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Biophysical Reviews

, Volume 10, Issue 1, pp 15–25 | Cite as

RBM20, a potential target for treatment of cardiomyopathy via titin isoform switching

  • Wei Guo
  • Mingming Sun
Review

Abstract

Cardiomyopathy, also known as heart muscle disease, is an unfavorable condition leading to alterations in myocardial contraction and/or impaired ability of ventricular filling. The onset and development of cardiomyopathy have not currently been well defined. Titin is a giant multifunctional sarcomeric filament protein that provides passive stiffness to cardiomyocytes and has been implicated to play an important role in the origin and development of cardiomyopathy and heart failure. Titin-based passive stiffness can be mainly adjusted by isoform switching and post-translational modifications in the spring regions. Recently, genetic mutations of TTN have been identified that can also contribute to variable passive stiffness, though the detailed mechanisms remain unclear. In this review, we will discuss titin isoform switching as it relates to alternative splicing during development stages and differences between species and muscle types. We provide an update on the regulatory mechanisms of TTN splicing controlled by RBM20 and cover the roles of TTN splicing in adjusting the diastolic stiffness and systolic compliance of the healthy and the failing heart. Finally, this review attempts to provide future directions for RBM20 as a potential target for pharmacological intervention in cardiomyopathy and heart failure.

Keywords

Titin isoform switching Alternative splicing Cardiomyopathy RBM20 

Notes

Acknowledgments

This work was supported by the National Institute of Health/National Institute of General Medical Sciences (NIGMSP20GM103432); the BGIA from the American Heart Association (16BGIA27790136 to WG); the USDA National Institute of Food and Agriculture (Hatch project 1009266 to WG). The authors would like to thank Dr. Marion Greaser and Dr. Rich McCormick for their helpful comments and proofreading of the manuscript.

