Sarcomeric Thin Filament Associated Cardiomyopathic Mouse Models
Main Article Content
Abstract
Cardiomyopathies are diseases primarily associated with defects in the structure and physiological function of the heart. Hypertrophic and dilated cardiomyopathies are two common conditions associated with severe pathological abnormalities that often lead to heart failure. Studies in the early 1990’s by the Seidman laboratories linked hypertrophic cardiomyopathy with mutations in both thick and thin sarcomeric protein genes. Since then, the development and analysis of animal models of both hypertrophic and dilated cardiomyopathy has significantly advanced our knowledge of the structural, molecular, biochemical, and physiological disease processes that lead to these cardiomyopathic conditions. The focus of this article is an examination of mouse models of hypertrophic and dilated cardiomyopathies with mutations in sarcomeric thin filament protein genes (actin, tropomyosin, troponin T, I, and C) and the information these models provide in our understanding of the disease processes. Special attention addresses the significant role that tropomyosin mutation models have contributed to this information. In addition, we address how various methods have been developed to phenotypically rescue these diseased hearts with respect to their morphological and physiological functions. By thorough analysis of these mouse models, not only can we better understand the disease processes, but there is a great potential for the development of effective therapeutics to treat these severe pathological conditions.
Article Details
How to Cite
WIECZOREK, David F..
Sarcomeric Thin Filament Associated Cardiomyopathic Mouse Models.
Medical Research Archives, [S.l.], v. 11, n. 9, sep. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4369>. Date accessed: 15 may 2024.
doi: https://doi.org/10.18103/mra.v11i9.4369.
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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6. Marian AJ. Molecular genetic basis of hypertrophic cardiomyopathy. Circ Res. 2021;128:1533-1553.
7. Maron B, Desai M, Nishimura R, et al. Diagnosis and evaluation of hypertrophic cardiomyopathy. J Am Coll Cardiol 2022;79:372-389.
8. Wieczorek DF. Cardiomyopathy: getting bigger all of the time – lessons learned about heart disease from tropomyosin. In Cardiomyopathy – Disease of the Heart Muscle (ed. G. Mattsson and P. Magnusson) IntechOpen, London, UK, 2021; pp287-303.
9. Muresan I, Agoston-Coldea L. Phenotypes of hypertrophic cardiomyopathy: genetics, clinics, and modular imaging. Heart Failure Rev 2021;26:1023-1036.
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12. Tardiff J. Sarcomeric proteins and familial hypertrophic cardiomyopathy: linking mutations in structural proteins to complex cardiovascular phenotypes. Heart Failure Rev 2005;10:237-248.
13. Nakajima-Taniguchi C, Matsui H, Nagata S. et al. Novel missense mutation in alpha-tropomyosin gene found in Japanese patients with hypertrophic cardiomyopathy. J Mol Cell Cardiol 1995;278:2053-2058.
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58. Schulz E, Wieczorek DF. Tropomyosin de-phosphorylation in the heart: what are the consequences? J Muscle Res Cell Motil 2013; 34:239-246.
59. Schulz E, Wilder T, Chowdhury S, et al. Decreasing tropomyosin phosphorylation rescues tropomyosin-induced familial hypertrophic cardiomyopathy. J Biol Chem 20113; 288:28925-28935.
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2. Solaro RJ, Powers F, Lao L, Gwathmey J. Control of myofilament activation in heart failure. Circ. 87[suppl VII] 1993; 38-43.
3. Braunwald E. Cardiomyopathies: an overview. Circ Res 2017;121-721.
4. Brieler J, Breeden M, Tucker J. Cardiomyopathy: an overview. Am Fam Physician 2017;96:641-646.
5. Shah M. Hypertrophic cardiomyopathy. Cardiology in the Young 2017;27:S25-S30.
6. Marian AJ. Molecular genetic basis of hypertrophic cardiomyopathy. Circ Res. 2021;128:1533-1553.
7. Maron B, Desai M, Nishimura R, et al. Diagnosis and evaluation of hypertrophic cardiomyopathy. J Am Coll Cardiol 2022;79:372-389.
8. Wieczorek DF. Cardiomyopathy: getting bigger all of the time – lessons learned about heart disease from tropomyosin. In Cardiomyopathy – Disease of the Heart Muscle (ed. G. Mattsson and P. Magnusson) IntechOpen, London, UK, 2021; pp287-303.
