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.
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
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.