© 2000 American Heart Association, Inc.
Cellular Biology |
Differential Expression of Cardiac Titin Isoforms and Modulation of Cellular Stiffness
From the Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology (O.C., M.H., M.M., Y.W., K.T., H.G.), Washington State University, Pullman, Wash; the Institut für Anästhesiologie und Operative Intensivmedizin (A.F., T.C., S.L.), Universitätsklinikum, Mannheim, Germany; and European Molecular Biology Laboratory (T.C., S.L.), Heidelberg, Germany.
Correspondence to Henk Granzier, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Wegner Hall 205, Washington State University, Pullman, WA 99164-6520. E-mail granzier{at}wsunix.wsu.edu
Abstract—Extension of the I-band
segment of titin gives rise to part of the diastolic force
of cardiac muscle. Previous studies of human cardiac titin transcripts
suggested a series of differential splicing events in the I-band
segment of titin leading to the so-called N2A and N2B isoform
transcripts. Here we investigated titin expression at the protein level
in a wide range of mammalian species. Results indicate that the
myocardium coexpresses 2 distinct titin isoforms: a smaller
isoform containing the N2B element only (N2B titin) and a larger
isoform with both the N2B and N2A elements (N2BA titin). The expression
ratio of large N2BA to small N2B titin isoforms was found to vary
greatly in different species; eg, in the left ventricle the ratio is
0.05 in mouse and 1.5 in pig. Differences in the expression ratio
were also found between atria and ventricles and between different
layers of the ventricular wall.
Immunofluorescence experiments with
isoform-specific antibodies suggest that coexpression of these isoforms
takes place at the single-myocyte level. The diastolic
properties of single cardiac myocytes isolated from various species
expressing high levels of the small (rat and mouse) or large (pig)
titin isoform were studied. On average, pig myocytes are significantly
less stiff than mouse and rat myocytes. Gel analysis indicates
that this result cannot be explained by varying amounts of titin in
mouse and pig myocardium. Rather, low stiffness of pig
myocytes can be explained by its high expression level of the large
isoform: the longer extensible region of this isoform results in a
lower fractional extension for a given sarcomere length and hence a
lower force. Implications of our findings to cardiac function are
discussed.
Key Words: compliance • passive tension • diastolic force • mechanical properties • myocyte • connectin
This article has been cited by other articles:
 |
|
 |
|
  A. Kontrogianni-Konstantopoulos, M. A. Ackermann, A. L. Bowman, S. V. Yap, and R. J. Bloch Muscle Giants: Molecular Scaffolds in Sarcomerogenesis Physiol Rev, October 1, 2009; 89(4): 1217 - 1267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Matsuba, T. Terui, J. O-Uchi, H. Tanaka, T. Ojima, I. Ohtsuki, S. Ishiwata, S. Kurihara, and N. Fukuda Protein kinase A-dependent modulation of Ca2+ sensitivity in cardiac and fast skeletal muscles after reconstitution with cardiac troponin J. Gen. Physiol., June 1, 2009; 133(6): 571 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G Campbell, S. N Flaim, C. H Leem, and A. D McCulloch Mechanisms of transmurally varying myocyte electromechanics in an integrated computational model Phil Trans R Soc A, September 28, 2008; 366(1879): 3361 - 3380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Jaber, C. Maniu, J. Krysiak, B. P. Shapiro, D. M. Meyer, W. A. Linke, and M. M. Redfield Titin Isoforms, Extracellular Matrix, and Global Chamber Remodeling in Experimental Dilated Cardiomyopathy: Functional Implications and Mechanistic Insight Circ Heart Fail, September 1, 2008; 1(3): 192 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. A. Shiels and E. White The Frank-Starling mechanism in vertebrate cardiac myocytes J. Exp. Biol., July 1, 2008; 211(13): 2005 - 2013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. L. Nelson, C. T. Robbins, Y. Wu, and H. Granzier Titin isoform switching is a major cardiac adaptive response in hibernating grizzly bears Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H366 - H371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Linke Sense and stretchability: The role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction Cardiovasc Res, March 1, 2008; 77(4): 637 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Pinz, J. Robbins, N. S. Rajasekaran, I. J. Benjamin, and J. S. Ingwall Unmasking different mechanical and energetic roles for the small heat shock proteins CryAB and HSPB2 using genetically modified mouse hearts FASEB J, January 1, 2008; 22(1): 84 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Joumaa, D. E. Rassier, T. R. Leonard, and W. Herzog The origin of passive force enhancement in skeletal muscle Am J Physiol Cell Physiol, January 1, 2008; 294(1): C74 - C78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. D. Jobsis, H. Ashikaga, H. Wen, E. C. Rothstein, K. A. Horvath, E. R. McVeigh, and R. S. Balaban The visceral pericardium: macromolecular structure and contribution to passive mechanical properties of the left