Abnormal sodium current properties contribute to cardiac electrical and contractile dysfunction in a mouse model of myotonic dystrophy type 1

Neuromuscul Disord. 2015 Apr;25(4):308-20. doi: 10.1016/j.nmd.2014.11.018. Epub 2014 Dec 10.


Myotonic dystrophy type 1 (DM1) is the most common neuromuscular disorder and is associated with cardiac conduction defects. However, the mechanisms of cardiac arrhythmias in DM1 are unknown. We tested the hypothesis that abnormalities in the cardiac sodium current (INa) are involved, and used a transgenic mouse model reproducing the expression of triplet expansion observed in DM1 (DMSXL mouse). The injection of the class-I antiarrhythmic agent flecainide induced prominent conduction abnormalities and significantly lowered the radial tissular velocities and strain rate in DMSXL mice compared to WT. These abnormalities were more pronounced in 8-month-old mice than in 3-month-old mice. Ventricular action potentials recorded by standard glass microelectrode technique exhibited a lower maximum upstroke velocity [dV/dt](max) in DMSXL. This decreased [dV/dt](max) was associated with a 1.7 fold faster inactivation of INa in DMSXL myocytes measured by the whole-cell patch-clamp technique. Finally in the DMSXL mouse, no mutation in the Scn5a gene was detected and neither cardiac fibrosis nor abnormalities of expression of the sodium channel protein were observed. Therefore, alterations in the sodium current markedly contributed to electrical conduction block in DM1. This result should guide pharmaceutical and clinical research toward better therapy for the cardiac arrhythmias associated with DM1.

Keywords: Arrhythmia basic study; Conduction disorders; Electrophysiology; Myotonic dystrophy type 1; Sodium current channelopathy; Steinert disease; Transgenic mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Aging
  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Arrhythmias, Cardiac / physiopathology
  • Brugada Syndrome
  • Cardiac Conduction System Disease
  • Computer Simulation
  • Disease Models, Animal
  • Echocardiography, Doppler
  • Flecainide / pharmacology
  • Heart Conduction System / abnormalities
  • Heart Conduction System / physiopathology
  • Male
  • Mice, Transgenic
  • Microelectrodes
  • Models, Cardiovascular
  • Models, Neurological
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / physiology*
  • Myotonic Dystrophy / genetics
  • Myotonic Dystrophy / physiopathology*
  • NAV1.5 Voltage-Gated Sodium Channel / genetics
  • Patch-Clamp Techniques
  • Sodium / metabolism*
  • Voltage-Gated Sodium Channel Blockers / pharmacology


  • Anti-Arrhythmia Agents
  • NAV1.5 Voltage-Gated Sodium Channel
  • Scn5a protein, mouse
  • Voltage-Gated Sodium Channel Blockers
  • Sodium
  • Flecainide