085339:apo-dystrophin 1