ventricle Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3379 - H3387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Granzier, M. Radke, J. Royal, Y. Wu, T. C. Irving, M. Gotthardt, and S. Labeit Functional genomics of chicken, mouse, and human titin supports splice diversity as an important mechanism for regulating biomechanics of striated muscle Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2007; 293(2): R557 - R567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. F. Edes, D. Czuriga, G. Csanyi, S. Chlopicki, F. A. Recchia, A. Borbely, Z. Galajda, I. Edes, J. van der Velden, G. J. M. Stienen, et al. Rate of tension redevelopment is not modulated by sarcomere length in permeabilized human, murine, and porcine cardiomyocytes Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R20 - R29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Garcia-Webb, A. J. Taberner, N. C. Hogan, and I. W. Hunter A modular instrument for exploring the mechanics of cardiac myocytes Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H866 - H874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Marian Phenotypic Plasticity of Sarcomeric Protein Mutations J. Am. Coll. Cardiol., June 26, 2007; 49(25): 2427 - 2429. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wu, Y. Yu, and S. J. Kovacs Contraction-relaxation coupling mechanism characterization in the thermodynamic phase plane: normal vs. impaired left ventricular ejection fraction J Appl Physiol, April 1, 2007; 102(4): 1367 - 1373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Peng, K. Raddatz, J. D. Molkentin, Y. Wu, S. Labeit, H. Granzier, and M. Gotthardt Cardiac Hypertrophy and Reduced Contractility in Hearts Deficient in the Titin Kinase Region Circulation, February 13, 2007; 115(6): 743 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Cazorla, Y. Ait Mou, L. Goret, G. Vassort, M. Dauzat, A. Lacampagne, S. Tanguy, and P. Obert Effects of high-altitude exercise training on contractile function of rat skinned cardiomyocyte Cardiovasc Res, September 1, 2006; 71(4): 652 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Hinken, F. S. Korte, and K. S. McDonald Porcine cardiac myocyte power output is increased after chronic exercise training J Appl Physiol, July 1, 2006; 101(1): 40 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. A. Shiels, S. C. Calaghan, and E. White The Cellular Basis for Enhanced Volume-modulated Cardiac Output in Fish Hearts J. Gen. Physiol., June 26, 2006; 128(1): 37 - 44. [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]
|
|
|
|
|
|
Y. L. Protsenko, S. M. Routkevitch, V. Y. Gur'ev, L. B. Katsnelson, O. Solovyova, O. N. Lookin, A. A. Balakin, P. Kohl, and V. S. Markhasin Hybrid duplex: a novel method to study the contractile function of heterogeneous myocardium Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2733 - H2746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Lim and D. B. Sawyer Modulation of Cardiac Function: Titin Springs into Action J. Gen. Physiol., February 28, 2005; 125(3): 249 - 252. [Full Text] [PDF]
|
|
|
|
|
|
N. Fukuda, Y. Wu, P. Nair, and H. L. Granzier Phosphorylation of Titin Modulates Passive Stiffness of Cardiac Muscle in a Titin Isoform-dependent Manner J. Gen. Physiol., February 28, 2005; 125(3): 257 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Fujita, D. Labeit, B. Gerull, S. Labeit, and H. L. Granzier Titin isoform-dependent effect of calcium on passive myocardial tension Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2528 - H2534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. LeWinter Titin Isoforms in Heart Failure: Are There Benefits to Supersizing? Circulation, July 13, 2004; 110(2): 109 - 111. [Full Text] [PDF]
|
|
|
|
|
|
S. F. Nagueh, G. Shah, Y. Wu, G. Torre-Amione, N. M.P. King, S. Lahmers, C. C. Witt, K. Becker, S. Labeit, and H. L. Granzier Altered Titin Expression, Myocardial Stiffness, and Left Ventricular Function in Patients With Dilated Cardiomyopathy Circulation, July 13, 2004; 110(2): 155 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. Lim, C. Zuppinger, X. Guo, G. M. Kuster, M. Helmes, H. M. Eppenberger, T. M. Suter, R. Liao, and D. B. Sawyer Anthracyclines Induce Calpain-dependent Titin Proteolysis and Necrosis in Cardiomyocytes J. Biol. Chem., February 27, 2004; 279(9): 8290 - 8299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. L. Granzier and S. Labeit The Giant Protein Titin: A Major Player in Myocardial Mechanics, Signaling, and Disease Circ. Res., February 20, 2004; 94(3): 284 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ashikaga, J. C. Criscione, J. H. Omens, J. W. Covell, and N. B. Ingels Jr. Transmural left ventricular mechanics underlying torsional recoil during relaxation Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H640 - H647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Fukuda, Y. Wu, G. Farman, T. C Irving, and H. Granzier Titin isoform variance and length dependence of activation in skinned bovine cardiac muscle J. Physiol., November 15, 2003; 553(1): 147 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Rankinen, T. Rice, A. Boudreau, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard Titin is a candidate