PUBLICATION

The ion channel Trpc6a regulates the cardiomyocyte regenerative response to mechanical stretch

Authors: Rolland, L., Abaroa, J.M., Faucherre, A., Drouard, A., Jopling, C.
ID: ZDB-PUB-240124-3
Date: 2024
Source: Frontiers in cardiovascular medicine 10: 11860861186086 (Journal)
Registered Authors: Faucherre, Adele, Jopling, Chris
Keywords: AP1 complex, TRPC6 channel, calcineurin/NFAT pathway, heart regeneration, mechanosensation
MeSH Terms: none
PubMed: 38259319 Full text @ Front Cardiovasc Med

Abstract

Myocardial damage caused, for example, by cardiac ischemia leads to ventricular volume overload resulting in increased stretch of the remaining myocardium. In adult mammals, these changes trigger an adaptive cardiomyocyte hypertrophic response which, if the damage is extensive, will ultimately lead to pathological hypertrophy and heart failure. Conversely, in response to extensive myocardial damage, cardiomyocytes in the adult zebrafish heart and neonatal mice proliferate and completely regenerate the damaged myocardium. We therefore hypothesized that in adult zebrafish, changes in mechanical loading due to myocardial damage may act as a trigger to induce cardiac regeneration. Based on this notion we sought to identify mechanosensors which could be involved in detecting changes in mechanical loading and triggering regeneration. Here we show using a combination of knockout animals, RNAseq and in vitro assays that the mechanosensitive ion channel Trpc6a is required by cardiomyocytes for successful cardiac regeneration in adult zebrafish. Furthermore, using a cyclic cell stretch assay, we have determined that Trpc6a induces the expression of components of the AP1 transcription complex in response to mechanical stretch. Our data highlights how changes in mechanical forces due to myocardial damage can be detected by mechanosensors which in turn can trigger cardiac regeneration.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	amputation: heart	Adult	cardiac muscle cell cell population proliferation normal process quality, normal	Figure 2
AB	amputation: heart	Adult	heart cardiac muscle tissue regeneration normal process quality, normal	Figure 2
AB	amputation: heart	Adult	heart vascular plexus normal distribution, normal	Figure 2
trpc6a^{sa23930/sa23930} (AB)	standard conditions	Protruding-mouth	heart contraction normal process quality, normal	Figure 1
trpc6a^{sa23930/sa23930} (AB)	standard conditions	Day 5	atrium heart contraction normal rate, normal	Figure 1
trpc6a^{sa23930/sa23930} (AB)	standard conditions	Day 5	cardiac ventricle heart contraction normal rate, normal	Figure 1
trpc6a^{sa23930/sa23930} (AB)	standard conditions	Day 5	ventricular myocardium normal thickness, normal	Figure 1
trpc6a^{sa23930/sa23930} (AB)	standard conditions	Adult	myocardium Ab1-trpc6 labeling absent, abnormal	Figure 1
trpc6a^{sa23930/sa23930} (AB)	amputation: heart	Adult	cardiac muscle cell cell population proliferation decreased process quality, abnormal	Figure 2
trpc6a^{sa23930/sa23930} (AB)	amputation: heart	Adult	heart cardiac muscle tissue regeneration decreased process quality, abnormal	Figure 2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
sa23930		Point Mutation	trpc6a

Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
AB
trpc6a^{sa23930/sa23930} (AB)

Antibodies

Name	Type	Isotypes	Host Organism
Ab1-act	monoclonal	IgM	Mouse
Ab1-trpc6
Ab4-mef2	monoclonal	IgG	Rabbit
Ab4-tpm	monoclonal	IgG1	Mouse

Orthology

Engineered Foreign Genes

Mapping

Rolland et al., 2024 ZDB-PUB-240124-3 PMID:38259319

The ion channel Trpc6a regulates the cardiomyocyte regenerative response to mechanical stretch

Rolland et al., 2024

ZDB-PUB-240124-3
PMID:38259319