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

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116 Citations (Scopus)

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

Original languageEnglish
Pages (from-to)185-194
Number of pages10
JournalCirculation research
Volume101
Issue number2
DOIs
Publication statusPublished - Jul 1 2007

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

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