Compliance with ethical standards

Conflict of interest

Wei Guo declares that he has no conflict of interest. Mingming Sun declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S (2001) The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res 89:1065–1072CrossRefPubMedGoogle Scholar
  2. Bell SP, Nyland L, Tischler MD, McNabb M, Granzier H, LeWinter MM (2000) Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 87:235–240CrossRefPubMedGoogle Scholar
  3. Borbély A, Falcao-Pires I, van Heerebeek L, Hamdani N, Edes I, Gavina C, Leite-Moreira AF, Bronzwaer JG, Papp Z, van der Velden J, Stienen GJ, Paulus WJ (2009) Hypophosphorylation of the Stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res 104:780–786CrossRefPubMedGoogle Scholar
  4. Brauch KM, Karst ML, Herron KJ, de Andrade M, Pellikka PA, Rodeheffer RJ, Michels VV, Olson TM (2009) Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J Am Coll Cardiol 54:930–941CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cazorla O, Freiburg A, Helmes M, Centner T, McNabb M, Wu Y, Trombitás K, Labeit S, Granzier H (2000) Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ Res 86:59–67CrossRefPubMedGoogle Scholar
  6. Chauveau C, Rowell J, Ferreiro A (2014) A rising titan: TTN review and mutation update. Hum Mutat 35:1046–1059CrossRefPubMedGoogle Scholar
  7. Daughenbaugh LA (2007) Cardiomyopathy: an overview. J Nurse Pract 3:248–258CrossRefGoogle Scholar
  8. Freiburg A, Gautel M (1996) A molecular map of the interactions between titin and myosin-binding protein C. Implications for sarcomeric assembly in familial hypertrophic cardiomyopathy. Eur J Biochem 235:317–323CrossRefPubMedGoogle Scholar
  9. Freiburg A, Trombitas K, Hell W, Cazorla O, Fougerousse F, Centner T, Kolmerer B, Witt C, Beckmann JS, Gregorio CC, Granzier H, Labeit S (2000) Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity. Circ Res 86:1114–1121CrossRefPubMedGoogle Scholar
  10. Fukuda N, Wu Y, Farman G, Irving TC, Granzier H (2003) Titin isoform variance and length dependence of activation in skinned bovine cardiac muscle. J Physiol 553:147–154CrossRefPubMedPubMedCentralGoogle Scholar
  11. Fürst DO, Osborn M, Nave R, Weber K (1988) The organization of titin filaments in the half-sarcomere revealed by monoclonal antibodies in immunoelectron microscopy: a map of ten nonrepetitive epitopes starting at the Z line extends close to the M line. J Cell Biol 106:1563–1572CrossRefPubMedGoogle Scholar
  12. Gautel M, Goulding D, Bullard B, Weber K, Fürst DO (1996) The central Z-disk region of titin is assembled from a novel repeat in variable copy numbers. J Cell Sci 109(Pt 11):2747–2754PubMedGoogle Scholar
  13. Gigli M, Begay RL, Morea G, Graw SL, Sinagra G, Taylor MR, Granzier H, Mestroni L (2016) A review of the giant protein titin in clinical molecular diagnostics of cardiomyopathies. Front Cardiovasc Med 3:21CrossRefPubMedPubMedCentralGoogle Scholar
  14. Granzier HL, Irving TC (1995) Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophys J 68:1027–1044CrossRefPubMedPubMedCentralGoogle Scholar
  15. Granzier H, Labeit S (2002) Cardiac titin: an adjustable multi-functional spring. J Physiol 541:335–342CrossRefPubMedPubMedCentralGoogle Scholar
  16. Granzier HL, Labeit S (2004) The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circ Res 94:284–295CrossRefPubMedGoogle Scholar
  17. Granzier HL, Labeit S (2005) Titin and its associated proteins: the third myofilament system of the sarcomere. Adv Protein Chem 71:89–119CrossRefPubMedGoogle Scholar
  18. Granzier HL, Labeit S (2006) The giant muscle protein titin is an adjustable molecular spring. Exerc Sport Sci Rev 34:50–53CrossRefPubMedGoogle Scholar
  19. Greaser ML, Krzesinski PR, Warren CM, Kirkpatrick B, Campbell KS, Moss RL (2005) Developmental changes in rat cardiac titin/connectin: transitions in normal animals and in mutants with a delayed pattern of isoform transition. J Muscle Res Cell Motil 26:325–332CrossRefPubMedGoogle Scholar
  20. Greaser ML, Warren CM, Esbona K, Guo W, Duan Y, Parrish AM, Krzesinski PR, Norman HS, Dunning S, Fitzsimons DP, Moss RL (2008) Mutation that dramatically alters rat titin isoform expression and cardiomyocyte passive tension. J Mol Cell Cardiol 44:983–991CrossRefPubMedPubMedCentralGoogle Scholar
