Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy

Nat Commun. 2015 Nov 6:6:8803. doi: 10.1038/ncomms9803.

Abstract

The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na(+) current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca(2+) cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca(2+) transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus, INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials*
  • Aging / metabolism*
  • Animals
  • Calcium / metabolism*
  • Cardiomyopathies / metabolism*
  • Cardiomyopathies / physiopathology
  • Collagen
  • Disease Models, Animal
  • Heart / physiopathology
  • Heart Ventricles / metabolism*
  • Heart Ventricles / physiopathology
  • Mice
  • Mice, Knockout
  • Myocardial Contraction
  • Myocardium / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Patch-Clamp Techniques
  • Sarcoplasmic Reticulum / metabolism*
  • Sodium / metabolism*
  • Voltage-Gated Sodium Channel beta-1 Subunit / genetics
  • Voltage-Gated Sodium Channel beta-1 Subunit / metabolism

Substances

  • Scn1b protein, mouse
  • Voltage-Gated Sodium Channel beta-1 Subunit
  • Collagen
  • Sodium
  • Calcium