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Peer-reviewedCC BY-NC-ND 4.0Journal of Molecular and Cellular Cardiology Plus

Impact of aging on catecholaminergic ventricular arrhythmia and cardiac transcriptome of cardiac calsequestrin null mice

  • Connor M. Kean1
  • Jacob Noeker1
  • Aditya S. Shirali1
  • Beenish Rahat1
  • Danielle Springer2
  • ThuyVy Duong1
  • Daniel J. Flores1
  • Luke O. Brandenberger1
  • Claudia M. Gebert1
  • Julia Grafstein1
  • Björn C. Knollmann3
  • Karl Pfeifer1
  1. 1Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
  2. 2Murine Phenotyping Core, National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
  3. 3Vanderbilt Center for Arrhythmia Research and Therapeutics, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
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Abstract

Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is associated typically with mutations in Ryanodine Receptor type 2 (RYR2) and cardiac Calsequestrin (CASQ2) genes. RyR2 and CASQ2 along with membrane proteins, junctin and triadin, constitute the Ca2+ release unit in the junctional sarcoplasmic reticulum in mammalian cardiomyocytes. Mouse models lacking Casq2 gene phenocopy CPVT and have been used to study CPVT pathophysiology and to identify novel therapies. Here, we analyze roles of normal aging for the development of cardiac dysfunctions of Casq2-null mice. We show that aging intensifies the disease phenotype. Age-dependent changes in triadin but not in RyR2 or junctin correlate with a more severe CPVT phenotype. We also examine transcriptomes at 1 month and 2 years of age. We identify 583 genes whose expression is dependent on Casq2 genotype with enrichment for genes associated with calcium handling and transport, sarcomere structures, extracellular matrix, and natriuretic peptide signaling. Age-stratified analyses identified 76 genes that were dysregulated only in aged mice and 22 genes that were dysregulated only in young animals.

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Cite

BibTeXRIS
BibTeX
@article{kean2026impact,
  title = {{Impact of aging on catecholaminergic ventricular arrhythmia and cardiac transcriptome of cardiac calsequestrin null mice}},
  author = {Connor M. Kean and Jacob Noeker and Aditya S. Shirali and Beenish Rahat and Danielle Springer and ThuyVy Duong and Daniel J. Flores and Luke O. Brandenberger and Claudia M. Gebert and Julia Grafstein and Björn C. Knollmann and Karl Pfeifer},
  journal = {Journal of Molecular and Cellular Cardiology Plus},
  year = {2026},
  month = oct,
  doi = {10.1016/j.jmccpl.2026.100872},
  url = {https://doi.org/10.1016/j.jmccpl.2026.100872},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Impact of aging on catecholaminergic ventricular arrhythmia and cardiac transcriptome of cardiac calsequestrin null mice
AU  - Connor M. Kean
AU  - Jacob Noeker
AU  - Aditya S. Shirali
AU  - Beenish Rahat
AU  - Danielle Springer
AU  - ThuyVy Duong
AU  - Daniel J. Flores
AU  - Luke O. Brandenberger
AU  - Claudia M. Gebert
AU  - Julia Grafstein
AU  - Björn C. Knollmann
AU  - Karl Pfeifer
PY  - 2026
DA  - 2026/10/06
JO  - Journal of Molecular and Cellular Cardiology Plus
DO  - 10.1016/j.jmccpl.2026.100872
UR  - https://doi.org/10.1016/j.jmccpl.2026.100872
AB  - Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is associated typically with mutations in Ryanodine Receptor type 2 (RYR2) and cardiac Calsequestrin (CASQ2) genes. RyR2 and CASQ2 along with membrane proteins, junctin and triadin, constitute the Ca2+ release unit in the junctional sarcoplasmic reticulum in mammalian cardiomyocytes. Mouse models lacking Casq2 gene phenocopy CPVT and have been used to study CPVT pathophysiology and to identify novel therapies. Here, we analyze roles of normal aging for the development of cardiac dysfunctions of Casq2-null mice. We show that aging intensifies the disease phenotype. Age-dependent changes in triadin but not in RyR2 or junctin correlate with a more severe CPVT phenotype. We also examine transcriptomes at 1 month and 2 years of age. We identify 583 genes whose expression is dependent on Casq2 genotype with enrichment for genes associated with calcium handling and transport, sarcomere structures, extracellular matrix, and natriuretic peptide signaling. Age-stratified analyses identified 76 genes that were dysregulated only in aged mice and 22 genes that were dysregulated only in young animals.
SN  - 2772-9761
ER  -