  21. Guo W, Bharmal SJ, Esbona K, Greaser ML (2010) Titin diversity—alternative splicing gone wild. J Biomed Biotechnol 2010:753675PubMedPubMedCentralGoogle Scholar
  22. Guo W, Schafer S, Greaser ML, Radke MH, Liss M, Govindarajan T, Maatz H, Schulz H, Li S, Parrish AM, Dauksaite V, Vakeel P, Klaassen S, Gerull B, Thierfelder L, Regitz-Zagrosek V, Hacker TA, Saupe KW, Dec GW, Ellinor PT, MacRae CA, Spallek B, Fischer R, Perrot A, Özcelik C, Saar K, Hubner N, Gotthardt M (2012) RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat Med 18:766–773CrossRefPubMedPubMedCentralGoogle Scholar
  23. Guo W, Pleitner JM, Saupe KW, Greaser ML (2013) Pathophysiological defects and transcriptional profiling in the RBM20−/− rat model. PLoS One 8:e84281CrossRefPubMedPubMedCentralGoogle Scholar
  24. Gutierrez-Cruz G, Van Heerden AH, Wang K (2001) Modular motif, structural folds and affinity profiles of the PEVK segment of human fetal skeletal muscle titin. J Biol Chem 276:7442–7449CrossRefPubMedGoogle Scholar
  25. Hamdani N, Bishu KG, von Frieling-Salewsky M, Redfield MM, Linke WA (2013) Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction. Cardiovasc Res 97:464–471CrossRefPubMedGoogle Scholar
  26. Henry LB (2003) Left ventricular systolic dysfunction and ischemic cardiomyopathy. Crit Care Nurs Q 26:16–21CrossRefPubMedGoogle Scholar
  27. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE (2012) Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366:619–628CrossRefPubMedPubMedCentralGoogle Scholar
  28. Hidalgo C, Granzier H (2013) Tuning the molecular giant titin through phosphorylation: role in health and disease. Trends Cardiovasc Med 23:165–171CrossRefPubMedPubMedCentralGoogle Scholar
  29. Hinze F, Dieterich C, Radke MH, Granzier H, Gotthardt M (2016) Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy. J Mol Med (Berl) 94:1349–1358CrossRefGoogle Scholar
  30. Hojayev B, Rothermel BA, Gillette TG, Hill JA (2012) FHL2 binds calcineurin and represses pathological cardiac growth. Mol Cell Biol 32:4025–4034CrossRefPubMedPubMedCentralGoogle Scholar
  31. Hoshijima M (2006) Mechanical stress–strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures. Am J Physiol Heart Circ Physiol 290:H1313–H1325CrossRefPubMedPubMedCentralGoogle Scholar
  32. Hudson B, Hidalgo C, Saripalli C, Granzier H (2011) Hyperphosphorylation of mouse cardiac titin contributes to transverse aortic constriction-induced diastolic dysfunction. Circ Res 109(8):858–866CrossRefPubMedPubMedCentralGoogle Scholar
  33. Ibrahim EC, Schaal TD, Hertel KJ, Reed R, Maniatis T (2005) Serine/arginine-rich protein-dependent suppression of exon skipping by exonic splicing enhancers. Proc Natl Acad Sci U S A 102:5002–5007CrossRefPubMedPubMedCentralGoogle Scholar
  34. Ito J, Iijima M, Yoshimoto N, Niimi T, Kuroda S, Maturana AD (2016) RBM20 and RBM24 cooperatively promote the expression of short enh splice variants. FEBS Lett 590:2262–2274CrossRefPubMedGoogle Scholar
  35. Kanopka A, Mühlemann O, Akusjärvi G (1996) Inhibition by SR proteins of splicing of a regulated adenovirus pre-mRNA. Nature 381:535–538CrossRefPubMedGoogle Scholar
  36. Kellermayer MS, Smith SB, Granzier HL, Bustamante C (1997) Folding–unfolding transitions in single titin molecules characterized with laser tweezers. Science 276:1112–1116CrossRefPubMedGoogle Scholar
  37. Kolmerer B, Olivieri N, Witt CC, Herrmann BG, Labeit S (1996) Genomic organization of M line titin and its tissue-specific expression in two distinct isoforms. J Mol Biol 256:556–563CrossRefPubMedGoogle Scholar
  38. Kontrogianni-Konstantopoulos A, Ackermann MA, Bowman AL, Yap SV, Bloch RJ (2009) Muscle giants: molecular scaffolds in sarcomerogenesis. Physiol Rev 89:1217–1267CrossRefPubMedPubMedCentralGoogle Scholar
  39. Kötter S, Andresen C, Krüger M (2014) Titin: central player of hypertrophic signaling and sarcomeric protein quality control. Biol Chem 395:1341–1352CrossRefPubMedGoogle Scholar
  40. Krüger M, Linke WA (2011) The giant protein titin: a regulatory node that integrates myocyte signaling pathways. J Biol Chem 286:9905–9912CrossRefPubMedPubMedCentralGoogle Scholar