9. Muresan I, Agoston-Coldea L. Phenotypes of hypertrophic cardiomyopathy: genetics, clinics, and modular imaging. Heart Failure Rev 2021;26:1023-1036.
10. Hershberger R, Hedges D, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat. Rev Cardiol 2013; 10:531-547.
11. McNally E, Golbus J, Puckelwartz M. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest. 2013; 123:19-26.
12. Tardiff J. Sarcomeric proteins and familial hypertrophic cardiomyopathy: linking mutations in structural proteins to complex cardiovascular phenotypes. Heart Failure Rev 2005;10:237-248.
13. Nakajima-Taniguchi C, Matsui H, Nagata S. et al. Novel missense mutation in alpha-tropomyosin gene found in Japanese patients with hypertrophic cardiomyopathy. J Mol Cell Cardiol 1995;278:2053-2058.
14. Yamauchi-Takihara K, Nakajima-Taniguchi C, Matsui H. et al. Clinical implications of hypertrophic cardiomyopathy associated with mutations in the alpha-tropomyosin gene. Heart 1996; 76:63-65.
15. Jaaskelainen P, Soranta M, Miettinen R. et al. The cardiac beta-myosin heavy chain gene is not the predominant gene for hypertrophic cardiomyopathy in the Finnish population. J Am Coll Cardiol 1998;32:1709-1716.
16. Jaaskelainen P, Miettinen R., Karkkainen P, et al. Genetics of hypertrophic cardiomyopathy in eastern Finland: few founder mutations with benigh or intermediatry phenotypes. Annals of Med 2004; 36:23-32.
17. Kuusisto J, Sipola P, Jaaskelainen P. et al. Current perspectives in hypertrophic cardiomyopathy with the focus o patients in the Finnish population: a review. Annals of Med 2016;48:496-508.
18. Coppini R, Ho C., Ashley E, et al. Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. J Am Coll Cardiol 2014; 64:2589-2600.
19. Sherrid M, Arabadjian M, Koulova A. Thin-filament mutations, hypertrophic cardiomyopathy, and risk. J Am Cell Cardiol 2014; 64:2601-2604.
20. Weintraub R, Semsarian C, Macdonald P. Dilated cardiomyopathy. Lancet 2017; 390:400-414.
21. Jefferies J, Towbin J. Dilated cardiomyopathy. Lancet 2010; 375:752-762.
22. Arimura T, Hayashi R, Kimura A. Molecular etiology of idiopathic cardiomyopathy. Acta Myol 2007; 26:153-158.
23. Ahmad F, Seidman J, Seidman C. The genetic basis for cardiac remodeling. Annu Rev Genomics Hum Genet. 2005; 6:185-216.
24. 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.
25. Maron M, Rowin E, Maron B. Editorial commentary: hold your horses (and mice, rats, and cats): how relevant really are animal models of hypertrophic cardiomyopathy? Trends in Cardiovasc Med 2021: 31:32-33.
26. Geisterfer-Lowrance A, Christe M, Conner D et al. A mouse model of familial hypertrophic cardiomyopathy. Science 1996; 272:731-734.
27. Muthuchamy M, Pieples K, Rethinasamy P, et al. Mouse model of a familial hypertrophic cardiomyopathy mutation in α-tropomyosin manifests cardiac dysfunction. Circ Res 1999; 85:47-56.
28. Prabhakar R, Boivin G, Gupp I, et al. A familial hypertrophic cardiomyopathy α-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. J Mol Cell Card 2001; 33:1815-1828.
29. Gannon M, Link M. Phenotypic cardiation and targeted therapy of hypertrophic cardiomyopathy using genetic animal models. Trends in Cardiovas Med. 2021; 31:20-31.
30. Liu S, Roberts W, Maron B. Comparison of morphologic findings in spontaneously occurring hypertrophic cardiomyopathy in human, cats, and dogs. Am J Cardiol 2993; 72:944-951.
31. Meurs K, Sanchez X, David R, et al. A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. Hum Mol Genet 2004; 14:3587-3593.
32. O’Rourke M. The kangaroo as a model for the study of hypertrophic cardiomyopathy in man. Cardiovasc Res 1986; 20:398.
