TY - JOUR T1 - The Calcineurin-FoxO-MuRF1 Signaling Pathway Regulates Myofibril Integrity in Cardiomyocytes JF - bioRxiv DO - 10.1101/130831 SP - 130831 AU - Hirohito Shimizu AU - Adam Langenbacher AU - Jie Huang AU - Kevin Wang AU - Georg W. Otto AU - Robert Geisler AU - Yibin Wang AU - Jau-Nian Chen Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/25/130831.abstract N2 - Altered Ca2+ handling is often present in diseased hearts undergoing structural remodeling and functional deterioration. The influences of Ca2+ signaling on cardiac function have been examined extensively, but whether Ca2+ directly regulates sarcomere structure has remained elusive. Using a mutant zebrafish model lacking NCX1 activity in the heart, we explored the impacts of impaired Ca2+ homeostasis on myofibril integrity. Gene expression profiling analysis revealed that the E3 ubiquitin ligase MuRF1 is upregulated in ncx1-deficient hearts. Intriguingly, knocking down MuRF1 activity or inhibiting proteasome activity preserved myofibril integrity in ncx1 deficient hearts, 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 the myofibril integrity in heart muscle cells by activating a Calcineurin-FoxO-MuRF1-proteosome signaling pathway. ER -