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

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

Author information

1
Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
2
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA.
3
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

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.

PMID:
26541940
PMCID:
PMC4638135
DOI:
10.1038/ncomms9803
[Indexed for MEDLINE]
Free PMC Article

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