33. Liu S. Hypertrophic cardiomyopathy in pigs: quantitative pathologic features in 55 cases. Cardiovasc Pathol 1994; 3:261-268.
34. Despond E, Dawson J. Classifying cardiac actin mutations associated with hypertrophic cardiomyopathy. Frontiers Physiol 2018; 9:1-6
35. Lu M, DiLullo C, Schultheiss T, et al. The vinculin/sarcomeric-alpha-actinin/alpha-actin nexus in cultured cardiac myocytes. J Cell Biol 1992; 117:1107-1022.
36. Gregoria C. Models of thin filament assembly in cardiac and skeletal muscle. Cell Struct Funct. 1997; 22:191-195.
37. 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.
38. Martin A, Phillips R, Kuman A, et al. Ca2+ activation and tension cost in myofilaments from mouse hearts ectopically expressing enteric γ-actin. Am J Physiol Heart Circ Physiol 2002; 283:H642-H649.
39. Abdelwahid E, Pelliniemi L, Szucsik J, et al. Cellular disorganization and extensive apoptosis in the developing heart of mice that lack cardiac muscle α-actin: apparent cause of perinatal death. Pediatric Res 2004; 55:197-204.
40. Kumar A, Crawford K, Flick R, et al. Transgenic overexpression of cardiac actin in the mouse heart suggests coregulation of cardiac, skeletal and vascular actin expression. Transgenic Res 2004; 13:531-540.
41. Muthuchamy M, Rethinasamy P, Wieczorek DF. Tropomyosin structure and function. Trends Cardiovas. Med 1997; 7:124-128.
42. 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.
43. Vrhovski B, Theze N, Thiebaud P. Structure and evolution of tropomyosin genes. In Tropomyosin (ed. P. Gunning) 2008; pp. 6-26.
44. Rajan S, Jagatheesan G, Karam C, et al. Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform. Circ 2010; 121:410-418.
45. Muthuchamy S, 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.
46. Thierfelder L, Watkins H, MacRae C et al. α-Tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 1994; 77:701-712.
47. Kremneva E, Boussouf S, Nikolaeva I, et al. Effects of two familial hypertrophic cardiomyopathy mutations in alpha-tropomyosin, Asp175Asn and Glu180Gly, on the thermal unfolding of actin-bound tropomyosin. Biophy J 2004; 87:3922-3933.
48. Prabhakar R, Petrashevskaya N, Schwartz A, et al. A mouse model of familial hypertrophic cardiomyopathy caused by a α-tropomyosin mutation. Mol Cell Biochem 2013; 251:33-42.
49. Muthuchamy M, Grupp I, Grupp G et al. Molecular and physiological effects of overexpressing striated muscle beta-tropomyosin in the adult murine heart. J Biol Chem 1995; 270:30593-30603.
50. Pieples K, Arteaga G, Solaro RJ, et al. Tropomyosin 3 expression leads to hypercontractility and attenuates myofilament length-dependent Ca2+ activation. Am J Physiol Heart Circ Physiol 2002; 283:H1344-H1353.
51. Alves M, Gaffin R, Wolska B. Rescue of familial cardiomyopathies by modifications at the level of sarcomere and Ca2+ fluxes. J Mol Cell Cardiol 2010; 48:834-842.
52. 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:H949-958.
53. Wieczorek DF, Wolska B. Rescue of familial hypertrophic cardiomyopathy by altering sarcomeric exposure and response to calcium. In Gene Therapy Applications (ed C. Kang) Intech 2011; pp. 85-94.
54. 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.
55. Jagatheesan G, Rajan S, Wieczorek DF. Investigations into tropomyosin function using mouse models. J Mol Cell Cardiol 2010; 48:893-898.
56. 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.
57. Schulz E, Correll R, Sheikh H. et al. Tropomyosin dephosphorylation results in compensated cardiac hypertrophy. J Biol Chem 2012; 287:44478-44489.
58. Schulz E, Wieczorek DF. Tropomyosin de-phosphorylation in the heart: what are the consequences? J Muscle Res Cell Motil 2013; 34:239-246.
59. Schulz E, Wilder T, Chowdhury S, et al. Decreasing tropomyosin phosphorylation rescues tropomyosin-induced familial hypertrophic cardiomyopathy. J Biol Chem 20113; 288:28925-28935.
60. 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.
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