gene for stroke volume response to endurance training: the HERITAGE Family Study Physiol Genomics, September 29, 2003; 15(1): 27 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Warren, M. C. Jordan, K. P. Roos, P. R. Krzesinski, and M. L. Greaser Titin isoform expression in normal and hypertensive myocardium Cardiovasc Res, July 1, 2003; 59(1): 86 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Huang, Q. Zhou, P. Liang, M. S. Hollander, F. Sheikh, X. Li, M. Greaser, G. D. Shelton, S. Evans, and J. Chen Characterization and in Vivo Functional Analysis of Splice Variants of Cypher J. Biol. Chem., February 21, 2003; 278(9): 7360 - 7365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hein, W. H. Gaasch, and J. Schaper Giant Molecule Titin and Myocardial Stiffness Circulation, September 10, 2002; 106(11): 1302 - 1304. [Full Text] [PDF]
|
|
|
|
|
|
Y. Wu, S. P. Bell, K. Trombitas, C. C. Witt, S. Labeit, M. M. LeWinter, and H. Granzier Changes in Titin Isoform Expression in Pacing-Induced Cardiac Failure Give Rise to Increased Passive Muscle Stiffness Circulation, September 10, 2002; 106(11): 1384 - 1389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Rankinen, P. An, L. Perusse, T. Rice, Y. C. Chagnon, J. Gagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, et al. Genome-wide linkage scan for exercise stroke volume and cardiac output in the HERITAGE Family Study Physiol Genomics, August 14, 2002; 10(2): 57 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A J Natali, L A Wilson, M Peckham, D L Turner, S M Harrison, and E White Different regional effects of voluntary exercise on the mechanical and electrical properties of rat ventricular myocytes J. Physiol., June 15, 2002; 541(3): 863 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Yamasaki, Y. Wu, M. McNabb, M. Greaser, S. Labeit, and H. Granzier Protein Kinase A Phosphorylates Titin's Cardiac-Specific N2B Domain and Reduces Passive Tension in Rat Cardiac Myocytes Circ. Res., June 14, 2002; 90(11): 1181 - 1188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Granzier and S. Labeit Cardiac titin: an adjustable multi-functional spring J. Physiol., June 1, 2002; 541(2): 335 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Toursel, L. Stevens, H. Granzier, and Y. Mounier Passive tension of rat skeletal soleus muscle fibers: effects of unloading conditions J Appl Physiol, April 1, 2002; 92(4): 1465 - 1472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Zile and D. L. Brutsaert New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part II: Causal Mechanisms and Treatment Circulation, March 26, 2002; 105(12): 1503 - 1508. [Full Text] [PDF]
|
|
|
|
|
|
K. Watanabe, P. Nair, D. Labeit, M. S. Z. Kellermayer, M. Greaser, S. Labeit, and H. Granzier Molecular Mechanics of Cardiac Titin's PEVK and N2B Spring Elements J. Biol. Chem., March 22, 2002; 277(13): 11549 - 11558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Dong, P. S. Hees, C. O. Siu, J. L. Weiss, and E. P. Shapiro MRI assessment of LV relaxation by untwisting rate: a new isovolumic phase measure of tau Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2002 - H2009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Sutko, N. G. Publicover, and R. L. Moss Titin: An Elastic Link Between Length and Active Force Production in Myocardium Circulation, October 2, 2001; 104(14): 1585 - 1587. [Full Text] [PDF]
|
|
|
|
|
|
N. Fukuda, D. Sasaki, S.'i. Ishiwata, and S. Kurihara Length Dependence of Tension Generation in Rat Skinned Cardiac Muscle: Role of Titin in the Frank-Starling Mechanism of the Heart Circulation, October 2, 2001; 104(14): 1639 - 1645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Trombitas, Y. Wu, D. Labeit, S. Labeit, and H. Granzier Cardiac titin isoforms are coexpressed in the half-sarcomere and extend independently Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1793 - H1799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Bell, L. Nyland, M. D. Tischler, M. McNabb, H. Granzier, and M. M. LeWinter Alterations in the Determinants of Diastolic Suction During Pacing Tachycardia Circ. Res., August 4, 2000; 87(3): 235 - 240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Freiburg, K. Trombitas, W. Hell, O. Cazorla, F. Fougerousse, T. Centner, B. Kolmerer, C. Witt, J. S. Beckmann, C. C. Gregorio, et al. Series of Exon-Skipping Events in the Elastic Spring Region of Titin as the Structural Basis for Myofibrillar Elastic Diversity Circ. Res., June 9, 2000; 86(11): 1114 - 1121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Cazorla, Y. Wu, T. C. Irving, and H. Granzier Titin-Based Modulation of Calcium Sensitivity of Active Tension in Mouse Skinned Cardiac Myocytes Circ. Res., May 25, 2001; 88(10): 1028 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-L. Bang, T. Centner, F. Fornoff, A. J. Geach, M. Gotthardt, M. McNabb, C. C. Witt, D. Labeit, C. C. Gregorio, H. Granzier, et al. The Complete Gene Sequence of Titin, Expression of an Unusual {approx}700-kDa Titin Isoform, and Its Interaction With Obscurin Identify a Novel Z-Line to I-Band Linking System Circ. Res., November 23, 2001; 89(11): 1065 - 1072. [Abstract] [Full Text] [PDF]
|
|