  41. Krüger M, Sachse C, Zimmermann WH, Eschenhagen T, Klede S, Linke WA (2008) Thyroid hormone regulates developmental titin isoform transitions via the phosphatidylinositol-3-kinase/AKT pathway. Circ Res 102:439–447CrossRefPubMedGoogle Scholar
  42. Krüger M, Babicz K, von Frieling-Salewsky M, Linke WA (2010) Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy. J Mol Cell Cardiol 48:910–916CrossRefPubMedGoogle Scholar
  43. Labeit S, Kolmerer B (1995) Titins: giant proteins in charge of muscle ultrastructure and elasticity. Science 270:293–296CrossRefPubMedGoogle Scholar
  44. Labeit S, Barlow DP, Gautel M, Gibson T, Holt J, Hsieh CL, Francke U, Leonard K, Wardale J, Whiting A, Trinick J (1990) A regular pattern of two types of 100-residue motif in the sequence of titin. Nature 345:273–276CrossRefPubMedGoogle Scholar
  45. Labeit S, Gautel M, Lakey A, Trinick J (1992) Towards a molecular understanding of titin. EMBO J 11:1711–1716PubMedPubMedCentralGoogle Scholar
  46. Lahmers S, Wu Y, Call DR, Labeit S, Granzier H (2004) Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ Res 94(4):505–513CrossRefPubMedGoogle Scholar
  47. Lange S, Auerbach D, McLoughlin P, Perriard E, Schäfer BW, Perriard JC, Ehler E (2002) Subcellular targeting of metabolic enzymes to titin in heart muscle may be mediated by DRAL/FHL-2. J Cell Sci 115:4925–4936CrossRefPubMedGoogle Scholar
  48. Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edström L, Ehler E, Udd B, Gautel M (2005) The kinase domain of titin controls muscle gene expression and protein turnover. Science 308:1599–1603CrossRefPubMedGoogle Scholar
  49. Lange S, Ehler E, Gautel M (2006) From A to Z and back? Multicompartment proteins in the sarcomere. Trends Cell Biol 16:11–18CrossRefPubMedGoogle Scholar
  50. LeWinter MM (2005) Functional consequences of sarcomeric protein abnormalities in failing myocardium. Heart Fail Rev 10:249–257CrossRefPubMedGoogle Scholar
  51. LeWinter MM, Granzier H (2010) Cardiac titin: a multifunctional giant. Circulation 121:2137–2145CrossRefPubMedPubMedCentralGoogle Scholar
  52. LeWinter MM, Granzier HL (2014) Cardiac titin and heart disease. J Cardiovasc Pharmacol 63:207–212CrossRefPubMedPubMedCentralGoogle Scholar
  53. Li S, Guo W, Schmitt BM, Greaser ML (2012) Comprehensive analysis of titin protein isoform and alternative splicing in normal and mutant rats. J Cell Biochem 113:1265–1273CrossRefPubMedGoogle Scholar
  54. Li S, Guo W, Dewey CN, Greaser ML (2013) Rbm20 regulates titin alternative splicing as a splicing repressor. Nucleic Acids Res 41:2659–2672CrossRefPubMedPubMedCentralGoogle Scholar
  55. Lim KH, Ferraris L, Filloux ME, Raphael BJ, Fairbrother WG (2011) Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes. Proc Natl Acad Sci U S A 108:11093–11098CrossRefPubMedPubMedCentralGoogle Scholar
  56. Linke WA (2008) Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc Res 77:637–648PubMedGoogle Scholar
  57. Linke WA (2009) Titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. In: Kamkin A, Kiseleva I (eds) Mechanosensitivity of the heart. Springer, Dordrecht, pp 3–34CrossRefGoogle Scholar
  58. Linke WA, Fernandez JM (2002) Cardiac titin: molecular basis of elasticity and cellular contribution to elastic and viscous stiffness components in myocardium. J Muscle Res Cell Motil 23:483–497CrossRefPubMedGoogle Scholar
  59. Linke WA, Hamdani N (2014) Gigantic business: titin properties and function through thick and thin. Circ Res 114:1052–1068CrossRefPubMedGoogle Scholar
  60. Linke WA, Krüger M (2010) The giant protein titin as an integrator of myocyte signaling pathways. Physiology (Bethesda) 25:186–198Google Scholar
  61. Linke WA, Ivemeyer M, Olivieri N, Kolmerer B, Rüegg JC, Labeit S (1996) Towards a molecular understanding of the elasticity of titin. J Mol Biol 261:62–71CrossRefPubMedGoogle Scholar
  62. Linke WA, Rudy DE, Centner T, Gautel M, Witt C, Labeit S, Gregorio CC (1999) I-band titin in cardiac muscle is a three-element molecular spring and is critical for maintaining thin filament structure. J Cell Biol 146:631–644CrossRefPubMedPubMedCentralGoogle Scholar
  63. Lynch KW (2007) Regulation of alternative splicing by signal transduction pathways. Adv Exp Med Biol 623:161–174CrossRefPubMedGoogle Scholar
