Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Jun 15;101(12):2630–2639. doi: 10.1172/JCI2825

Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice.

J G Fewell 1, T E Hewett 1, A Sanbe 1, R Klevitsky 1, E Hayes 1, D Warshaw 1, D Maughan 1, J Robbins 1
PMCID: PMC508853  PMID: 9637696

Abstract

The different functions of the ventricular- and atrial-specific essential myosin light chains are unknown. Using transgenesis, cardiac-specific overexpression of proteins can be accomplished. The transgenic paradigm is more useful than originally expected, in that the mammalian heart rigorously controls sarcomeric protein stoichiometries. In a clinical subpopulation suffering from heart disease caused by congenital malformations of the outflow tract, an ELC1v-->ELC1a isoform shift correlated with increases in cross-bridge cycling kinetics as measured in skinned fibers derived from the diseased muscle. We have used transgenesis to replace the ventricular isoform of the essential myosin light chain with the atrial isoform. The ELC1v--> ELC1a shift in the ventricle resulted in similar functional alterations. Unloaded velocities as measured by the ability of the myosin to translocate actin filaments in the in vitro motility assay were significantly increased as a result of the isoform substitution. Unloaded shortening velocity was also increased in skinned muscle fibers, and at the whole organ level, both contractility and relaxation were significantly increased. This increase in cardiac function occurred in the absence of a hypertrophic response. Thus, ELC1a expression in the ventricle appears to be advantageous to the heart, resulting in increased cardiac function.

