The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes
- University of California, Los Angeles, United States
- UCL Institute of Child Health, United Kingdom
- Karlsruhe Institute of Technology (KIT), Germany
- David Geffen School of Medicine, University of California, Los Angeles, United States
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
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).
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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The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes
eLife 6:e27955.
https://doi.org/10.7554/eLife.27955
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