The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes.

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 <i>ncx1</i> mutant, we explored the impacts of impaired Ca²⁺ homeostasis on myofibril integrity. We found that the E3 ubiquitin ligase <i>murf1</i> is upregulated in <i>ncx1-</i>deficient hearts. Intriguingly, knocking down <i>murf1</i> 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 <i>murf1</i> regulator FoxO in the nuclei of <i>ncx1</i>-deficient cardiomyocytes. Overexpression of FoxO in wild type cardiomyocytes induced <i>murf1</i> expression and caused myofibril disarray, whereas inhibiting Calcineurin activity attenuated FoxO-mediated <i>murf1</i> expression and protected sarcomeres from degradation in <i>ncx1</i>-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.