Knock-In Mouse Model of Dilated Cardiomyopathy Caused by Troponin Mutation

Author:

Du Cheng-Kun1,Morimoto Sachio1,Nishii Kiyomasa1,Minakami Reiko1,Ohta Mika1,Tadano Naoto1,Lu Qun-Wei1,Wang Yuan-Yuan1,Zhan Dong-Yun1,Mochizuki Misato1,Kita Satomi1,Miwa Yoshikazu1,Takahashi-Yanaga Fumi1,Iwamoto Takahiro1,Ohtsuki Iwao1,Sasaguri Toshiyuki1

Affiliation:

1. From the Departments of Clinical Pharmacology (C.-K.D., S.M., Q.-W. L., Y.-Y.W., D.-Y.Z., M.M., Y.M., F.T.-Y., T.S.) and Health Sciences (R.M.), Kyushu University Graduate School of Medicine, Fukuoka, Japan; Department of Cell Biology (K.N.), Tokyo Medical and Dental University; Clinical Genome Informatics Center (M.O.), Kobe University Graduate School of Medicine, Kobe, Japan; Research Laboratory (N.T.), Zenyaku Kogyo Co Ltd, Tokyo, Japan; Department of Pharmacology (S.K., T.I.), Fukuoka University...

Abstract

We created knock-in mice in which a deletion of 3 base pairs coding for K210 in cardiac troponin (cTn)T found in familial dilated cardiomyopathy patients was introduced into endogenous genes. Membrane-permeabilized cardiac muscle fibers from mutant mice showed significantly lower Ca 2+ sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca 2+ transient in cardiomyocytes was increased in mutant mice, and maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from that of wild-type mice, suggesting that Ca 2+ transient was augmented to compensate for decreased myofilament Ca 2+ sensitivity. Nevertheless, mutant mice developed marked cardiac enlargement, heart failure, and frequent sudden death recapitulating the phenotypes of dilated cardiomyopathy patients, indicating that global functional defect of the heart attributable to decreased myofilament Ca 2+ sensitivity could not be fully compensated by only increasing the intracellular Ca 2+ transient. We found that a positive inotropic agent, pimobendan, which directly increases myofilament Ca 2+ sensitivity, had profound effects of preventing cardiac enlargement, heart failure, and sudden death. These results verify the hypothesis that Ca 2+ desensitization of cardiac myofilament is the absolute cause of the pathogenesis of dilated cardiomyopathy associated with this mutation and strongly suggest that Ca 2+ sensitizers are beneficial for the treatment of dilated cardiomyopathy patients affected by sarcomeric regulatory protein mutations.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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