PUBLICATION
The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes
- Authors
- Shimizu, H., Langenbacher, A.D., Huang, J., Wang, K., Otto, G., Geisler, R., Wang, Y., Chen, J.N.
- ID
- ZDB-PUB-170823-10
- Date
- 2017
- 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
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Calcineurin/genetics*
- Calcineurin/metabolism
- Calcium/metabolism*
- Calcium Signaling
- Embryo, Nonmammalian
- Forkhead Box Protein O1/genetics*
- Forkhead Box Protein O1/metabolism
- Gene Deletion
- Gene Expression Regulation, Developmental
- Muscle Proteins/genetics
- Muscle Proteins/metabolism
- Myocardium/metabolism
- Myocardium/ultrastructure
- Myocytes, Cardiac/metabolism*
- Myocytes, Cardiac/ultrastructure
- Myofibrils/metabolism*
- Myofibrils/ultrastructure
- Proteasome Endopeptidase Complex/metabolism
- Protein Isoforms/genetics
- Protein Isoforms/metabolism
- Proteolysis
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Sodium-Calcium Exchanger/genetics
- Sodium-Calcium Exchanger/metabolism
- Ubiquitin-Protein Ligases/antagonists & inhibitors
- Ubiquitin-Protein Ligases/genetics*
- Ubiquitin-Protein Ligases/metabolism
- Zebrafish
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 28826496 Full text @ Elife
Citation
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.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping