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

Sergio Signore, Andrea Sorrentino, Giulia Borghetti, Antonio Cannata, Marianna Meo, Yu Zhou, Ramaswamy Kannappan, Francesco Pasqualini, Heather O'Malley, Mark Sundman, Nikolaos Tsigkas, Eric Zhang, Christian Arranto, Chiara Mangiaracina, Kazuya Isobe, Brena F. Sena, Junghyun Kim, Polina Goichberg, Matthias Nahrendorf, Lori L. Isom, Annarosa Leri, Piero Anversa and Marcello Rota ()
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Sergio Signore: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Andrea Sorrentino: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Giulia Borghetti: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Antonio Cannata: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Marianna Meo: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Yu Zhou: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Ramaswamy Kannappan: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Francesco Pasqualini: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Heather O'Malley: University of Michigan
Mark Sundman: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Nikolaos Tsigkas: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Eric Zhang: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Christian Arranto: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Chiara Mangiaracina: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Kazuya Isobe: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Brena F. Sena: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School
Junghyun Kim: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Polina Goichberg: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Matthias Nahrendorf: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School
Lori L. Isom: University of Michigan
Annarosa Leri: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Piero Anversa: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA
Marcello Rota: Brigham and Women’s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA

Nature Communications, 2015, vol. 6, issue 1, 1-18

Abstract: 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 Ca2+ cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca2+ 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.

Date: 2015
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DOI: 10.1038/ncomms9803

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