  64. Maatz H, Jens M, Liss M, Schafer S, Heinig M, Kirchner M, Adami E, Rintisch C, Dauksaite V, Radke MH, Selbach M, Barton PJ, Cook SA, Rajewsky N, Gotthardt M, Landthaler M, Hubner N (2014) RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing. J Clin Invest 124:3419–3430CrossRefPubMedPubMedCentralGoogle Scholar
  65. Makarenko I, Opitz CA, Leake MC, Neagoe C, Kulke M, Gwathmey JK, del Monte F, Hajjar RJ, Linke WA (2004) Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts. Circ Res 95:708–716CrossRefPubMedGoogle Scholar
  66. Manley JL, Tacke R (1996) SR proteins and splicing control. Genes Dev 10:1569–1579CrossRefPubMedGoogle Scholar
  67. Maruyama K (1976) Connectin, an elastic protein from myofibrils. J Biochem 80:405–407CrossRefPubMedGoogle Scholar
  68. Methawasin M, Hutchinson KR, Lee EJ, Smith JE 3rd, Saripalli C, Hidalgo CG, Ottenheijm CA, Granzier H (2014) Experimentally increasing titin compliance in a novel mouse model attenuates the Frank–Starling mechanism but has a beneficial effect on diastole. Circulation 129(19):1924–1936CrossRefPubMedPubMedCentralGoogle Scholar
  69. Methawasin M, Strom JG, Slater RE, Fernandez V, Saripalli C, Granzier H (2016) Experimentally increasing the compliance of titin through RNA binding motif-20 (RBM20) inhibition improves diastolic function in a mouse model of heart failure with preserved ejection fraction. Circulation 134:1085–1099CrossRefPubMedPubMedCentralGoogle Scholar
  70. Meyer LC, Wright NT (2013) Structure of giant muscle proteins. Front Physiol 4:368CrossRefPubMedPubMedCentralGoogle Scholar
  71. Miyata S, Minobe W, Bristow MR, Leinwand LA (2000) Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res 86:386–390CrossRefPubMedGoogle Scholar
  72. Nagueh SF, Shah G, Wu Y, Torre-Amione G, King NM, Lahmers S, Witt CC, Becker K, Labeit S, Granzier HL (2004) Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 110:155–162CrossRefPubMedGoogle Scholar
  73. Neagoe C, Kulke M, del Monte F, Gwathmey JK, de Tombe PP, Hajjar RJ, Linke WA (2002) Titin isoform switch in ischemic human heart disease. Circulation 106:1333–1341CrossRefPubMedGoogle Scholar
  74. Neagoe C, Opitz CA, Makarenko I, Linke WA (2003) Gigantic variety: expression patterns of titin isoforms in striated muscles and consequences for myofibrillar passive stiffness. J Muscle Res Cell Motil 24:175–189CrossRefPubMedGoogle Scholar
  75. Opitz CA, Linke WA (2005) Plasticity of cardiac titin/connectin in heart development. J Muscle Res Cell Motil 26:333–342CrossRefPubMedGoogle Scholar
  76. Opitz CA, Leake MC, Makarenko I, Benes V, Linke WA (2004) Developmentally regulated switching of titin size alters myofibrillar stiffness in the perinatal heart. Circ Res 94:967–975CrossRefPubMedGoogle Scholar
  77. Ottenheijm CA, Knottnerus AM, Buck D, Luo X, Greer K, Hoying A, Labeit S, Granzier H (2009) Tuning passive mechanics through differential splicing of titin during skeletal muscle development. Biophys J 97:2277–2286CrossRefPubMedPubMedCentralGoogle Scholar
  78. Peters S (2016) Ion channel diseases as a part in the definition and classification of cardiomyopathies recently confirmed in Brugada syndrome. Int J Cardiol 207:103CrossRefPubMedGoogle Scholar
  79. Puchner EM, Alexandrovich A, Kho AL, Hensen U, Schäfer LV, Brandmeier B, Gräter F, Grubmüller H, Gaub HE, Gautel M (2008) Mechanoenzymatics of titin kinase. Proc Natl Acad Sci U S A 105:13385–13390CrossRefPubMedPubMedCentralGoogle Scholar
  80. Scholl FA, McLoughlin P, Ehler E, de Giovanni C, Schäfer BW (2000) DRAL is a p53-responsive gene whose four and a half LIM domain protein product induces apoptosis. J Cell Biol 151:495–506CrossRefPubMedPubMedCentralGoogle Scholar
  81. Shapiro BP, Lam CS, Patel JB, Mohammed SF, Kruger M, Meyer DM, Linke WA, Redfield MM (2007) Acute and chronic ventricular-arterial coupling in systole and diastole: insights from an elderly hypertensive model. Hypertension 50:503–511CrossRefPubMedGoogle Scholar
  82. Sheikh F, Raskin A, Chu PH, Lange S, Domenighetti AA, Zheng M, Liang X, Zhang T, Yajima T, Gu Y, Dalton ND, Mahata SK, Dorn GW 2nd, Brown JH, Peterson KL, Omens JH, McCulloch AD, Chen J (2008) An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice. J Clin Invest 118:3870–3880CrossRefPubMedPubMedCentralGoogle Scholar
