Rescuing Cardiovascular Disease Caused by Tropomyosin Mutations
Main Article Content
Abstract
Cardiovascular diseases are a leading cause of death worldwide and health care expenditure. There are a variety of treatments for individuals diagnosed with cardiovascular disease depending upon the severity of symptoms, which include diet and exercise, medications, stents, and newly-developed gene therapies and drugs. The focus of this article will be on the molecular and biochemical mechanisms of how different genetic mutations in cardiac sarcomeric contractile proteins can lead to cardiomyopathic disease in mice. We will use the tropomyosin gene family and its associated proteins as a paradigm to illustrate the wide variety of clinical phenotypes that mutations in tropomyosin can impart. Potential therapeutic approaches for the rescue of cardiomyopathies, such as normalization of myofilament calcium sensitivity and introduction of chimeric genes/proteins, will be discussed as examples of “proof-of-concept” ideas. Researchers stand on the precipice of making exponential advances in the treatment of cardiovascular diseases – let us hope that we can soon take that forward step into this promising future.
Article Details
How to Cite
WIECZOREK, David F..
Rescuing Cardiovascular Disease Caused by Tropomyosin Mutations.
Medical Research Archives, [S.l.], v. 13, n. 9, sep. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6843>. Date accessed: 14 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i9.6843.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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45. Prabhakar R, Boivin G, Grupp I, et al. A familial hypertrophic cardiomyopathy α-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. J Mol Cell Cardiol 2001; 33:1815-1828.
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55. Takimoto E, Kass D. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 2007; 49:241-248.
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2. Brieler J, Breeden M, Tucker J. Cardiomyopathy: an overview. Am Fam Physician 2017; 96:641-646.
3. Jagatheesan G, Rajan S, Wieczorek DF. Investigations into tropomyosin function using mouse models. J Mol Cell Cardiol 2010; 48:893-898.
4. Wieczorek DF, Smith C, Nadal-Ginard B. The rat α-tropomyosin gene generates a minimum of six different mRNAs coding for striated, smooth, and nonmuscle isoforms by alternative splicing. Mol Cell Biol 1988; 8:679-694.
5. Vrhovski B, Theze N, Thiebaud P. Structure and evolution of tropomyosin genes. Adv Exp Med Biol 2008; 644:6-26.
6. Lees-Miller J, Helfman D. The molecular basis for tropomyosin isoform diversity. Bioessays 1991; 13:429-437.
7. Rajan S, Jagatheesan G, Karam C, et al. Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform. Circulation 2010; 121:410-418.
8. Denz C, Narshi A, Zajdel R, et al. Expression of a novel cardiac-specific tropomyosin isoform in humans. Biochem Biophys Res Commun 2004; 320:1291-1297.
9. Rethinasamy P, Muthuchamy M, Hewett T, et al. Molecular and physiological effects of a-tropomyosin ablation in the mouse. Circ Res 1998; 82:116-123.
10. Jagatheesan G, Rajan S, Petrashevskaya N, et al. Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis. Am J Physiol Heart Circ Physiol 2007; 293:H949-H958.
11. Jagatheesan G, Rajan S, Ahmed R, et al. Striated muscle tropomyosin isoforms differentially regulate cardiac performance and myofilament calcium sensitivity. J Muscle Res Cell Motil 2010; 31:227-239.
12. Muthuchamy M, Grupp I, Grupp H, et al. Molecular and physiological effects of overexpressing striated muscle β-tropomyosin in the adult murine heart. J Biol Chem 1995; 270:30593-30603.
13. Palmiter K, Kitada Y, Muthuchamy M, et al. Exchange of β- for α-tropomyosin in hearts of transgenic mice induces changes in thin filament response to Ca2+, strong cross-bridge binding, and protein phosphorylation. J Biol Chem 1996; 271: 11611-11614.
14. Muthuchamy M, Pieples K, Rethinasamy P, et al., Mouse model of a familial hypertrophic cardiomyopathy mutation in α-tropomysoin manifests cardiac dysfunction. Circ Res 1999; 85:47-56.
15. Coumans J, Yeoh R, Seeto R, et al. Variations in the relative mRNA levels of actins and myosin heavy chains do not produce corresponding differences in their proteins in the adult human heart. J Mol Cell Cardiol. 1997;29:895-905.
16. Miyata S, Minobe W, Bristow M, et al. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res. 2000; 86:386-390.
17. Coutu P, Bennett C, Favre E, et al. Parvalbumin corrects slowed relaxation in adult cardiac myocytes expressing hypertrophic cardiomyopathy-linked alpha-tropomyosin mutations. Circ Res. 2004; 94: 1235-1241.
