Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform
Open accessAbstract
Background— Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1α (also called α-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear. Methods and Results— In this study, we quantified for the first time the levels of striated muscle TM isoforms in human heart, including a novel isoform called TPM1κ. By developing a TPM1κ-specific antibody, we found that the TPM1κ protein is expressed and incorporated into organized myofibrils in hearts and that its level is increased in human dilated cardiomyopathy and heart failure. To investigate the role of TPM1κ in sarcomeric function, we generated transgenic mice overexpressing cardiac-specific TPM1κ. Incorporation of increased levels of TPM1κ protein in myofilaments leads to dilated cardiomyopathy. Physiological alterations include decreased fractional shortening, systolic and diastolic dysfunction, and decreased myofilament calcium sensitivity with no change in maximum developed tension. Additional biophysical studies demonstrate less structural stability and weaker actin-binding affinity of TPM1κ compared with TPM1α. Conclusions— This functional analysis of TPM1κ provides a possible mechanism for the consequences of the TM isoform switch observed in dilated cardiomyopathy and heart failure patients.
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A second TPM1 isoform was significantly upregulated (logFC, 0.73; adj.P, 3.9e-2) and differed from the canonical TPM1 sequence by residues 41-80 by MXE, corresponding to the TPM1 kappa isoform (P09493-6) on SwissProt that was previously found in single-target immunobiological studies to be increased in dilated cardiomyopathy patients.
“The second isoform was significantly upregulated (logFC, 0.73; adj.P, 3.9e–2) and differed from the canonical TPM1 sequence by residues 41–80 by MXE, corresponding to the TPM1 kappa isoform (P09493–6) on SwissProt that was previously found in single-target immunobiological studies to be increased in dilated cardiomyopathy patients (Rajan et al., 2010).”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Rajan et al., 2010
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Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome
Lau, E., Han, Y., Williams, D. R., Thomas, C. T., Shrestha, R., Wu, J. C., & Lam, M. P. Y. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.026 · Cited by 67 · see citing works
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- Authors
- Rajan, S., Jagatheesan, G., Karam, C. N., Alves, M. L., Bodi, I., Schwartz, A., Bulcao, C. F., D'Souza, K. M., Akhter, S. A., Boivin, G. P., Dube, D. K., Petrashevskaya, N., Herr, A. B., Hullin, R., Liggett, S. B., Wolska, B. M., Solaro, R. J., & Wieczorek, D. F.
- Affiliations
- University of Maryland Medical Center (US)
- From the Department of Molecular Genetics, Biochemistry, and Microbiology (S.R., G.J., A.B.H., D.F.W.), Institute of Molecular Pharmacology and Biophysics (I.B., A.S.), Department of Surgery, Section of Cardiothoracic Surgery (C.F.B., K.M.D., S.A.A.), and Department of Pathology and Laboratory Medicine (G.P.B.), University of Cincinnati Medical Center, Cincinnati, Ohio; Department of Physiology and Biophysics (C.N.K., M.L.A., B.M.W., R.J.S.), University of Illinois, Chicago; Department of Medicine ...
- ORCID
- Venue
- Circulation
- Published
- 2010-01-26
- Volume
- 121
- Issue
- 3
- Pages
- 410-418
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2822663
- OpenAlex
- W2147694838
- Cited by
- 92
- References
- 46
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 8 · 2017: 7 · 2016: 6 · 2015: 4 · 2014: 8 · 2013: 12 · 2012: 6
- FWCI
- 6.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion, other-oa)
- Funders
- National Heart, Lung, and Blood Institute (HL062426, R01HL081680, HL 22231, HL-081680, R01HL022231, R01HL079032, HL79032, R37HL022231, P01HL062426)
- 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 › Cardiac electrophysiology and arrhythmias
- Keywords
- tropomyosin, dilated cardiomyopathy, heart failure, myofibrils, myofilament calcium sensitivity, actin binding affinity, transgenic mice, cardiomyocyte contractility, striated muscle contraction
- MeSH terms
- Actins, Adult, Animals, Calcium, Cardiomyopathy, Dilated, Female, Heart Failure, Homeostasis, Humans, Isomerism, Male, Mice, Transgenic, Actin Cytoskeleton, Myocardial Contraction, Myocardium, Myofibrils, Temperature, Tropomyosin, Gene Expression, Dimerization, Protein Isoforms, Mice
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