© 1997 American Heart Association, Inc.
Articles |
Transgenic Remodeling of the Regulatory Myosin Light Chains in the Mammalian Heart
From the Children's Hospital Research Foundation, Department of Pediatrics, Division of Molecular Cardiovascular Biology (J.G., T.E.H., R.K., J.R.), Cincinnati, Ohio, and the Departments of Physiology (R.L.M.) and Pediatrics (S.H.B.), University of Wisconsin, Madison.
Correspondence to J. Robbins, PhD, Division of Molecular Cardiovascular Biology, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.robbins{at}chmcc.org
Abstract The regulatory myosin light chain (MLC) regulates contraction in smooth muscle. However, its function in striated muscle remains obscure, and the different functional activities of the various isoforms that are expressed in the mammalian heart (ventricle- and atrium-specific MLC2) remain undefined. To begin to explore these issues, we used transgenesis to determine the feasibility of effecting a complete or partial replacement of the cardiac regulatory light chains with the isoform that is normally expressed in fast skeletal muscle fibers (fast muscle–specific MLC2). Multiple lines of transgenic mice were generated that expressed the transgene at varying levels in the heart in a copy number–dependent fashion. There is a major discordance in the manner in which the different cardiac compartments respond to high levels of overexpression of the transgene. In atria, isoform replacement with the skeletal protein was quite efficient, even at low copy number. The ventricle is much more refractory to replacement, and despite high levels of transgenic transcript, protein replacement was incomplete. Replacement could be further increased by breeding the transgenic lines with one another. Despite very high levels of transgenic transcript in these mice, the overall level of the regulatory light chain in both compartments remained essentially constant; only the protein isoform ratios were altered. The partial replacement of the ventricular with the skeletal isoform reduced both left ventricular contractility and relaxation, although the unloaded shortening velocity of isolated ventricular cardiomyocytes was not significantly different.
Key Words: transgene • myosin light chain • gene • muscle
This article has been cited by other articles:
 |
|
 |
|
  G. Schevzov, T. Fath, B. Vrhovski, N. Vlahovich, S. Rajan, J. Hook, J. E. Joya, F. Lemckert, F. Puttur, J. J.-C. Lin, et al. Divergent Regulation of the Sarcomere and the Cytoskeleton J. Biol. Chem., January 4, 2008; 283(1): 275 - 283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bupha-Intr, J. W. Holmes, and P. M. L. Janssen Induction of hypertrophy in vitro by mechanical loading in adult rabbit myocardium Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3759 - H3767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Herron, R. Vandenboom, E. Fomicheva, L. Mundada, T. Edwards, and J. M. Metzger Calcium-Independent Negative Inotropy by {beta}-Myosin Heavy Chain Gene Transfer in Cardiac Myocytes Circ. Res., April 27, 2007; 100(8): 1182 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hambleton, H. Hahn, S. T. Pleger, M. C. Kuhn, R. Klevitsky, A. N. Carr, T. F. Kimball, T. E. Hewett, G. W. Dorn II, W. J. Koch, et al. Pharmacological- and Gene Therapy-Based Inhibition of Protein Kinase C{alpha}/{beta} Enhances Cardiac Contractility and Attenuates Heart Failure Circulation, August 8, 2006; 114(6): 574 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Gaffin, K. Gokulan, J. C. Sacchettini, T. E. Hewett, R. Klevitsky, J. Robbins, V. Sarin, D. C. Zawieja, G. A. Meininger, and M. Muthuchamy Changes in end-to-end interactions of tropomyosin affect mouse cardiac muscle dynamics Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H552 - H563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xu, T. R. Kimball, J. N. Lorenz, D. A. Brown, A. R. Bauskin, R. Klevitsky, T. E. Hewett, S. N. Breit, and J. D. Molkentin GDF15/MIC-1 Functions As a Protective and Antihypertrophic Factor Released From the Myocardium in Association With SMAD Protein Activation Circ. Res., February 17, 2006; 98(3): 342 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Kaiser, Q. Liang, O. Bueno, Y. Huang, T. Lackey, R. Klevitsky, T. E. Hewett, and J. D. Molkentin Genetic Inhibition or