18. Greenberg B. Gene therapy for heart failure. J Cardiol 2015; 66:195-200.
19. Muthuchamy M, Pajak L, Howles, P. et al. Developmental analysis of tropomyosin gene expression in embryonic stem cells and mouse embryos. Mol Cell Biol 1993; 13:3311-3323.
20. Dehann R. Morphogenesis of the vertebrate heart. In R. L. DeHann and H. Ursprung (ed.), Organogenesis. Holt, Rinehart & Winston, New York, 1965; pp. 377-419.
21. Snell G, Stevens L. Early embryology. In E. Green (ed.), Biology of the laboratory mouse. Dover Publications, Inc., New York, 1965; pp. 205-245.
22. Sanchez A, Jones W, Gulick J, et al. Myosin heavy chain gene expression in mouse embryoid bodies. An in vitro developmental study. J. Biol Chem 1991; 266:22419-22426.
23. Blanchard E, Iizuka K, Christe M, et al., Targeted ablation of the murine α-tropomyosin gene. Circ Res 1997; 81:1005-1010.
24. Hook J, Lemckert F, Qin H, et al. Gamma tropomyosin gene products are required for embryonic development. Mol Cell Biol 2004; 2318-2323.
25. Fath T, Chan Y-K, Vrhovski B, et al. New aspects of tropomyosin-regulated neuritogenesis revealed by the deletion of Tm5NM1 and 2. Euro J Cell Biol 2010;89:489-498.
26. Liu H, Bretscher A. Disruption of the single tropomyosin gene in yeast results in the disappearance of actin cables from the cytoskeleton. Cell 1989; 57:233-242.
27. Balasubramanian M, Helfman D, Hemmingsen S. A new tropomyosin essential for cytokinesis in the fission yeast S. pombe. Nature 1992; 360:84-87.
28. Karlik C, Fyrberg E. An insertion within a variably spliced Drosophila tropomyosin gene blocks accumulation on only ne encoded isoform. Cell 1985; 41:57-66.
29. Beall C, Sepanski M, Fryberg E. Genetic dissection of Drosophila myofibril formation: effects of actin and myosin heavy chain null alleles. Genes Dev 1989; 3:131-140.
30. Lemanski L. Morphology of developing heart in cardiac lethal mutant Mexican axolotls, Ambystoma mexicanum. Dev Biol 1973; 33:313-333.
31. Kumar A, Crawford K, Close L, et al, Rescue of cardiac α-actin-deficient mice by enteric smooth muscle γ-actin. Proc Natl Acad Sci USA 1997; 94: 4406-4411.
32. Jones W, Grupp I, Doetschman T, et al. Ablation of the murine α-myosin heavy chain gene leads to dosage effects and functional deficits in the heart. J Clin Invest 1996; 98:1906-1917.
33. Jagatheesan G, Rajan S, Petrashevskaya N, et al., Physiological significance of troponin T binding domains in striated muscle tropomyosin. Am J Physiol Heart Circ Physiol 2004; 287:H1484-H1494.
34. Muthuchamy M., Boivin G, Grupp I, et al., b-tropomyosin overexpression induces severe cardiac abnormalities. J Mol Cell Cardiol 1998; 30:1545-1557.
35. Prabhakar R, Boivin G, Hoit B, et al., Rescue of high expression β-tropomyosin transgenic mice by 5-propyl-2-thiouracil. J Biol Chem 1999; 274:295 58-29563.
36. Sussman M, Lim H, Gude N, et al., Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science 1998; 281:1690-1693.
37. Jagatheesan G, Rajan S, Petrashevskaya N, et al. Functional importance of the carboxyl-terminal region of striated muscle tropomyosin. J Biol Chem 2003; 278:23204-23211.
38. Jagatheesan G, Rajan S, Schulz E, et al. An internal domain of β-tropomyosin increases myofilament Ca2+ sensitivity. Am J Physiol Heat Circ Physiol 2009; 297:H181-H190.
39. Pieples K, Wieczorek DF. Tropomyosin 3 increases striated muscle isoform diversity. Biochemistry 2000; 39:8291-8297.
40. Pieples K, Arteaga G, Solaro RJ, et al. Tropomyosin 3 expression leads to hypercontractility and attenuates myofilament length-0dependent Ca2+ activation. Am J Physiol Heart Circ Physiol 2002; 283:H1344-H1353.
41. Geisterfer-Lowrance A, Kass S, Tanigawa G et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 1990; 62:999-1006.
42. Wieczorek D. Cardiomyopathy: getting bigger all the time – lessons learned about heart disease from tropomyosin. In Cardiomyopathy – Disease of the Heart Muscle (ed. G. Mattson and P Magnusson). London, UK. 2021; pp. 287-303.
