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Differential Expression of Cardiac Titin Isoforms and Modulation of Cellular Stiffness
Open accessAbstract
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.
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“Human ventricles express both compliant N2BA and stiff N2B titin isoforms with a relative N2BA:N2B ratio of ~0.4–1.2”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Cazorla, et al., 2000
In the citing paper
“Mouse and rat predominately express N2B titin and considerably lower N2BA titin isoform with N2BA:N2B ratio ranges of ~0.05–0.25 in mouse and ~0.06–0.1 in rat”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Cazorla, et al., 2000
In the citing paper
“Both compliant N2BA and stiff N2B isoforms are expressed in canines (N2BA:N2B ratio of ~ 0.6–1) and humans (N2BA:N2B ratio of ~0.4–1.2) (Bell, et al., 2000; Cazorla, et al., 2000; Jaber, et al., 2008; Makarenko, et al., 2004; Nagueh, et al., 2004).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Cazorla, et al., 2000
In the citing paper
“Both stiff N2B and compliant N2BA titin isoforms are expressed at considerable levels in swine myocardium (Cazorla, et al., 2000; Chung, et al., 2011; Opitz & Linke, 2005).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Cazorla, et al., 2000
In the citing paper
“the swine expresses more N2BA isoform (N2BA:N2B ratio of 1–1.5) than humans (N2BA:N2B ratio of 0.4–1.2) (Cazorla, et al., 2000; Chung, et al., 2011; Makarenko, et al., 2004; Nagueh, et al., 2004).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Cazorla, et al., 2000
In the citing paper
“Sheep and human left ventricles express both major titin isoforms in considerable amounts with N2BA:N2B ratios of ~0.35–0.43 and ~0.4–1.2, respectively (Cazorla, et al., 2000; Kruger & Linke, 2006; Makarenko, et al., 2004; Nagueh, et al., 2004; Neagoe, et al., 2003).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Cazorla, et al., 2000
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Cites
Reversible Unfolding of Individual Titin Immunoglobulin Domains by AFM
Rief, M., Gautel, M., Oesterhelt, F., Fernández, J. M., & Gaub, H. E. (1997) · Science · doi:10.1126/science.276.5315.1109 · Cited by 3,081
Titins: Giant Proteins in Charge of Muscle Ultrastructure and Elasticity
Labeit, S., & Kolmerer, B. (1995) · Science · doi:10.1126/science.270.5234.293 · Cited by 1,257
Self-citationFolding-Unfolding Transitions in Single Titin Molecules Characterized with Laser Tweezers
Kellermayer, M., Smith, S. B., Granzier, H. L., & Bustamante, C. (1997) · Science · doi:10.1126/science.276.5315.1112 · Cited by 1,217
Self-citationGranzier, H. L., & Irving, T. C. (1995) · Biophysical Journal · doi:10.1016/s0006-3495(95)80278-x · Cited by 638
Self-citationGregorio, C. C., Trombitás, K., Centner, T., Kolmerer, B., Stier, G., Kunke, K., Suzuki, K., Obermayr, F., Herrmann, B. G., Granzier, H. L. M., et al. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.143.4.1013 · Cited by 328
Self-citationMuscle assembly: a titanic achievement?
Gregorio, C. C., Granzier, H., Sorimachi, H., & Labeit, S. (1999) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(99)80003-9 · Cited by 327
Self-citationTowards a Molecular Understanding of the Elasticity of Titin
Linke, W. A., Ivemeyer, M., Olivieri, N., Kolmerer, B., Rüegg, C., & Labeit, S. (1996) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0441 · Cited by 287
Self-citationFabiato, A., & Fabiato, F. (1978) · The Journal of General Physiology · doi:10.1085/jgp.72.5.667 · Cited by 270
Titin Develops Restoring Force in Rat Cardiac Myocytes
Helmes, M., ́s, K. ́. T., & Granzier, H. (1996) · Circulation Research · doi:10.1161/01.res.79.3.619 · Cited by 260
Self-citationLabeit, S., Kolmerer, B., & Linke, W. A. (1997) · Circulation Research · doi:10.1161/01.res.80.2.290 · Cited by 251
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New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part I
Zile, M. R., & Brutsaert, D. L. (2002) · Circulation · doi:10.1161/hc1102.105289 · Cited by 1,185
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Metadata
- Authors
- Cazorla, O., Freiburg, A., Helmes, M., Centner, T., McNabb, M., Wu, Y., Trombitás, K., Labeit, S., & Granzier, H.
- Affiliations
- European Molecular Biology Laboratory (DE)
- 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.
- Venue
- Circulation Research
- Published
- 2000-01-07
- Volume
- 86
- Issue
- 1
- Pages
- 59-67
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2114879284
- Cited by
- 418
- References
- 36
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 17 · 2023: 15 · 2022: 12 · 2021: 21 · 2020: 14 · 2019: 13 · 2018: 21 · 2017: 20 · 2016: 12 · 2015: 17 · 2014: 9 · 2013: 14 · 2012: 15
- FWCI
- 14.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- American Heart Association (HL62881)
- Washington State University
- Deutsche Forschungsgemeinschaft
- National Heart, Lung, and Blood Institute (R01HL061497, HL-62881, R01HL062881, HL 61497)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- titin isoforms, differential splicing, diastolic stiffness, cardiomyocytes, species differences, sarcomere length, myocardium
- MeSH terms
- Animals, Diastole, Elasticity, Fluorescent Antibody Technique, Heart, Muscle Proteins, Myocardium, Protein Kinases, Swine, Blotting, Western, Electrophoresis, Gel, Two-Dimensional, Protein Isoforms, Mice, Rats, Connectin
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