Biophysical mechanisms for QRS- and QTc-interval prolongation in mice with cardiac expression of expanded CUG-repeat...

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.