43. Thierfelder L, Watkins H, MacRae C, et al., α-tropomyosin and cardiac troponinT mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 1994; 77:701-712.
44. Wieczorek DF. Sarcomeric thin filament associated cardiomyopathic mouse models. Med Res Arch 2023; 11(9). http://doi.org/10.18103/mra.v11i9.4369.
45. Prabhakar R, Boivin G, Grupp I, et al. A familial hypertrophic cardiomyopathy α-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. J Mol Cell Cardiol 2001; 33:1815-1828.
46. Prabhakar R, Petrashevskaya N, Schwartz A, et al. A mouse model of familial hypertrophic cardiomyopathy caused by a α-tropomyosin mutation. Mol Cell Biochem 2003; 251:33-42.
47. Wieczorek DF, Wolska B. Rescue of familial hypertrophic cardiomyopathy -by altering sarcomeric exposure and response to calcium. In Gene Therapy Applications. Kang C, (ed); Rijeka, Croatia: Intech. 2011; pp.85-94.
48. Gaffin R., Pena J, Alves M, et al. Long-term rescue of a familial hypertrophic cardiomyopathy caused by a mutation in the thin filament protein, tropomyosin, via modulation of a calcium cycling protein. J Mol Cell Cardiol 2011; 51:812-820.
49. Rajan S, Pena J, Jegga A et al. Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout. Physiol Genomics 2013;45:764-773.
50. Pena J, Szkudlarek A, Warrren C, et al. Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 2010; 49:993-1002.
51. Jaski B, Jessup M, Mancini D, et al., Calcium upregulation by percutaneous administration of gene therapy in cardiac diseases (CUPID trial), a first-in-human phase ½ clinical trial. J Card Fail 2009; 15:171-181.
52. Gwathmey J, Yerevanian A, Hajjar R. Cardiac gene therapy with SERCA2a: from bench to bedside. J Mol Cell Cardiol 2011; 50:803-812.
53. Wilder, T, Ryba D, Wieczorek DF, et al., N-acetylcysteine reverses diastolic dysfunction and hypertrophy in familial hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 2015; 309:H1720-H1730.
54. Seddon M, Looi Y, Shah A. Oxidative stress and redox signaling in cardiac hypertrophy and heart failure. Heart 2007; 93:903-907.
55. Takimoto E, Kass D. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 2007; 49:241-248.
56. Liu, W, Zi M, Tsui H, et al., A novel immunomodulator, FTY-720 reverses existing cardiac hypertrophy and fibrosis from pressure overload by targeting NFAT (nuclear factor of activated T-cells) signaling and periostin. Circ Heart Fail 2013; 6:833-844.
57. Ryba D, Warren C, Karam C, et al. The sphingosine-1-phosphoate receptor modulator, FTY720, improves diastolic dysfunction and partially reveres atrial remodeling in a Tm-E180G mouse model linked to hypertrophic cardiomyopathy. Circ Heart Fail November ; 12(11): e005835. doi:10.116 1/CIRCHEARTFAILURE.118.005835
58. Wong S, Geng H-Z, Jin H-P. The evolutionary conserved C-terminal peptide of troponin I is an independently configured regulatory structure to function as a myofilament Ca2+-desensitizer. J Mol Cell Cardiol 2019; 136:42-52.
59. Hornos F, Feng H-Z, Rizzuti B, et al. The muscle-relaxing C-terminal peptide from troponin I populates a nascent helix, facilitating binding to tropomyosin with a potent therapeutic effect. J Biol Chem 2021; 296:100228. doi: 10.1074/jbc.RA120.016012
60. Hershberger R, Hedges D, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat. Rev. Cardiol. 2013;10:531-547.
61. Wieczorek DF. Dilated cardiomyopathy – exploring the underlying causes. Medical Research Arch 12(12).
https://doi.org/10.18103/mrav12i12.6111
62. Olson T, Kishimoto N, Whitby F, et al. Mutation that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. J. Mol Cell Cardiol 2001;33:723-732.
63. Rajan S, Ahmed R, Jagatheesan G. et al., Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity. Circ Res 2007; 101:205-214.
64. Warren C, Arteaga G, Rajan S, et al., Use of 2-D DIGE analysis reveals altered phosphorylation in a tropomyosin mutant Glu54Lys) linked to dilated cardiomyopathy. Proteomics 2008; 8:100-105.
65. Mak A, Smillie L, Barany M. Specific phosphorylation at serine-283 of alpha tropomyosin from frog skeletal and rabbit skeletal and cardiac muscle. Proc Natl Acad Sci USA 1978; 75:3588-3592.
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