Title

Dysferlin deficiency and the development of cardiomyopathy in a mouse model of limb-girdle muscular dystrophy 2B.

Document Type

Article

Publication Date

2009

Keywords

Cardiomyopathies, Disease-Models-Animal, Image-Processing-Computer-Assisted, Immunohistochemistry, Membrane-Proteins, Mice, Microscopy-Electron-Transmission, Muscle-Proteins, Muscular-Dystrophies-Limb-Girdle, Myocardium

JAX Source

Am J Pathol 2009 Dec; 175(6):2299-308.

Abstract

Limb-girdle muscular dystrophy 2B, Miyoshi myopathy, and distal myopathy of anterior tibialis are severely debilitating muscular dystrophies caused by genetically determined dysferlin deficiency. In these muscular dystrophies, it is the repair, not the structure, of the plasma membrane that is impaired. Though much is known about the effects of dysferlin deficiency in skeletal muscle, little is known about the role of dysferlin in maintenance of cardiomyocytes. Recent evidence suggests that dysferlin deficiency affects cardiac muscle, leading to cardiomyopathy when stressed. However, neither the morphological location of dysferlin in the cardiomyocyte nor the progression of the disease with age are known. In this study, we examined a mouse model of dysferlinopathy using light and electron microscopy as well as echocardiography and conscious electrocardiography. We determined that dysferlin is normally localized to the intercalated disk and sarcoplasm of the cardiomyocytes. In the absence of dysferlin, cardiomyocyte membrane damage occurs and is localized to the intercalated disk and sarcoplasm. This damage results in transient functional deficits at 10 months of age, but, unlike in skeletal muscle, the cell injury is sublethal and causes only mild cardiomyopathy even at advanced ages.