1. The nutrient sensor CRTC and Sarcalumenin/thinman represent an alternate pathway in cardiac hypertrophy.
- Author
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Dondi C, Vogler G, Gupta A, Walls SM, Kervadec A, Marchant J, Romero MR, Diop S, Goode J, Thomas JB, Colas AR, Bodmer R, Montminy M, and Ocorr K
- Subjects
- Animals, Humans, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Signal Transduction, Calcineurin metabolism, Drosophila melanogaster metabolism, Calcium-Binding Proteins metabolism, Calcium-Binding Proteins genetics, Cardiomegaly metabolism, Cardiomegaly genetics, Cardiomegaly pathology, Zebrafish metabolism, Transcription Factors metabolism, Transcription Factors genetics, Drosophila Proteins metabolism, Drosophila Proteins genetics
- 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 Ca
2+ -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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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