The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes

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Abstract

Altered Ca²⁺handling is often present in diseased hearts undergoing structural remodeling and functional deterioration. However, whether Ca²⁺ directly regulates sarcomere structure has remained elusive. Using a zebrafish ncx1 mutant, we explored the impacts of impaired Ca²⁺homeostasis on myofibril integrity. We found that the E3 ubiquitin ligase murf1 is upregulated in ncx1-deficient hearts. Intriguingly, knocking down murf1 activity or inhibiting proteasome activity preserved myofibril integrity, revealing a MuRF1-mediated proteasome degradation mechanism that is activated in response to abnormal Ca²⁺ homeostasis. Furthermore, we detected an accumulation of the murf1 regulator FoxO in the nuclei of ncx1-deficient cardiomyocytes. Overexpression of FoxO in wild type cardiomyocytes induced murf1 expression and caused myofibril disarray, whereas inhibiting Calcineurin activity attenuated FoxO-mediated murf1 expression and protected sarcomeres from degradation in ncx1-deficient hearts. Together, our findings reveal a novel mechanism by which Ca²⁺ overload disrupts myofibril integrity by activating a Calcineurin-FoxO-MuRF1-proteosome signaling pathway.

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Hirohito Shimizu

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Adam D Langenbacher

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Jie Huang

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Kevin Wang

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Georg Otto

Genetics and Genomic Medicine, UCL Institute of Child Health, London, United Kingdom

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3929-948X
Robert Geisler

Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany

Competing interests
The authors declare that no competing interests exist.
Yibin Wang

Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Jau-Nian Chen

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States

For correspondence
chenjn@mcdb.ucla.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8807-3607

Funding

National Institutes of Health (HL096980)

Jau-Nian Chen

European Commission (ZF-MODELS)

Robert Geisler

European Commission (ZF-HEALTH)

Robert Geisler

National Institutes of Health (HL126051)

Jau-Nian Chen

National Institutes of Health (HL108186)

Yibin Wang

Nakajima Foundation

Hirohito Shimizu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of California, Los Angeles. The protocol was approved by the Chancellor's Animal Research Committee of the University of California, Los Angeles (ARC#2000-051-51A).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.