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The Calcineurin-FoxO-MuRF1 Signaling Pathway Regulates Myofibril Integrity in Cardiomyocytes

By Hirohito Shimizu, Adam Langenbacher, Jie Huang, Kevin Wang, Georg W. Otto, Robert Geisler, Yibin Wang, Jau-Nian Chen

Posted 25 Apr 2017
bioRxiv DOI: 10.1101/130831 (published DOI: 10.7554/eLife.27955)

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 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 the myofibril integrity by activating a Calcineurin-FoxO-MuRF1-proteosome signaling pathway.

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