Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.
Am J Physiol Heart Circ Physiol. 2014 Feb 15;306(4):H564-H573. doi: 10.1152/ajpheart.00441.2013. Epub 2013 Dec 13.
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.
杜氏肌营养不良症（DMD）是由编码细胞骨架蛋白肌营养不良蛋白的基因突变引起的遗传性疾病，其特征是进行性肌肉无力。除了相对明确的骨骼肌退行性过程外，DMD 还与心脏并发症有关。这些并发症包括心肌病的发展和心律失常。目前对心脏发病机制的了解非常有限，但最近的研究表明，营养不良的心肌细胞中功能失调的离子通道起作用。本研究的目的是描述成年营养不良性心室心肌细胞中 L 型钙通道功能的异常。通过使用全细胞膜片钳技术，比较了从正常和营养不良成年小鼠心脏分离的心室心肌细胞中钙通道电流的特性。除了常用的人类 DMD 的肌营养不良蛋白缺陷型 mdx 小鼠模型外，我们还使用了 mdx-utr 小鼠，该模型既缺乏肌营养不良蛋白又缺乏 utrophin。我们发现，钙通道电流显著增加，通道失活减少，这两种作用都增强了动作电位（AP）期间的钙内流。虽然营养不良型小鼠心肌细胞的 AP 几乎正常，但在人类心室心肌细胞的计算机模型中实施增强的营养不良型钙电导会显著延长 AP。最后，描述的营养不良型钙通道异常导致营养不良型小鼠心电图的改变。我们得出结论，心脏 L 型钙通道的功能获得可能会扰乱营养不良心脏的电生理学，从而导致心律失常。
