Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes

Abstract

Background/Aims: Dysferlin plays a decisive role in calcium-dependent membrane repair in myocytes. Mutations in the encoding DYSF gene cause a number of myopathies, e.g. limb-girdle muscular dystrophy type 2B (LGMD2B). Besides skeletal muscle degenerative processes, dysferlin deficiency is also associated with cardiac complications. Thus, both LGMD2B patients and dysferlin-deficient mice develop a dilated cardiomyopathy. We and others have recently reported that dystrophin-deficient ventricular cardiomyocytes from mouse models of Duchenne muscular dystrophy show significant abnormalities in voltage-dependent ion channels, which may contribute to the pathophysiology in dystrophic cardiomyopathy. The aim of the present study was to investigate if dysferlin, like dystrophin, is a regulator of cardiac ion channels. Methods and Results: By using the whole cell patch-clamp technique, we compared the properties of voltage-dependent calcium and sodium channels, as well as action potentials in ventricular cardiomyocytes isolated from the hearts of normal and dysferlin-deficient (dysf) mice. In contrast to dystrophin deficiency, the lack of dysferlin did not impair the ion channel properties and left action potential parameters unaltered. In connection with normal ECGs in dysf mice these results suggest that dysferlin deficiency does not perturb cardiac electrophysiology. Conclusion: Our study demonstrates that dysferlin does not regulate cardiac voltage-dependent ion channels, and implies that abnormalities in cardiac ion channels are not a universal characteristic of all muscular dystrophy types.

Functions of Vertebrate Ferlins

“…One fifth of the patients developed respiratory problems and 9% required non-invasive ventilation. Accordingly, heart function in dysferlinopathy mouse models is either not or mildly affected [187,190,[193][194][195]. However, also membrane repair in cardiomyocytes is dependent on dysferlin [196] and in a model of ischemia/reperfusion injury, dysferlin was shown to be cardioprotective [196,197].…”

A modified density gradient proteomic-based method to analyze endolysosomal proteins in cardiac tissue

“…Dysferlin (DYSF) acts as a Ca 2+ sensor in Ca 2+ -triggered synaptic vesicle-plasma membrane fusion in myocytes ( Rubi et al., 2015 ). Mutations in DYSF cause limb-girdle muscular dystrophy type 2B (LGMD2B) due to defective Ca 2+ -dependent, vesicle-mediated membrane repair ( Liu et al., 1998 ).…”

Cardiac Atrial Compartmentalisation Proteomics: A Modified Density Gradient Method to Analyse Endo-lysosomal Proteins

“…Dysferlin (DYSF), acts as a Ca 2+ sensor in Ca 2+ -triggered synaptic vesicle-plasma membrane fusion in myocytes 54 . Mutations in dysferlin cause limb-girdle muscular dystrophy type 2B (LGMD2B) due to defective Ca 2+ -dependent, vesicle-mediated membrane repair 55 .…”