Activation of JNK1/2 Protects the Myocardium from Ischemia-Reperfusion-induced Cell Death in Vivo J. Biol. Chem., September 23, 2005; 280(38): 32602 - 32608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. James, L. Martin, M. Krenz, C. Quatman, F. Jones, R. Klevitsky, J. Gulick, and J. Robbins Forced Expression of {alpha}-Myosin Heavy Chain in the Rabbit Ventricle Results in Cardioprotection Under Cardiomyopathic Conditions Circulation, May 10, 2005; 111(18): 2339 - 2346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Krenz and J. Robbins Impact of beta-myosin heavy chain expression on cardiac function during stress J. Am. Coll. Cardiol., December 21, 2004; 44(12): 2390 - 2397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D Gaffin, C. W Tong, D. C Zawieja, T. E Hewett, R. Klevitsky, J. Robbins, and M. Muthuchamy Charged residue alterations in the inner-core domain and carboxy-terminus of {alpha}-tropomyosin differentially affect mouse cardiac muscle contractility J. Physiol., December 15, 2004; 561(3): 777 - 791. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Gaffin, K. Gokulan, J. C. Sacchettini, T. Hewett, R. Klevitsky, J. Robbins, and M. Muthuchamy Charged residue changes in the carboxy-terminus of {alpha}-tropomyosin alter mouse cardiac muscle contractility J. Physiol., April 15, 2004; 556(2): 531 - 543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Szczesna-Cordary, G. Guzman, S.-S. Ng, and J. Zhao Familial Hypertrophic Cardiomyopathy-linked Alterations in Ca2+ Binding of Human Cardiac Myosin Regulatory Light Chain Affect Cardiac Muscle Contraction J. Biol. Chem., January 30, 2004; 279(5): 3535 - 3542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. F. Bueno, D. J. Lips, R. A. Kaiser, B. J. Wilkins, Y.-S. Dai, B. J. Glascock, R. Klevitsky, T. E. Hewett, T. R. Kimball, B. J. Aronow, et al. Calcineurin A{beta} Gene Targeting Predisposes the Myocardium to Acute Ischemia-Induced Apoptosis and Dysfunction Circ. Res., January 9, 2004; 94(1): 91 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Krenz, A. Sanbe, F. Bouyer-Dalloz, J. Gulick, R. Klevitsky, T. E. Hewett, H. E. Osinska, J. N. Lorenz, C. Brosseau, A. Federico, et al. Analysis of Myosin Heavy Chain Functionality in the Heart J. Biol. Chem., May 2, 2003; 278(19): 17466 - 17474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sanbe, J. Gulick, M. C. Hanks, Q. Liang, H. Osinska, and J. Robbins Reengineering Inducible Cardiac-Specific Transgenesis With an Attenuated Myosin Heavy Chain Promoter Circ. Res., April 4, 2003; 92(6): 609 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Roopnarine Mechanical Defects of Muscle Fibers with Myosin Light Chain Mutants that Cause Cardiomyopathy Biophys. J., April 1, 2003; 84(4): 2440 - 2449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Lacour-Gayet, D. Piot, J. Zoghbi, A. Serraf, P. Gruber, L. Mace, A. Touchot, and C. Planche Surgical management and indication of left ventricular retraining in arterial switch for transposition of the great arteries with intact ventricular septum Eur. J. Cardiothorac. Surg., October 1, 2001; 20(4): 824 - 829. [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]
|
|
|
|
|
|
X. Wang, H. Osinska, G. W. Dorn II, M. Nieman, J. N. Lorenz, A. M. Gerdes, S. Witt, T. Kimball, J. Gulick, and J. Robbins Mouse Model of Desmin-Related Cardiomyopathy Circulation, May 15, 2001; 103(19): 2402 - 2407. [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]
|
|
|
|
|
|
J. James, A. Sanbe, K. Yager, L. Martin, R. Klevitsky, and J. Robbins Genetic Manipulation of the Rabbit Heart via Transgenesis Circulation, April 11, 2000; 101(14): 1715 - 1721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Sussman, S. Welch, A. Walker, R. Klevitsky, T. E. Hewett, S. A. Witt, T. R. Kimball, R. Price, H. W. Lim, and J. D. Molkentin Hypertrophic defect unmasked by calcineurin expression in asymptomatic tropomodulin overexpressing transgenic mice Cardiovasc Res, April 1, 2000; 46(1): 90 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Tardiff, T. E. Hewett, S. M. Factor, K. L. Vikstrom, J. Robbins, and L. A. Leinwand Expression of the beta (slow)-isoform of MHC in the adult mouse heart causes dominant-negative functional effects Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H412 - H419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.