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

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.

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

“…We and others have recently reported that dystrophin-deficient cardiomyocytes derived from adult mdx and mdx-utr mice (mouse models of Duchenne muscular dystrophy) have significantly enhanced L-type calcium currents [12,13]. Moreover, calcium channel inactivation was impaired in dystrophic myocytes [12,14,15].…”

“…A detailed description of the electrophysiological methods applied can be found in our previous studies [10,12]. Briefly, measurements were performed at room temperature (22 ± 1.5°C) up to 10 hours after isolation of ventricular cardiomyocytes.…”

“…Moreover, calcium channel inactivation was impaired in dystrophic myocytes [12,14,15]. Here we tested if cardiomyocytes derived from dysf mice exhibited similar abnormalities in currents through calcium channels (Fig.…”

“…These abnormal "dystrophic" cardiac ion channel properties, i.e. enhanced L-type Ca v 1.2 calcium currents [12,13], slowed Ca v 1.2 channel inactivation [12,14,15], and reduced Na v 1.5 sodium currents [10,11], may contribute to the pathophysiology in dystrophic cardiomyopathy. Direct regulation of Ca v 1.2 channels by dystrophin accords with the finding that, in mouse cardiomyocytes, Ca v 1.2 colocalizes with dystrophin [14].…”

Pro-arrhythmic action of autoantibodies against the second extracellular loop of β1-adrenoceptor and its underlying molecular mechanisms

“…Dysfunction of L-type calcium currents prolongs the QT interval in various species [8,9]. However, whether potassium currents and L-type calcium currents contribute to β 1 -AAbs-related long QT interval is still unknown.…”