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 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.

USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance

“…Atrogin-1 associates with S-phase kinaseassociated protein 1 (SKP1), Cullin 1 (CUL1), and RING-box protein 1 (RBX1) to assemble the E3 ubiquitin ligase SCF atrogin-1 , which promotes the ubiquitin-dependent proteolysis of CNA in cardiac muscle (45). CNA is also ubiquitinated and degraded by muscle RING-finger 1 (MuRF1), and thereby negatively regulates cardiac hypertrophy in response to pressure overload (PO) (46,47). In addition to CNA, the regulatory subunit of calcineurin CNB has been found to be degraded by interacting with TNF-receptor associated factor 3 (TRAF3) (48).…”

MuRF1/TRIM63, Master Regulator of Muscle Mass

“…However, high fat-induced obesity induces cardiac hypertrophy through repressed FoxO3a activity and consequently lower MuRF1 transcription levels [87], which suggests an important role of FoxOs in the heart. Likewise, FoxO3a is also implicated in the control of MuRF1 transcription upon abnormal Ca 2+ homeostasis, FoxO3a being controlled by calcineurin [88]. FoxO1 and 3a were also proposed to be important drivers of cardiac atrophy upon sympathetic denervation although direct effect was not addressed (Giulia, Circ Res, 2013).…”

Identification of Potentially Relevant Genes for Excessive Exercise-Induced Pathological Cardiac Hypertrophy in Zebrafish

“…The expression of the effectors of the FoxO pathway, such as foxo1a, foxo4, fbox32, and fbox25, was upregulated in the hearts of excessively exercised zebrafish, which may lead to myopathy (Shimizu et al, 2017). Pathological cardiac hypertrophy is the most common primary cardiomyopathy, which represents a disease with decreased myocardial contractility and insufficient cardiac pump function.…”