|ZFIN ID: ZDB-PUB-170823-10|
The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes
Shimizu, H., Langenbacher, A.D., Huang, J., Wang, K., Otto, G., Geisler, R., Wang, Y., Chen, J.N.
|Source:||eLIFE 6: (Journal)|
|Registered Authors:||Chen, Jau-Nian, Geisler, Robert, Huang, Jie, Langenbacher, Adam, Otto, Georg|
|Keywords:||cell biology, developmental biology, stem cells, zebrafish|
|PubMed:||28826496 Full text @ Elife|
Shimizu, H., Langenbacher, A.D., Huang, J., Wang, K., Otto, G., Geisler, R., Wang, Y., Chen, J.N. (2017) The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes. eLIFE. 6.
ABSTRACTAltered 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.