PUBLICATION

The nutrient sensor CRTC and Sarcalumenin/thinman represent an alternate pathway in cardiac hypertrophy

Authors

Dondi, C., Vogler, G., Gupta, A., Walls, S.M., Kervadec, A., Marchant, J., Romero, M.R., Diop, S., Goode, J., Thomas, J.B., Colas, A.R., Bodmer, R., Montminy, M., Ocorr, K.

ID

ZDB-PUB-240803-8

Date

2024

Source

Cell Reports 43: 114549114549 (Journal)

Registered Authors

Keywords

CP: Cell biology, CP: Metabolism, CRTC, Calcineurin, Drosophila, Sarcalumenin, cardiac, fibrosis, hiPSC-cardiomyocytes, hypertrophy, thinman, zebrafish

MeSH Terms

Myocytes, Cardiac/metabolism
Myocytes, Cardiac/pathology
Drosophila melanogaster/metabolism
Humans
Calcium-Binding Proteins/genetics
Calcium-Binding Proteins/metabolism
Calcineurin/metabolism
Signal Transduction
Drosophila Proteins*/genetics
Drosophila Proteins*/metabolism
Zebrafish*/metabolism
Cardiomegaly*/genetics
Cardiomegaly*/metabolism
Cardiomegaly*/pathology
Animals
Transcription Factors*/genetics
Transcription Factors*/metabolism

PubMed

39093699 Full text @ Cell Rep.

Abstract

CREB-regulated transcription co-activator (CRTC) is activated by Calcineurin (CaN) to regulate gluconeogenic genes. CaN also has roles in cardiac hypertrophy. Here, we explore a cardiac-autonomous role for CRTC in cardiac hypertrophy. In Drosophila, CRTC mutants exhibit severe cardiac restriction, myofibrillar disorganization, fibrosis, and tachycardia. Cardiac-specific CRTC knockdown (KD) phenocopies mutants, and cardiac overexpression causes hypertrophy. CaN-induced hypertrophy in Drosophila is reduced in CRTC mutants, suggesting that CRTC mediates the effects. RNA sequencing (RNA-seq) of CRTC-KD and -overexpressing hearts reveals contraregulation of metabolic genes. Genes with conserved CREB sites include the fly ortholog of Sarcalumenin, a Ca²⁺-binding protein. Cardiac manipulation of this gene recapitulates the CRTC-KD and -overexpression phenotypes. CRTC KD in zebrafish also causes cardiac restriction, and CRTC KD in human induced cardiomyocytes causes a reduction in Srl expression and increased action potential duration. Our data from three model systems suggest that CaN-CRTC-Sarcalumenin signaling represents an alternate, conserved pathway underlying cardiac function and hypertrophy.

Genes / Markers

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