Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY.
Department of Pharmacology, Upstate Medical University, Syracuse, NY.
J Gen Physiol. 2020 Feb 3;152(2). doi: 10.1085/jgp.201912450.
Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, results from the expression of toxic gain-of-function transcripts containing expanded CUG-repeats. DM1 patients experience cardiac electrophysiological defects, including prolonged PR-, QRS-, and QT-intervals, that increase susceptibility to sudden cardiac death (SCD). However, the specific biophysical and molecular mechanisms that underlie the electrocardiograph (ECG) abnormalities and SCD in DM1 are unclear. Here, we addressed this issue using a novel transgenic mouse model that exhibits robust cardiac expression of expanded CUG-repeat RNA (LC15 mice). ECG measurements in conscious LC15 mice revealed significantly prolonged QRS- and corrected QT-intervals, but a normal PR-interval. Although spontaneous arrhythmias were not observed in conscious LC15 mice under nonchallenged conditions, acute administration of the sodium channel blocker flecainide prolonged the QRS-interval and unveiled an increased susceptibility to lethal ventricular arrhythmias. Current clamp measurements in ventricular myocytes from LC15 mice revealed significantly reduced action potential upstroke velocity at physiological pacing (9 Hz) and prolonged action potential duration at all stimulation rates (1-9 Hz). Voltage clamp experiments revealed significant rightward shifts in the voltage dependence of sodium channel activation and steady-state inactivation, as well as a marked reduction in outward potassium current density. Together, these findings indicate that expression of expanded CUG-repeat RNA in the murine heart results in reduced sodium and potassium channel activity that results in QRS- and QT-interval prolongation, respectively.
肌强直性营养不良 1 型（DM1）是成人中最常见的肌肉营养不良症，其原因是表达含有扩展 CUG-重复的毒性功能获得性转录本。DM1 患者会出现心脏电生理缺陷，包括 PR-、QRS-和 QT 间期延长，这会增加心脏性猝死（SCD）的易感性。然而，DM1 中导致心电图（ECG）异常和 SCD 的具体生物物理和分子机制尚不清楚。在这里，我们使用一种新型的转基因小鼠模型来解决这个问题，该模型在心脏中表现出强烈的扩展 CUG-重复 RNA 的表达（LC15 小鼠）。在清醒的 LC15 小鼠中进行的 ECG 测量显示 QRS-和校正 QT-间期显著延长，但 PR-间期正常。尽管在非挑战条件下，清醒的 LC15 小鼠中没有观察到自发性心律失常，但钠离子通道阻滞剂氟卡尼的急性给药会延长 QRS-间期，并揭示出对致命性室性心律失常的易感性增加。在 LC15 小鼠的心室肌细胞中进行的电流钳测量显示，在生理起搏（9 Hz）时动作电位上升速度显著降低，并且在所有刺激率（1-9 Hz）下动作电位持续时间延长。电压钳实验显示钠离子通道激活和稳态失活的电压依赖性明显右移，以及外向钾电流密度显著降低。综上所述，这些发现表明，在小鼠心脏中表达扩展的 CUG-重复 RNA 会导致钠和钾通道活性降低，分别导致 QRS-和 QT-间期延长。