-P. Xiao, H. Cheng, Y.-Y. Zhou, M. Kuschel, and E. G. Lakatta Recent Advances in Cardiac {beta}2-Adrenergic Signal Transduction Circ. Res., November 26, 1999; 85(11): 1092 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yang, A. Sanbe, H. Osinska, T. E. Hewett, R. Klevitsky, and J. Robbins In Vivo Modeling of Myosin Binding Protein C Familial Hypertrophic Cardiomyopathy Circ. Res., October 29, 1999; 85(9): 841 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Lewis, Y. Xia, S. K. Datta, J. McMillin, and R. E. Kellems Combinatorial Interactions Regulate Cardiac Expression of the Murine Adenylosuccinate Synthetase 1 Gene J. Biol. Chem., May 14, 1999; 274(20): 14188 - 14197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B. Low, J. Mitchell, J. Woodcock-Mitchell, A. S. Rovner, and S. L. White Smooth-Muscle Myosin Heavy-Chain SM-B Isoform Expression in Developing and Adult Rat Lung Am. J. Respir. Cell Mol. Biol., April 1, 1999; 20(4): 651 - 657. [Abstract] [Full Text]
|
|
|
|
|
|
S. H. Buck, P. J. Konyn, J. Palermo, J. Robbins, and R. L. Moss Altered kinetics of contraction of mouse atrial myocytes expressing ventricular myosin regulatory light chain Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1167 - H1171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Loukianov, Y. Ji, I. L. Grupp, D. L. Kirkpatrick, D. L. Baker, T. Loukianova, G. Grupp, J. Lytton, R. A. Walsh, and M. Periasamy Enhanced Myocardial Contractility and Increased Ca2+ Transport Function in Transgenic Hearts Expressing the Fast-Twitch Skeletal Muscle Sarcoplasmic Reticulum Ca2+-ATPase Circ. Res., November 2, 1998; 83(9): 889 - 897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sato, D. G. Ferguson, H. Sako, G. W. Dorn II, V. J. Kadambi, A. Yatani, B. D. Hoit, R. A. Walsh, and E. G. Kranias Cardiac-specific Overexpression of Mouse Cardiac Calsequestrin Is Associated with Depressed Cardiovascular Function and Hypertrophy in Transgenic Mice J. Biol. Chem., October 23, 1998; 273(43): 28470 - 28477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Bonne, L. Carrier, P. Richard, B. Hainque, and K. Schwartz Familial Hypertrophic Cardiomyopathy : From Mutations to Functional Defects Circ. Res., September 21, 1998; 83(6): 580 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. James, T. E. Hewett, and J. Robbins Cardiac Physiology in Transgenic Mice Circ. Res., March 9, 1998; 82(4): 407 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Schaub, M. A. Hefti, R. A. Zuellig, and I. Morano Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms Cardiovasc Res, February 1, 1998; 37(2): 381 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Rethinasamy, M. Muthuchamy, T. Hewett, G. Boivin, B. M. Wolska, C. Evans, R. J. Solaro, and D. F. Wieczorek Molecular and Physiological Effects of {alpha}-Tropomyosin Ablation in the Mouse Circ. Res., January 23, 1998; 82(1): 116 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Robbins {alpha}-Tropomyosin Knockouts : A Blow Against Transcriptional Chauvinism Circ. Res., January 23, 1998; 82(1): 134 - 136. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Gruber, S. Kubalak, and K. Chien Downregulation of atrial markers during cardiac chamber morphogenesis is irreversible in murine embryos Development, January 11, 1998; 125(22): 4427 - 4438. [Abstract] [PDF]
|
|
|
|
|
|
J. James and J. Robbins Molecular remodeling of cardiac contractile function Am J Physiol Heart Circ Physiol, November 1, 1997; 273(5): H2105 - H2118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kelly and M. Buckingham Manipulating Myosin Light Chain 2 Isoforms In Vivo : A Transgenic Approach to Understanding Contractile Protein Diversity Circ. Res., May 19, 1997; 80(5): 751 - 753. [Full Text]
|
|
|
|
|
|
J. S.'A. Pereira, D. Pavlov, M. Nili, M. Greaser, E. Homsher, and R. L. Moss Kinetic Differences in Cardiac Myosins with Identical Loop 1 Sequences J. Biol. Chem., February 2, 2001; 276(6): 4409 - 4415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, H. Osinska, R. Klevitsky, A. M. Gerdes, M. Nieman, J. Lorenz, T. Hewett, and J. Robbins Expression of R120G-{alpha}B-Crystallin Causes Aberrant Desmin and {alpha}B-Crystallin Aggregation and Cardiomyopathy in Mice Circ. Res., July 6, 2001; 89(1): 84 - 91. [Abstract] [Full Text] [PDF]
|
|