Unknown

Dataset Information

0

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


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.

SUBMITTER: Shimizu H 

PROVIDER: S-EPMC5576919 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC4118290 | biostudies-literature
| S-EPMC4011666 | biostudies-other
2014-04-01 | E-GEOD-54217 | biostudies-arrayexpress
| S-EPMC7075038 | biostudies-literature
| S-EPMC7670845 | biostudies-literature
| S-EPMC6484331 | biostudies-literature
2014-04-01 | GSE54217 | GEO
| S-EPMC3630833 | biostudies-other
| S-EPMC3026445 | biostudies-literature
| S-EPMC3000987 | biostudies-literature