Knock-in mice harboring a Ca2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy

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