  83. Shen M, Mattox W (2012) Activation and repression functions of an SR splicing regulator depend on exonic versus intronic-binding position. Nucleic Acids Res 40(1):428–437CrossRefPubMedGoogle Scholar
  84. Sorimachi H, Freiburg A, Kolmerer B, Ishiura S, Stier G, Gregorio CC, Labeit D, Linke WA, Suzuki K, Labeit S (1997) Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs. J Mol Biol 270:688–695CrossRefPubMedGoogle Scholar
  85. Taylor M, Graw S, Sinagra G, Barnes C, Slavov D, Brun F, Pinamonti B, Salcedo EE, Sauer W, Pyxaras S, Anderson B, Simon B, Bogomolovas J, Labeit S, Granzier H, Mestroni L (2011) Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy—overlap syndromes. Circulation 124:876–885CrossRefPubMedPubMedCentralGoogle Scholar
  86. Trinick J (1996) Titin as a scaffold and spring. Cytoskeleton. Curr Biol 6:258–260CrossRefPubMedGoogle Scholar
  87. Trombitás K, Greaser M, Labeit S, Jin JP, Kellermayer M, Helmes M, Granzier H (1998) Titin extensibility in situ: entropic elasticity of permanently folded and permanently unfolded molecular segments. J Cell Biol 140:853–859CrossRefPubMedPubMedCentralGoogle Scholar
  88. Trombitás K, Redkar A, Centner T, Wu Y, Labeit S, Granzier H (2000) Extensibility of isoforms of cardiac titin: variation in contour length of molecular subsegments provides a basis for cellular passive stiffness diversity. Biophys J 79:3226–3234CrossRefPubMedPubMedCentralGoogle Scholar
  89. Tskhovrebova L, Trinick J (2003) Titin: properties and family relationships. Nat Rev Mol Cell Biol 4:679–689CrossRefPubMedGoogle Scholar
  90. Tskhovrebova L, Trinick J (2004) Properties of titin immunoglobulin and fibronectin-3 domains. J Biol Chem 279:46351–46354CrossRefPubMedGoogle Scholar
  91. Wang K, McClure J, Tu A (1979) Titin: major myofibrillar components of striated muscle. Proc Natl Acad Sci U S A 76:3698–3702CrossRefPubMedPubMedCentralGoogle Scholar
  92. Wang K, McCarter R, Wright J, Beverly J, Ramirez-Mitchell R (1991) Regulation of skeletal muscle stiffness and elasticity by titin isoforms: a test of the segmental extension model of resting tension. Proc Natl Acad Sci U S A 88:7101–7105CrossRefPubMedPubMedCentralGoogle Scholar
  93. Wang Y, Xiao X, Zhang J, Choudhury R, Robertson A, Li K, Ma M, Burge CB, Wang Z (2013) A complex network of factors with overlapping affinities represses splicing through intronic elements. Nat Struct Mol Biol 20:36–45CrossRefPubMedGoogle Scholar
  94. Warren CM, Jordan MC, Roos KP, Krzesinski PR, Greaser ML (2003a) Titin isoform expression in normal and hypertensive myocardium. Cardiovasc Res 59:86–94CrossRefPubMedGoogle Scholar
  95. Warren CM, Krzesinski PR, Greaser ML (2003b) Vertical agarose gel electrophoresis and electroblotting of high-molecular-weight proteins. Electrophoresis 24:1695–1702CrossRefPubMedGoogle Scholar
  96. Warren CM, Krzesinski PR, Campbell KS, Moss RL, Greaser ML (2004) Titin isoform changes in rat myocardium during development. Mech Dev 121:1301–1312CrossRefPubMedGoogle Scholar
  97. Watanabe K, Nair P, Labeit D, Kellermayer MS, Greaser M, Labeit S, Granzier H (2002) Molecular mechanics of cardiac titin’s PEVK and N2B spring elements. J Biol Chem 277:11549–11558CrossRefPubMedGoogle Scholar
  98. Wu Y, Bell SP, Trombitas K, Witt CC, Labeit S, LeWinter MM, Granzier H (2002) Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness. Circulation 106:1384–1389CrossRefPubMedGoogle Scholar
  99. Yin Z, Ren J, Guo W (2015) Sarcomeric protein isoform transitions in cardiac muscle: a journey to heart failure. Biochim Biophys Acta 1852:47–52CrossRefPubMedGoogle Scholar
  100. Zhu C, Yin Z, Ren J, McCormick RJ, Ford SP, Guo W (2015) RBM20 is an essential factor for thyroid hormone-regulated titin isoform transition. J Mol Cell Biol 7:88–90CrossRefPubMedPubMedCentralGoogle Scholar
  101. Zhu C, Chen Z, Guo W (2016) Pre-mRNA mis-splicing of sarcomeric genes in heart failure. Biochim Biophys Acta (in press). pii: S0925-4439(16)30290-3. doi: 10.1016/j.bbadis.2016.11.008

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© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Animal ScienceUniversity of WyomingLaramieUSA
  2. 2.Center for Cardiovascular Research and Integrative MedicineUniversity of WyomingLaramieUSA

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