This Article Free upon publication Full Text Full Text (PDF) Data Supplement Correction (v101,pe80) All Versions of this Article: 101/2/205    most recent CIRCRESAHA.107.148379v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rajan, S. Articles by Wieczorek, D. F. Search for Related Content PubMed PubMed Citation Articles by Rajan, S. Articles by Wieczorek, D. F. Related Collections Contractile function Animal models of human disease Heart failure - basic studies Myocardial cardiomyopathy disease

(Circulation Research. 2007;101:205.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Dilated Cardiomyopathy Mutant Tropomyosin Mice Develop Cardiac Dysfunction With Significantly Decreased Fractional Shortening and Myofilament Calcium Sensitivity

Sudarsan Rajan^*, Rafeeq P.H. Ahmed^*, Ganapathy Jagatheesan, Natalia Petrashevskaya, Greg P. Boivin, Dalia Urboniene, Grace M. Arteaga, Beata M. Wolska, R. John Solaro, Stephen B. Liggett, David F. Wieczorek

From the Department of Molecular Genetics, Biochemistry, and Microbiology (S.R., R.P.H.A., G.J., D.F.W.), University of Cincinnati Medical Center, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine (G.P.B.), University of Cincinnati Medical Center, Ohio; Department of Physiology and Biophysics (D.U., G.M.A., B.M.W., R.J.S.), University of Illinois, Chicago College of Medicine; and Department of Medicine (N.P., S.B.L.), University of Maryland, Baltimore.

Correspondence to David F. Wieczorek, Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati Medical Center, Cincinnati, OH 45267-0524. E-mail David.Wieczorek{at}uc.edu

Mutations in striated muscle -tropomyosin (-TM), an essential thin filament protein, cause both dilated cardiomyopathy (DCM) and familial hypertrophic cardiomyopathy. Two distinct point mutations within -tropomyosin are associated with the development of DCM in humans: Glu40Lys and Glu54Lys. To investigate the functional consequences of -TM mutations associated with DCM, we generated transgenic mice that express mutant -TM (Glu54Lys) in the adult heart. Results showed that an increase in transgenic protein expression led to a reciprocal decrease in endogenous -TM levels, with total myofilament TM protein levels remaining unaltered. Histological and morphological analyses revealed development of DCM with progression to heart failure and frequently death by 6 months. Echocardiographic analyses confirmed the dilated phenotype of the heart with a significant decrease in the left ventricular fractional shortening. Work-performing heart analyses showed significantly impaired systolic, and diastolic functions and the force measurements of cardiac myofibers revealed that the myofilaments had significantly decreased Ca²⁺ sensitivity and tension generation. Real-time RT-PCR quantification demonstrated an increased expression of ß-myosin heavy chain, brain natriuretic peptide, and skeletal actin and a decreased expression of the Ca²⁺ handling proteins sarcoplasmic reticulum Ca²⁺-ATPase and ryanodine receptor. Furthermore, our study also indicates that the -TM54 mutation decreases tropomyosin flexibility, which may influence actin binding and myofilament Ca²⁺ sensitivity. The pathological and physiological phenotypes exhibited by these mice are consistent with those seen in human DCM and heart failure. As such, this is the first mouse model in which a mutation in a sarcomeric thin filament protein, specifically TM, leads to DCM.

Key Words: mouse model • transgenic • myocardial contractility • thin filament

This article has been cited by other articles:

				J. Naghshin, K. R. McGaffin, W. G. Witham, M. A. Mathier, L. C. Romano, S. H. Smith, A. M. Janczewski, J. A. Kirk, S. G. Shroff, and C. P. O'Donnell Chronic intermittent hypoxia increases left ventricular contractility in C57BL/6J mice J Appl Physiol, September 1, 2009; 107(3): 787 - 793. [Abstract] [Full Text] [PDF]

				E. C. Dyer, A. M. Jacques, A. C. Hoskins, D. G. Ward, C. E. Gallon, A. E. Messer, J. P. Kaski, M. Burch, J. C. Kentish, and S. B. Marston Functional Analysis of a Unique Troponin C Mutation, GLY159ASP, that Causes Familial Dilated Cardiomyopathy, Studied in Explanted Heart Muscle Circ Heart Fail, September 1, 2009; 2(5): 456 - 464. [Abstract] [Full Text] [PDF]

				S. Morimoto Expanded Spectrum of Gene Causing Both Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy Circ. Res., August 14, 2009; 105(4): 313 - 315. [Full Text] [PDF]

				L. Mestroni Phenotypic heterogeneity of sarcomeric gene mutations: a matter of gain and loss? J. Am. Coll. Cardiol., July 21, 2009; 54(4): 343 - 345. [Full Text] [PDF]

				G. Jagatheesan, S. Rajan, E. M. Schulz, R. P. H. Ahmed, N. Petrashevskaya, A. Schwartz, G. P. Boivin, G. M. Arteaga, T. Wang, Y.-G. Wang, et al. An internal domain of {beta}-tropomyosin increases myofilament Ca2+ sensitivity Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H181 - H190. [Abstract] [Full Text] [PDF]

				D. Dweck, N. Hus, and J. D. Potter Challenging Current Paradigms Related to Cardiomyopathies: ARE CHANGES IN THE Ca2+ SENSITIVITY OF MYOFILAMENTS CONTAINING CARDIAC TROPONIN C MUTATIONS (G159D AND L29Q) GOOD PREDICTORS OF THE PHENOTYPIC OUTCOMES? J. Biol. Chem., November 28, 2008; 283(48): 33119 - 33128. [Abstract] [Full Text] [PDF]

				S. Morimoto Sarcomeric proteins and inherited cardiomyopathies Cardiovasc Res, March 1, 2008; 77(4): 659 - 666. [Abstract] [Full Text] [PDF]