This Article Full Text Full Text (PDF) 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 Yang, Q. Articles by Robbins, J. Search for Related Content PubMed PubMed Citation Articles by Yang, Q. Articles by Robbins, J. Related Collections Animal models of human disease Functional genomics Heart failure - basic studies

(Circulation Research. 1999;85:841-847.)
© 1999 American Heart Association, Inc.

Integrative Physiology

In Vivo Modeling of Myosin Binding Protein C Familial Hypertrophic Cardiomyopathy

Qinglin Yang, Atsushi Sanbe, Hanna Osinska, Timothy E. Hewett, Raisa Klevitsky, Jeffrey Robbins

From the Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio.

Abstract—Myosin binding protein C (MyBP-C) is an integral part of the striated muscle sarcomere. As is the case for other sarcomeric genes in human populations, multiple mutations within the gene have been linked to familial hypertrophic cardiomyopathy. Although some MyBP-C lesions are the result of missense mutations, most show truncated polypeptides lacking either the myosin or myosin and titin binding sites. Previously, we generated transgenic (TG) mice with cardiac-specific expression of a MyBP-C mutant lacking the myosin and titin binding domains. Surprisingly, the mutant protein was stable and made up a majority of the MyBP-C species, with concomitant reductions in endogenous MyBP-C such that overall MyBP-C stoichiometry was conserved. In the present study, we created a second series of TG mice that express, in the heart, a mutant MyBP-C lacking only the myosin binding site. In contrast to the previous data for the MyBP-C lacking both titin and myosin binding sites, only very modest levels of protein were found, consistent with data obtained from human biopsies in which mutated MyBP-C could not be detected. Despite normal levels of wild-type MyBP-C, there were significant changes in the structure and ultrastructure of the heart. Fiber mechanics showed decreased unloading shortening velocity, maximum shortening velocity, and relative maximal power output.

Key Words: transgenic • myosin • cardiac disease • muscle

This article has been cited by other articles:

				L. Carrier, S. Schlossarek, M. S. Willis, and T. Eschenhagen The ubiquitin-proteasome system and nonsense-mediated mRNA decay in hypertrophic cardiomyopathy Cardiovasc Res, January 15, 2010; 85(2): 330 - 338. [Abstract] [Full Text] [PDF]

				S. Marston, O. Copeland, A. Jacques, K. Livesey, V. Tsang, W. J. McKenna, S. Jalilzadeh, S. Carballo, C. Redwood, and H. Watkins Evidence From Human Myectomy Samples That MYBPC3 Mutations Cause Hypertrophic Cardiomyopathy Through Haploinsufficiency Circ. Res., July 31, 2009; 105(3): 219 - 222. [Abstract] [Full Text] [PDF]

				J. L. Theis, J. M. Bos, J. D. Theis, D. V. Miller, J. A. Dearani, H. V. Schaff, B. J. Gersh, S. R. Ommen, R. L. Moss, and M. J. Ackerman Expression Patterns of Cardiac Myofilament Proteins: Genomic and Protein Analysis of Surgical Myectomy Tissue From Patients With Obstructive Hypertrophic Cardiomyopathy Circ Heart Fail, July 1, 2009; 2(4): 325 - 333. [Abstract] [Full Text] [PDF]

				F. Cambronero, F. Marin, V. Roldan, D. Hernandez-Romero, M. Valdes, and G. Y.H. Lip Biomarkers of pathophysiology in hypertrophic cardiomyopathy: implications for clinical management and prognosis Eur. Heart J., January 9, 2009; (2009) ehn538v1. [Abstract] [Full Text] [PDF]

				M. J. McGrath, D. L. Cottle, M.-A. Nguyen, J. M. Dyson, I. D. Coghill, P. A. Robinson, M. Holdsworth, B. S. Cowling, E. C. Hardeman, C. A. Mitchell, et al. Four and a Half LIM Protein 1 Binds Myosin-binding Protein C and Regulates Myosin Filament Formation and Sarcomere Assembly J. Biol. Chem., March 17, 2006; 281(11): 7666 - 7683. [Abstract] [Full Text] [PDF]

				O. Cazorla, S. Szilagyi, N. Vignier, G. Salazar, E. Kramer, G. Vassort, L. Carrier, and A. Lacampagne Length and protein kinase A modulations of myocytes in cardiac myosin binding protein C-deficient mice Cardiovasc Res, February 1, 2006; 69(2): 370 - 380. [Abstract] [Full Text] [PDF]

				S. Sadayappan, J. Gulick, H. Osinska, L. A. Martin, H. S. Hahn, G. W. Dorn II, R. Klevitsky, C. E. Seidman, J. G. Seidman, and J. Robbins Cardiac Myosin-Binding Protein-C Phosphorylation and Cardiac Function Circ. Res., November 25, 2005; 97(11): 1156 - 1163. [Abstract] [Full Text] [PDF]

				H.-P. Vosberg The ubiquitin-proteasome system may be involved in the pathogenesis of hypertrophic cardiomyopathy Cardiovasc Res, April 1, 2005; 66(1): 1 - 3. [Full Text] [PDF]

				A. Sarikas, L. Carrier, C. Schenke, D. Doll, J. Flavigny, K. S. Lindenberg, T. Eschenhagen, and O. Zolk Impairment of the ubiquitin-proteasome system by truncated cardiac myosin binding protein C mutants Cardiovasc Res, April 1, 2005; 66(1): 33 - 44. [Abstract] [Full Text] [PDF]

