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(Circulation. 2008;117:2437-2448.)
© 2008 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Selective Vacuolar Degeneration in Dystrophin-Deficient Canine Purkinje Fibers Despite Preservation of Dystrophin-Associated Proteins With Overexpression of Dp71

Nobuyuki Urasawa, MD; Michiko R. Wada, PhD; Noboru Machida, DVM, PhD; Katsutoshi Yuasa, PhD; Yoshiki Shimatsu, PhD; Yoshito Wakao, DVM, PhD; Shigeki Yuasa, MD, PhD; Toshiaki Sano, MD, PhD; Ikuya Nonaka, MD, PhD; Akinori Nakamura, MD, PhD; Shin’ichi Takeda, MD, PhD

From the Departments of Molecular Therapy (N.U., M.R.W., K.Y., Y.S., A.N., S.T.) and Ultrastructural Research (S.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; Department of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan (N.M.); Department of Veterinary Surgery I, Azabu University, Sagamihara, Kanagawa, Japan (Y.W.); Department of Pathology, University of Tokushima Graduate School of Medicine, Tokushima, Japan (T.S.); and National Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan (I.N.).

Correspondence to Shin’ichi Takeda, MD, PhD, Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan. E-mail takeda{at}ncnp.go.jp

Received September 9, 2007; accepted March 5, 2008.

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.

Methods and 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 µ-calpain to the cell periphery near the sarcolemma or in the vacuoles. Immunoblotting of the microdissected fraction showed that µ-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 -, β-, -, and -sarcoglycans and β-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.

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CLINICAL PERSPECTIVE