1. Cell Biology
  2. Developmental Biology
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The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes

  1. Hirohito Shimizu
  2. Adam D Langenbacher
  3. Jie Huang
  4. Kevin Wang
  5. Georg Otto
  6. Robert Geisler
  7. Yibin Wang
  8. Jau-Nian Chen  Is a corresponding author
  1. University of California, Los Angeles, United States
  2. UCL Institute of Child Health, United Kingdom
  3. Karlsruhe Institute of Technology (KIT), Germany
  4. David Geffen School of Medicine, University of California, Los Angeles, United States
Research Article
  • Cited 20
  • Views 1,560
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Cite this article as: eLife 2017;6:e27955 doi: 10.7554/eLife.27955

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.

Article and author information

Author details

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Georg Otto

    Genetics and Genomic Medicine, UCL Institute of Child Health, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3929-948X
  6. Robert Geisler

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. 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.
  8. 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.
    ORCID icon "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).

Reviewing Editor

  1. Deborah Yelon, University of California, San Diego, United States

Publication history

  1. Received: April 20, 2017
  2. Accepted: August 18, 2017
  3. Accepted Manuscript published: August 19, 2017 (version 1)
  4. Version of Record published: August 30, 2017 (version 2)

Copyright

© 2017, Shimizu et al.

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.

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