AUTHOR=McConnell Bradley K., Singh Sonal , Fan Qiying , Hernandez Adriana , Portillo Jesus P., Reiser Peter J., Tikunova Svetlana TITLE=Knock-in mice harboring a Ca2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy JOURNAL=Frontiers in Physiology VOLUME=6 YEAR=2015 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2015.00242 DOI=10.3389/fphys.2015.00242 ISSN=1664-042X ABSTRACT=

The physiological consequences of aberrant Ca2+ binding and exchange with cardiac myofilaments are not clearly understood. In order to examine the effect of decreasing Ca2+ sensitivity of cTnC on cardiac function, we generated knock-in mice carrying a D73N mutation (not known to be associated with heart disease in human patients) in cTnC. The D73N mutation was engineered into the regulatory N-domain of cTnC in order to reduce Ca2+ sensitivity of reconstituted thin filaments by increasing the rate of Ca2+ dissociation. In addition, the D73N mutation drastically blunted the extent of Ca2+ desensitization of reconstituted thin filaments induced by cTnI pseudo-phosphorylation. Compared to wild-type mice, heterozygous knock-in mice carrying the D73N mutation exhibited a substantially decreased Ca2+ sensitivity of force development in skinned ventricular trabeculae. Kaplan-Meier survival analysis revealed that median survival time for knock-in mice was 12 weeks. Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls. Echocardiographic analysis also revealed that measures of systolic function, such as ejection fraction (EF) and fractional shortening (FS), were dramatically reduced in knock-in mice. In addition, knock-in mice displayed electrophysiological abnormalities, namely prolonged QRS and QT intervals. Furthermore, ventricular myocytes isolated from knock-in mice did not respond to β-adrenergic stimulation. Thus, knock-in mice developed pathological features similar to those observed in human patients with dilated cardiomyopathy (DCM). In conclusion, our results suggest that decreasing Ca2+ sensitivity of the regulatory N-domain of cTnC is sufficient to trigger the development of DCM.