Filamin C is Essential for mammalian myocardial integrity

Author summaryThe precise role of filamin C in mammalian heart development had not been determined, in part due to the lack of cardiac phenotypes in previously described Flnc knockout mice, which still had truncated filamin C expressed in the heart. In this study, we analyzed a true Flnc knockout mouse line, in which filamin C protein was completely ablated. Flnc knockout mice developed massive ruptures in their myocardium but not in the endocardium, suggesting filamin C is essential for the structural integrity of myocardium. On the other hand, we did not find overt abnormalities of sarcomeric structure in cardiomyocytes of Flnc knockout mice, indicating that filamin C is likely not required for sarcomeric assembly as previously observed in FLNC null iPSC-CMs. Moreover, contrary to the dogma that filamins are integrin inactivators, we found that filamin C plays an unexpected role in integrin activation and works in concert with beta 1 integrin to ensure the structural integrity of the myocardium. FLNC, encoding filamin C, is one of the most mutated genes in dilated and hypertrophic cardiomyopathy. However, the precise role of filamin C in mammalian heart remains unclear. In this study, we demonstrated Flnc global (Flnc(gKO)) and cardiomyocyte-specific knockout (Flnc(cKO)) mice died in utero from severely ruptured ventricular myocardium, indicating filamin C is required to maintain the structural integrity of myocardium in the mammalian heart. Contrary to the common belief that filamin C acts as an integrin inactivator, we observed attenuated activation of beta 1 integrin specifically in the myocardium of Flnc(gKO) mice. Although deleting beta 1 integrin from cardiomyocytes did not recapitulate the heart rupture phenotype in Flnc knockout mice, deleting both beta 1 integrin and filamin C from cardiomyocytes resulted in much more severe heart ruptures than deleting filamin C alone. Our results demonstrated that filamin C works in concert with beta 1 integrin to maintain the structural integrity of myocardium during mammalian heart development.

Automated summary

In this study, a true Flnc knockout mouse line was analyzed, in which filamin C protein was completely absent. The results showed that Flnc knockout mice developed massive ruptures in their myocardium, indicating that filamin C is essential for the structural integrity of myocardium. Additionally, it was observed that filamin C is not required for sarcomeric assembly and plays an unexpected role in integrin activation, working together with beta 1 integrin.