Full Text

The Full Text of this article is available as a PDF (481.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Auckland L. M., Lambert S. J., Cummins P. Cardiac myosin light and heavy chain isotypes in tetralogy of Fallot. Cardiovasc Res. 1986 Nov;20(11):828–836. doi: 10.1093/cvr/20.11.828. [DOI] [PubMed] [Google Scholar]
  2. Azizi C., Bouissou P., Galen F. X., Lattion A. L., Lartigue M., Carayon A. Alterations in atrial natriuretic peptide gene expression during endurance training in rats. Eur J Endocrinol. 1995 Sep;133(3):361–365. doi: 10.1530/eje.0.1330361. [DOI] [PubMed] [Google Scholar]
  3. Barton P. J., Cohen A., Robert B., Fiszman M. Y., Bonhomme F., Guénet J. L., Leader D. P., Buckingham M. E. The myosin alkali light chains of mouse ventricular and slow skeletal muscle are indistinguishable and are encoded by the same gene. J Biol Chem. 1985 Jul 15;260(14):8578–8584. [PubMed] [Google Scholar]
  4. Barton P. J., Robert B., Cohen A., Garner I., Sassoon D., Weydert A., Buckingham M. E. Structure and sequence of the myosin alkali light chain gene expressed in adult cardiac atria and fetal striated muscle. J Biol Chem. 1988 Sep 5;263(25):12669–12676. [PubMed] [Google Scholar]
  5. Buckingham M. E. The control of muscle gene expression: a review of molecular studies on the production and processing of primary transcripts. Br Med Bull. 1989 Jul;45(3):608–629. doi: 10.1093/oxfordjournals.bmb.a072348. [DOI] [PubMed] [Google Scholar]
  6. Bárány M. ATPase activity of myosin correlated with speed of muscle shortening. J Gen Physiol. 1967 Jul;50(6 Suppl):197–218. doi: 10.1085/jgp.50.6.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Colbert M. C., Hall D. G., Kimball T. R., Witt S. A., Lorenz J. N., Kirby M. L., Hewett T. E., Klevitsky R., Robbins J. Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice. J Clin Invest. 1997 Oct 15;100(8):1958–1968. doi: 10.1172/JCI119727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Edman K. A. The velocity of unloaded shortening and its relation to sarcomere length and isometric force in vertebrate muscle fibres. J Physiol. 1979 Jun;291:143–159. doi: 10.1113/jphysiol.1979.sp012804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fewell J. G., Osinska H., Klevitsky R., Ng W., Sfyris G., Bahrehmand F., Robbins J. A treadmill exercise regimen for identifying cardiovascular phenotypes in transgenic mice. Am J Physiol. 1997 Sep;273(3 Pt 2):H1595–H1605. doi: 10.1152/ajpheart.1997.273.3.H1595. [DOI] [PubMed] [Google Scholar]
  10. Gulick J., Hewett T. E., Klevitsky R., Buck S. H., Moss R. L., Robbins J. Transgenic remodeling of the regulatory myosin light chains in the mammalian heart. Circ Res. 1997 May;80(5):655–664. doi: 10.1161/01.res.80.5.655. [DOI] [PubMed] [Google Scholar]
  11. Ho G., Chen T. L., Chisholm R. L. Both the amino and carboxyl termini of Dictyostelium myosin essential light chain are required for binding to myosin heavy chain. J Biol Chem. 1995 Nov 17;270(46):27977–27981. doi: 10.1074/jbc.270.46.27977. [DOI] [PubMed] [Google Scholar]
  12. Izumo S., Lompré A. M., Matsuoka R., Koren G., Schwartz K., Nadal-Ginard B., Mahdavi V. Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals. J Clin Invest. 1987 Mar;79(3):970–977. doi: 10.1172/JCI112908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Izumo S., Nadal-Ginard B., Mahdavi V. Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci U S A. 1988 Jan;85(2):339–343. doi: 10.1073/pnas.85.2.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jones W. K., Grupp I. L., Doetschman T., Grupp G., Osinska H., Hewett T. E., Boivin G., Gulick J., Ng W. A., Robbins J. Ablation of the murine alpha myosin heavy chain gene leads to dosage effects and functional deficits in the heart. J Clin Invest. 1996 Oct 15;98(8):1906–1917. doi: 10.1172/JCI118992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lowes B. D., Minobe W., Abraham W. T., Rizeq M. N., Bohlmeyer T. J., Quaife R. A., Roden R. L., Dutcher D. L., Robertson A. D., Voelkel N. F. Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium. J Clin Invest. 1997 Nov 1;100(9):2315–2324. doi: 10.1172/JCI119770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lowey S., Waller G. S., Trybus K. M. Function of skeletal muscle myosin heavy and light chain isoforms by an in vitro motility assay. J Biol Chem. 1993 Sep 25;268(27):20414–20418. [PubMed] [Google Scholar]
  17. Lowey S., Waller G. S., Trybus K. M. Skeletal muscle myosin light chains are essential for physiological speeds of shortening. Nature. 1993 Sep 30;365(6445):454–456. doi: 10.1038/365454a0. [DOI] [PubMed] [Google Scholar]
  18. Lyons G. E., Schiaffino S., Sassoon D., Barton P., Buckingham M. Developmental regulation of myosin gene expression in mouse cardiac muscle. J Cell Biol. 1990 Dec;111(6 Pt 1):2427–2436. doi: 10.1083/jcb.111.6.2427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. McAuliffe J. J., Gao L. Z., Solaro R. J. Changes in myofibrillar activation and troponin C Ca2+ binding associated with troponin T isoform switching in developing rabbit heart. Circ Res. 1990 May;66(5):1204–1216. doi: 10.1161/01.res.66.5.1204. [DOI] [PubMed] [Google Scholar]
  20. Morano I., Hädicke K., Haase H., Böhm M., Erdmann E., Schaub M. C. Changes in essential myosin light chain isoform expression provide a molecular basis for isometric force regulation in the failing human heart. J Mol Cell Cardiol. 1997 Apr;29(4):1177–1187. doi: 10.1006/jmcc.1996.0353. [DOI] [PubMed] [Google Scholar]
