NYMC Faculty Publications

Phosphorylation of Cardiac Sodium Channel at Ser571 Anticipates Manifestations of the Aging Myopathy

Emanuele Pizzo, Department of Physiology, New York Medical College, Valhalla, New York, United States.
Daniel O. Cervantes, Department of Physiology, New York Medical College, Valhalla, New York, United States.
Harshada Ketkar, Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, New York, United States.
Valentina Ripa, Department of Physiology, New York Medical College, Valhalla, New York, United States.
Drew M. Nassal, The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States.
Benjamin Buck, Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States.
Sreema P. Parambath, Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, New York, United States.
Valeria Di Stefano, Department of Physiology, New York Medical College, Valhalla, New York, United States.
Kanwardeep Singh, Department of Physiology, New York Medical College, Valhalla, New York, United States.
Carl I. Thompson, Department of Physiology, New York Medical College, Valhalla, New York, United States.
Peter J. Mohler, The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States.
Thomas J. Hund, The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States.
Jason T. Jacobson, Department of Physiology, New York Medical College, Valhalla, New York, United States.
Sudhir Jain, Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, New York, United States.Follow
Marcello Rota, Department of Physiology, New York Medical College, Valhalla, New York, United States.

Author Type(s)

Faculty

DOI

10.1152/ajpheart.00325.2023

Journal Title

American Journal of Physiology. Heart and Circulatory Physiology

First Page

H1424

Last Page

H1445

Document Type

Article

Publication Date

6-1-2024

Department

Physiology

Second Department

Medicine

Third Department

Pathology, Microbiology and Immunology

Abstract

Diastolic dysfunction and delayed ventricular repolarization are typically observed in the elderly, but whether these defects are intimately associated with the progressive manifestation of the aging myopathy remains to be determined. In this regard, aging in experimental animals is coupled with increased late Na current () in cardiomyocytes, raising the possibility that conditions the modality of electrical recovery and myocardial relaxation of the aged heart. For this purpose, aging male and female wild-type (WT) C57Bl/6 mice were studied together with genetically engineered mice with phosphomimetic (gain of function, GoF) or ablated (loss of function, LoF) mutations of the sodium channel Nav1.5 at Ser571 associated with, respectively, increased and stabilized . At ∼18 mo of age, WT mice developed prolonged duration of the QT interval of the electrocardiogram and impaired diastolic left ventricular (LV) filling, defects that were reversed by inhibition. Prolonged repolarization and impaired LV filling occurred prematurely in adult (∼5 mo) GoF mutant mice, whereas these alterations were largely attenuated in aging LoF mutant animals. Ca transient decay and kinetics of myocyte shortening/relengthening were delayed in aged (∼24 mo) WT myocytes, with respect to adult cells. In contrast, delayed Ca transients and contractile dynamics occurred at adult stage in GoF myocytes and further deteriorated in old age. Conversely, myocyte mechanics were minimally affected in aging LoF cells. Collectively, these results document that Nav1.5 phosphorylation at Ser571 and the late Na current modulate the modality of myocyte relaxation, constituting the mechanism linking delayed ventricular repolarization and diastolic dysfunction. We have investigated the impact of the late Na current () on cardiac and myocyte function with aging by using genetically engineered animals with enhanced or stabilized , due to phosphomimetic or phosphoablated mutations of Nav1.5. Our findings support the notion that phosphorylation of Nav1.5 at Ser571 prolongs myocardial repolarization and impairs diastolic function, contributing to the manifestations of the aging myopathy.

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