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Am J Physiol Heart Circ Physiol. 2014 Feb 15;306(4):H564-73. doi: 10.1152/ajpheart.00441.2013. Epub 2013 Dec 13.

Enhanced currents through L-type calcium channels in cardiomyocytes disturb the electrophysiology of the dystrophic heart.

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1
Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria;

Abstract

Duchenne muscular dystrophy (DMD), induced by mutations in the gene encoding for the cytoskeletal protein dystrophin, is an inherited disease characterized by progressive muscle weakness. Besides the relatively well characterized skeletal muscle degenerative processes, DMD is also associated with cardiac complications. These include cardiomyopathy development and cardiac arrhythmias. The current understanding of the pathomechanisms in the heart is very limited, but recent research indicates that dysfunctional ion channels in dystrophic cardiomyocytes play a role. The aim of the present study was to characterize abnormalities in L-type calcium channel function in adult dystrophic ventricular cardiomyocytes. By using the whole cell patch-clamp technique, the properties of currents through calcium channels in ventricular cardiomyocytes isolated from the hearts of normal and dystrophic adult mice were compared. Besides the commonly used dystrophin-deficient mdx mouse model for human DMD, we also used mdx-utr mice, which are both dystrophin- and utrophin-deficient. We found that calcium channel currents were significantly increased, and channel inactivation was reduced in dystrophic cardiomyocytes. Both effects enhance the calcium influx during an action potential (AP). Whereas the AP in dystrophic mouse cardiomyocytes was nearly normal, implementation of the enhanced dystrophic calcium conductance in a computer model of a human ventricular cardiomyocyte considerably prolonged the AP. Finally, the described dystrophic calcium channel abnormalities entailed alterations in the electrocardiograms of dystrophic mice. We conclude that gain of function in cardiac L-type calcium channels may disturb the electrophysiology of the dystrophic heart and thereby cause arrhythmias.

KEYWORDS:

Duchenne muscular dystrophy; L-type calcium channels; cardiac action potential; dystrophin-deficient mouse models; ventricular cardiomyocytes

PMID:
24337461
PMCID:
PMC4892346
DOI:
10.1152/ajpheart.00441.2013
[Indexed for MEDLINE]
Free PMC Article
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