Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility

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Summary

Developmental causes of the most common arrhythmia, atrial fibrillation (AF), are poorly defined, with compensation potentially masking arrhythmic risk. Here, we delete 9 amino acids (Δ9) within a conserved domain of the giant protein titin’s A-band in zebrafish and human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that ttna ^Δ9/Δ9 zebrafish embryos’ cardiac morphology is perturbed and accompanied by reduced functional output, but ventricular function recovers within days. Despite normal ventricular function, ttna ^Δ9/Δ9 adults exhibit AF and atrial myopathy, which are recapitulated in TTN ^Δ9/Δ9-hiPSC-aCMs. Additionally, action potential is shortened and slow delayed rectifier potassium current ( I _Ks) is increased due to aberrant atrial natriuretic peptide (ANP) levels. Strikingly, suppression of I _Ks in both models prevents AF and improves atrial contractility. Thus, a small internal deletion in titin causes developmental abnormalities that increase the risk of AF via ion channel remodeling, with implications for patients who harbor disease-causing variants in sarcomeric proteins.

Graphical abstract

Highlights

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A 9-amino acid internal deletion was generated in the titin A-band ( ttna ^Δ9/ TTN ^Δ9)
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ttna ^Δ9/Δ9 zebrafish exhibit developmental defects followed by atrial fibrillation
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Aberrant ANP-regulated I _Ks remodeling contributes to cardiac defects in mutants
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Pharmacological blockade of I _Ks rescues arrhythmia and improves atrial contraction

Abstract

Biological sciences; Protein; Cell biology; Developmental biology

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Author and article information

Contributors

Dawood Darbar

Ankur Saxena

Journal

Journal ID (nlm-ta): iScience

Journal ID (iso-abbrev): iScience

Title: iScience

Publisher: Elsevier

ISSN (Electronic): 2589-0042

Publication date PMC-release: 27 June 2024

Publication date Collection: 19 July 2024

Publication date (Electronic): 27 June 2024

Volume: 27

Issue: 7

Electronic Location Identifier: 110395

Affiliations

[1 ]Department of Cell, Developmental, and Integrative Biology, UAB Heersink School of Medicine, Birmingham, AL 35233, USA

[2 ]Department of Biological Sciences, University of Illinois Chicago, Chicago, IL 60607, USA

[3 ]University of Illinois Cancer Center, Chicago, IL 60612, USA

[4 ]Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA

[5 ]Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA

[6 ]Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL 60612, USA

[7 ]Department of Physiology, University of Illinois Chicago, Chicago, IL 60612, USA

[8 ]Department of Medicine, Jesse Brown Veterans Administration, Chicago, IL 60612, USA

[9 ]Department of Pharmacology, Northwestern University, Chicago, IL 60611, USA

[10 ]Department of Biochemistry and Molecular Genetics, University of Illinois Chicago, Chicago, IL 60607, USA

[11 ]O'Neal Comprehensive Cancer Center, Birmingham, AL 35233, USA

Author notes

[∗ ]Corresponding author darbar@ 123456uic.edu

[∗∗ ]Corresponding author asaxena1@ 123456uab.edu

[12]

These authors contributed equally

[13]

Lead contact

Article

Publisher Item ID: S2589-0042(24)01620-1 Publisher ID: 110395

DOI: 10.1016/j.isci.2024.110395

PMC ID: 11296057

SO-VID: 11b8cfbc-68f3-4054-8e22-65875a8b035a

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 14 March 2024

Date revision received : 28 May 2024

Date accepted : 25 June 2024

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