FGF13 Regulates VGSC-Independent Cardiomyocyte Impulse Propagation via Cx43 Trafficking

Authors

Lala Tanmoy Das
Mattia Malvezzi
Aravind R Gade
Maiko Matsui
Margaret McKay
Eric Q Wei
Matea J Zelich
Keon Mazdisnian
Jared Kushner
Bi-Xing Chen
Isabella DiStefano
Daniel Roybal
Lin Yang
Lisa Stoll
James C Lo
Marian Kalocsay
Fadi G Akar
Steven O Marx
Geoffrey S Pitt

Publication Date

12-5-2025

Journal

Circulation Research

DOI

10.1161/CIRCRESAHA.125.327177

PMID

41200819

PMCID

PMC12903045

PubMedCentral® Posted Date

2-14-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: FHF (fibroblast growth factor homologous factor) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage-gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC-related functions, including regulation of Cx43 (connexin 43) gap junctions and hemichannels, mechanisms that have generally been understudied or disregarded.

Methods: We assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cardiac-specific Fgf13 ablation (cFgf13KO) while targeting Cx43 gap junctions and hemichannels pharmacologically. We characterized FGF13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43.

Results: FGF13 ablation prolonged the QRS and QT intervals. Carbenoxolone, a Cx43 gap junction uncoupler, markedly prolonged the QRS duration, leading to conduction system block in cFgf13KO but not in wild-type mice. Optical mapping revealed markedly decreased conduction velocity during ventricular pacing. Microscopy revealed perturbed trafficking of Cx43, reduced localization in the intercalated disc, and suggested decreased membrane Cx43 but increased Cx43 hemichannels in cardiomyocytes from cFgf13KO mice. Resting membrane potential was depolarized, and action potential duration at 50% repolarization was prolonged in cFgf13KO cardiomyocytes. Both were restored toward wild-type values with Gap19 (a Cx43 hemichannel inhibitor), expression of FGF13, or expression of a mutant FGF13 incapable of binding to VGSCs, emphasizing VGSC-independent regulation by FGF13. To assess the functional impact of resting membrane potential depolarization, hearts were subjected to hypokalemia, which had no effect in wild-type hearts but fully rescued conduction velocity in cFgf13KO hearts. Proteomic analyses revealed candidate roles for FGF13 in the regulation of vesicular-mediated transport. FGF13 ablation destabilized microtubules and reduced the expression of tubulins and MAP4, the major cardiac microtubule regulator.

Conclusions: FGF13 regulates microtubule-dependent trafficking and targeting of Cx43 and impacts cardiac impulse propagation via VGSC-independent mechanisms.

Keywords

Animals, Connexin 43, Myocytes, Cardiac, Fibroblast Growth Factors, Mice, Knockout, Action Potentials, Mice, Gap Junctions, Protein Transport, Arrhythmias, Cardiac, Mice, Inbred C57BL, Sodium Channels, Male, connexin 43, fibroblast growth factor, mice, knockout, mice, transgenic, myocytes

Published Open-Access

yes

Recommended Citation

Das, Lala Tanmoy; Malvezzi, Mattia; Gade, Aravind R; et al., "FGF13 Regulates VGSC-Independent Cardiomyocyte Impulse Propagation via Cx43 Trafficking" (2025). Faculty, Staff and Student Publications. 5947.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5947