Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation.
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.
Du
Cheng-Kun
CK
Department of Clinical Pharmacology, Kyushu University Graduate School of Medicine, Maidashi, Higashi-ku, Fukuoka, Japan.
Morimoto
Sachio
S
Nishii
Kiyomasa
K
Minakami
Reiko
R
Ohta
Mika
M
Tadano
Naoto
N
Lu
Qun-Wei
QW
Wang
Yuan-Yuan
YY
Zhan
Dong-Yun
DY
Mochizuki
Misato
M
Kita
Satomi
S
Miwa
Yoshikazu
Y
Takahashi-Yanaga
Fumi
F
Iwamoto
Takahiro
T
Ohtsuki
Iwao
I
Sasaguri
Toshiyuki
T
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000235:genetics; D016757:Death, Sudden, Cardiac / Q000473:pathology; D004195:Disease Models, Animal; D030342:Genetic Diseases, Inborn / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion; D019209:Troponin C / Q000235:genetics* / Q000378:metabolism
D002316:Cardiotonic Agents; D011724:Pyridazines; D019209:Troponin C; C041648:pimobendan; D002118:Calcium