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The calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes

Shimizu, Hirohito; Langenbacher, Adam D.; Huang, Jie; Wang, Kevin; Otto, Georg; Geisler, Robert 1; Wang, Yibin; Chen, Jau-Nian
1 Institut für Toxikologie und Genetik (ITG), Karlsruher Institut für Technologie (KIT)

Abstract:
Altered Ca$^{2+}$ handling is often present in diseased hearts undergoing structural remodeling and functional deterioration. However, whether Ca$^{2+}$ directly regulates sarcomere structure has remained elusive. Using a zebrafish ncx1 mutant, we explored the impacts of impaired Ca$^{2+}$ 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 Ca$^{2+}$ 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 Ca$^{2+}$ overload disrupts myofibril integrity by activating a Calcineurin-FoxO-MuRF1-proteosome signaling pathway.


Volltext §
DOI: 10.5445/IR/1000075414
Originalveröffentlichung
DOI: 10.7554/eLife.27955
Scopus
Zitationen: 22
Web of Science
Zitationen: 21
Dimensions
Zitationen: 21
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Toxikologie und Genetik (ITG)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2017
Sprache Englisch
Identifikator ISSN: 2050-084X
urn:nbn:de:swb:90-754147
KITopen-ID: 1000075414
HGF-Programm 47.01.01 (POF III, LK 01) Biol.Netzwerke u.Synth.Regulat. ITG+ITC
Erschienen in eLife
Verlag eLife Sciences Publications
Band 6
Seiten Art.Nr. e27955
Vorab online veröffentlicht am 19.08.2017
Nachgewiesen in Web of Science
Dimensions
Scopus
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