The Calcineurin-FoxO-MuRF1 Signaling Pathway Regulates Myofibril Integrity in Cardiomyocytes

Altered Ca 2+ handling is often present in diseased hearts undergoing structural remodeling and functional deterioration. The influences of Ca 2+ signaling on cardiac function have been examined extensively, but whether Ca 2+ directly regulates sarcomere structure has remained elusive. Using a mutant zebrafish model lacking NCX1 activity in the heart, we explored the impacts of impaired Ca 2+ 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 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 the myofibril integrity in heart muscle cells by activating a Calcineurin-FoxO-MuRF1-proteosome signaling pathway.