				S. P. Harris, E. Rostkova, M. Gautel, and R. L. Moss Binding of Myosin Binding Protein-C to Myosin Subfragment S2 Affects Contractility Independent of a Tether Mechanism Circ. Res., October 29, 2004; 95(9): 930 - 936. [Abstract] [Full Text] [PDF]

				L. Carrier, R. Knoll, N. Vignier, D. I Keller, P. Bausero, B. Prudhon, R. Isnard, M.-L. Ambroisine, M. Fiszman, J. Ross Jr., et al. Asymmetric septal hypertrophy in heterozygous cMyBP-C null mice Cardiovasc Res, August 1, 2004; 63(2): 293 - 304. [Abstract] [Full Text] [PDF]

				E. Flashman, C. Redwood, J. Moolman-Smook, and H. Watkins Cardiac Myosin Binding Protein C: Its Role in Physiology and Disease Circ. Res., May 28, 2004; 94(10): 1279 - 1289. [Abstract] [Full Text] [PDF]

				B. M. Palmer, D. Georgakopoulos, P. M. Janssen, Y. Wang, N. R. Alpert, D. F. Belardi, S. P. Harris, R. L. Moss, P. G. Burgon, C. E. Seidman, et al. Role of Cardiac Myosin Binding Protein C in Sustaining Left Ventricular Systolic Stiffening Circ. Res., May 14, 2004; 94(9): 1249 - 1255. [Abstract] [Full Text] [PDF]

				F. S. Korte, K. S. McDonald, S. P. Harris, and R. L. Moss Loaded Shortening, Power Output, and Rate of Force Redevelopment Are Increased With Knockout of Cardiac Myosin Binding Protein-C Circ. Res., October 17, 2003; 93(8): 752 - 758. [Abstract] [Full Text] [PDF]

				N. Sato, T. Kawakami, A. Nakayama, H. Suzuki, H. Kasahara, and T. Obinata A Novel Variant of Cardiac Myosin-binding Protein-C That Is Unable to Assemble into Sarcomeres Is Expressed in the Aged Mouse Atrium Mol. Biol. Cell, August 1, 2003; 14(8): 3180 - 3191. [Abstract] [Full Text] [PDF]

				C. I. Berul Electrophysiological phenotyping in genetically engineered mice Physiol Genomics, May 13, 2003; 13(3): 207 - 216. [Abstract] [Full Text] [PDF]

				J. P Konhilas, T. C Irving, B. M Wolska, E. E Jweied, A. F Martin, R John Solaro, and P. P de Tombe Troponin I in the murine myocardium: influence on length-dependent activation and interfilament spacing J. Physiol., March 15, 2003; 547(3): 951 - 961. [Abstract] [Full Text] [PDF]

				J. Robbins and D. W. Benson Structure-Function Relationships in Myosin Binding Protein-C: Taking Off the Blinders and Collaring Hypertrophic Cardiomyopathy Circ. Res., October 18, 2002; 91(8): 656 - 658. [Full Text] [PDF]

				J. Moolman-Smook, E. Flashman, W. de Lange, Z. Li, V. Corfield, C. Redwood, and H. Watkins Identification of Novel Interactions Between Domains of Myosin Binding Protein-C That Are Modulated by Hypertrophic Cardiomyopathy Missense Mutations Circ. Res., October 18, 2002; 91(8): 704 - 711. [Abstract] [Full Text] [PDF]

				S. P. Harris, C. R. Bartley, T. A. Hacker, K. S. McDonald, P. S. Douglas, M. L. Greaser, P. A. Powers, and R. L. Moss Hypertrophic Cardiomyopathy in Cardiac Myosin Binding Protein-C Knockout Mice Circ. Res., March 22, 2002; 90(5): 594 - 601. [Abstract] [Full Text] [PDF]

				Q. Yang, T. E. Hewett, R. Klevitsky, A. Sanbe, X. Wang, and J. Robbins PKA-dependent phosphorylation of cardiac myosin binding protein C in transgenic mice Cardiovasc Res, July 1, 2001; 51(1): 80 - 88. [Abstract] [Full Text] [PDF]

				J. James, Y. Zhang, H. Osinska, A. Sanbe, R. Klevitsky, T. E. Hewett, and J. Robbins Transgenic Modeling of a Cardiac Troponin I Mutation Linked to Familial Hypertrophic Cardiomyopathy Circ. Res., October 27, 2000; 87(9): 805 - 811. [Abstract] [Full Text] [PDF]

				C. C. Witt, B. Gerull, M. J. Davies, T. Centner, W. A. Linke, and L. Thierfelder Hypercontractile Properties of Cardiac Muscle Fibers in a Knock-in Mouse Model of Cardiac Myosin-binding Protein-C J. Biol. Chem., February 9, 2001; 276(7): 5353 - 5359. [Abstract] [Full Text] [PDF]

				S. P. Harris, C. R. Bartley, T. A. Hacker, K. S. McDonald, P. S. Douglas, M. L. Greaser, P. A. Powers, and R. L. Moss Hypertrophic Cardiomyopathy in Cardiac Myosin Binding Protein-C Knockout Mice Circ. Res., March 22, 2002; 90(5): 594 - 601. [Abstract] [Full Text] [PDF]