  21. Morano I., Ritter O., Bonz A., Timek T., Vahl C. F., Michel G. Myosin light chain-actin interaction regulates cardiac contractility. Circ Res. 1995 May;76(5):720–725. doi: 10.1161/01.res.76.5.720. [DOI] [PubMed] [Google Scholar]
  22. Morano M., Zacharzowski U., Maier M., Lange P. E., Alexi-Meskishvili V., Haase H., Morano I. Regulation of human heart contractility by essential myosin light chain isoforms. J Clin Invest. 1996 Jul 15;98(2):467–473. doi: 10.1172/JCI118813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Moss R. L. Effects on shortening velocity of rabbit skeletal muscle due to variations in the level of thin-filament activation. J Physiol. 1986 Aug;377:487–505. doi: 10.1113/jphysiol.1986.sp016199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mulieri L. A., Hasenfuss G., Ittleman F., Blanchard E. M., Alpert N. R. Protection of human left ventricular myocardium from cutting injury with 2,3-butanedione monoxime. Circ Res. 1989 Nov;65(5):1441–1449. doi: 10.1161/01.res.65.5.1441. [DOI] [PubMed] [Google Scholar]
  25. Nakao K., Minobe W., Roden R., Bristow M. R., Leinwand L. A. Myosin heavy chain gene expression in human heart failure. J Clin Invest. 1997 Nov 1;100(9):2362–2370. doi: 10.1172/JCI119776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ng W. A., Grupp I. L., Subramaniam A., Robbins J. Cardiac myosin heavy chain mRNA expression and myocardial function in the mouse heart. Circ Res. 1991 Jun;68(6):1742–1750. doi: 10.1161/01.res.68.6.1742. [DOI] [PubMed] [Google Scholar]
  27. Nguyen T. T., Hayes E., Mulieri L. A., Leavitt B. J., ter Keurs H. E., Alpert N. R., Warshaw D. M. Maximal actomyosin ATPase activity and in vitro myosin motility are unaltered in human mitral regurgitation heart failure. Circ Res. 1996 Aug;79(2):222–226. doi: 10.1161/01.res.79.2.222. [DOI] [PubMed] [Google Scholar]
  28. Palermo J., Gulick J., Colbert M., Fewell J., Robbins J. Transgenic remodeling of the contractile apparatus in the mammalian heart. Circ Res. 1996 Mar;78(3):504–509. doi: 10.1161/01.res.78.3.504. [DOI] [PubMed] [Google Scholar]
  29. Palermo J., Gulick J., Ng W., Grupp I. L., Grupp G., Robbins J. Remodeling the mammalian heart using transgenesis. Cell Mol Biol Res. 1995;41(6):501–509. [PubMed] [Google Scholar]
  30. Robbins J., Palermo J., Rindt H. In vivo definition of a cardiac specific promoter and its potential utility in remodeling the heart. Ann N Y Acad Sci. 1995 Mar 27;752:492–505. doi: 10.1111/j.1749-6632.1995.tb17458.x. [DOI] [PubMed] [Google Scholar]
  31. Schaub M. C., Hirzel H. O. Atrial and ventricular isomyosin composition in patients with different forms of cardiac hypertrophy. Basic Res Cardiol. 1987;82 (Suppl 2):357–367. doi: 10.1007/978-3-662-11289-2_35. [DOI] [PubMed] [Google Scholar]
  32. Schaub M. C., Tuchschmid C. R., Srihari T., Hirzel H. O. Myosin isoenzymes in human hypertrophic hearts. Shift in atrial myosin heavy chains and in ventricular myosin light chains. Eur Heart J. 1984 Dec;5 (Suppl F):85–93. doi: 10.1093/eurheartj/5.suppl_f.85. [DOI] [PubMed] [Google Scholar]
  33. Schiaffino S., Reggiani C. Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Physiol Rev. 1996 Apr;76(2):371–423. doi: 10.1152/physrev.1996.76.2.371. [DOI] [PubMed] [Google Scholar]
  34. Schwartz K., Lecarpentier Y., Martin J. L., Lompré A. M., Mercadier J. J., Swynghedauw B. Myosin isoenzymic distribution correlates with speed of myocardial contraction. J Mol Cell Cardiol. 1981 Dec;13(12):1071–1075. doi: 10.1016/0022-2828(81)90297-2. [DOI] [PubMed] [Google Scholar]
  35. Schwartz K., de la Bastie D., Bouveret P., Oliviéro P., Alonso S., Buckingham M. Alpha-skeletal muscle actin mRNA's accumulate in hypertrophied adult rat hearts. Circ Res. 1986 Nov;59(5):551–555. doi: 10.1161/01.res.59.5.551. [DOI] [PubMed] [Google Scholar]
  36. Sussman M. A., Welch S., Cambon N., Klevitsky R., Hewett T. E., Price R., Witt S. A., Kimball T. R. Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice. J Clin Invest. 1998 Jan 1;101(1):51–61. doi: 10.1172/JCI1167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Trahair T., Yeoh T., Cartmill T., Keogh A., Spratt P., Chang V., dos Remedios C. G., Gunning P. Myosin light chain gene expression associated with disease states of the human heart. J Mol Cell Cardiol. 1993 May;25(5):577–585. doi: 10.1006/jmcc.1993.1067. [DOI] [PubMed] [Google Scholar]
  38. VanBuren P., Waller G. S., Harris D. E., Trybus K. M., Warshaw D. M., Lowey S. The essential light chain is required for full force production by skeletal muscle myosin. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12403–12407. doi: 10.1073/pnas.91.26.12403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Whalen R. G., Sell S. M., Butler-Browne G. S., Schwartz K., Bouveret P., Pinset-Härstöm I. Three myosin heavy-chain isozymes appear sequentially in rat muscle development. Nature. 1981 Aug 27;292(5826):805–809. doi: 10.1038/292805a0. [DOI] [PubMed] [Google Scholar]
  40. Whittaker M., Wilson-Kubalek E. M., Smith J. E., Faust L., Milligan R. A., Sweeney H. L. A 35-A movement of smooth muscle myosin on ADP release. Nature. 1995 Dec 14;378(6558):748–751. doi: 10.1038/378748a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES