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(Circulation Research. 2007;101:185.)
© 2007 American Heart Association, Inc.

Integrative Physiology

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

Cheng-Kun Du, Sachio Morimoto, Kiyomasa Nishii, Reiko Minakami, Mika Ohta, Naoto Tadano, Qun-Wei Lu, Yuan-Yuan Wang, Dong-Yun Zhan, Misato Mochizuki, Satomi Kita, Yoshikazu Miwa, Fumi Takahashi-Yanaga, Takahiro Iwamoto, Iwao Ohtsuki, Toshiyuki Sasaguri

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 School of Medicine, Fukuoka, Japan; and Department Physiology II (I.O.), Jikei University School of Medicine, Tokyo, Japan.

Correspondence to Sachio Morimoto, PhD, Department of Clinical Pharmacology, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail morimoto{at}med.kyushu-u.ac.jp

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 Ca²⁺ sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca²⁺ 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 Ca²⁺ transient was augmented to compensate for decreased myofilament Ca²⁺ 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 Ca²⁺ sensitivity could not be fully compensated by only increasing the intracellular Ca²⁺ transient. We found that a positive inotropic agent, pimobendan, which directly increases myofilament Ca²⁺ sensitivity, had profound effects of preventing cardiac enlargement, heart failure, and sudden death. These results verify the hypothesis that Ca²⁺ desensitization of cardiac myofilament is the absolute cause of the pathogenesis of dilated cardiomyopathy associated with this mutation and strongly suggest that Ca²⁺ sensitizers are beneficial for the treatment of dilated cardiomyopathy patients affected by sarcomeric regulatory protein mutations.

Key Words: dilated cardiomyopathy • troponin • mutation • calcium sensitivity • knock-in mouse

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