Probing the Functional Roles of Titin Ligands in Cardiac Myofibril Assembly and Maintenance

  • Abigail S. McElhinny
  • Siegfried Labeit
  • Carol C. Gregorio
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 481)


Sarcomeres of cardiac muscle are comprised of numerous proteins organized in an elegantly precise order. The exact mechanism of how these proteins are assembled into myofibrils during heart development is not yet understood, although existing in vitro and in vivo model systems have provided great insight into this complex process. It has been proposed by several groups that the giant elastic protein titin acts as a “molecular template” to orchestrate sarcomeric organization during myofibrillogenesis. Titin’s highly modular structure, composed of both repeating and unique domains that interact with a wide spectrum of contractile and regulatory ligands, supports this hypothesis. Recent functional studies have provided clues to the physiological significance of the interaction of titin with several titin-binding proteins in the context of live cardiac cells. Improved models of cardiac myofibril assembly, along with the application of powerful functional studies in live cells, as well as the characterization of additional titin ligands, is likely to reveal surprising new functions for the titin third filament system.


Cardiac Myocytes Thin Filament Thick Filament Somite Stage Familial Hypertrophic Cardiomyopathy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Antin PB, Taylor RG, Yatskievych TA. Precardiac mesoderm is specified during gastrulation in quail. Dev Dyn 1994;200:144–153.PubMedCrossRefGoogle Scholar
  2. Ayme-Southgate A, Vigoreaux J, Benian G, Pardue ML. Drosophila has a twitchin/titin-related gene that appears to encode projectin. Proc NatlAcad Sci USA 1991;88:7973–7977.CrossRefGoogle Scholar
  3. Benian GM, Kiff JE, Neckelmann N, Moerman DG, Waterston RH. Sequence of an unusually large protein implicated in regulation of myosin activity in C. elegans. Nature 1989;342:45–50.PubMedCrossRefGoogle Scholar
  4. Bennett CF. Antisense research. Science 1996;271:434.PubMedCrossRefGoogle Scholar
  5. Bishop SP, Anderson PG, Tucker DC. Morphological development of the rat heart growing in oculo in the absence of hemodynamic work load. Circ Res 1990;66:84–102.PubMedCrossRefGoogle Scholar
  6. Bonne G, Carrier L, Richard P, Hainque B, Schwartz K. Familial hypertrophic cardiomyopathy: from mutations to functional defects. Circ Res 1998;83:580–593.PubMedCrossRefGoogle Scholar
  7. Bouche M, Goldfme SM, Fischman DA. Posttranslational incorporation of contractile proteins into myofibrils in a cell-free system. J Cell Biol 1988;107:587–596.PubMedCrossRefGoogle Scholar
  8. Choudhury M, Bag J. Stabilization of slow troponin C polypeptide compensates for its reduced synthesis in antisense oligodeoxynucleotide-treated cells. Nucleic Acids Res 1998;26:4765–4770.PubMedCrossRefGoogle Scholar
  9. Dabiri GA, Turnacioglu KK, Sanger JM, Sanger JW. Myofibrillogenesis visualized in living embryonic cardiomyocytes. Proc. Natl. Acad. Sci USA 1997;19:9493–9498.CrossRefGoogle Scholar
  10. DeHaan RL. Migration patterns of the precardiac mesoderm in the early chick embryo. Exptl Cell Res 1963;29:544–560.CrossRefGoogle Scholar
  11. Dlugosz AA, Antin PB, Nachmias VT, Holtzer H. The relation between stress fiber-like structures and nascent myofibrils in cultured cardiac myocytes. J Cell Biol 1984;99:2268–2278.PubMedCrossRefGoogle Scholar
  12. Dunckley MG, Manoharan M, Villiet P, Eperon IC, Dickson G. Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides. Hum Mol Genet 1998;7:1083–90.PubMedCrossRefGoogle Scholar
  13. Ehler E, Rothen BM, Hämmerle SP, Komiyama M, Perriard J-C. Myofibrillogenesis in the developing chicken heart: assembly of Z-disc, M-line and the thick filaments. J Cell Sci 1999,112:1529–1539.PubMedGoogle Scholar
  14. Eilertsen KJ, Keller TC 3rd. Identification and characterization of two huge protein components of the brush border cytoskeleton: evidence for a cellular isoform of titin. J Cell Biol 1992;119:549–557.PubMedCrossRefGoogle Scholar
  15. Eilertsen KJ, Kazmierski S, Keller TC 3rd. Interaction of alpha-actinin with cellular titin. Eur J Cell Biol 1997;74:361–364.PubMedGoogle Scholar
  16. Epstein HF, Fischman DA. Molecular analysis of protein assembly in muscle development. Science 1991;251:1039–1044.PubMedCrossRefGoogle Scholar
  17. Erickson HP. Stretching single protein molecules: titin is a weird spring. Science 1997;276:1090–1092.PubMedCrossRefGoogle Scholar
  18. Fowler VM. Regulation of actin filament length in erythrocytes and striated muscle. Curr Opin Cell Biol 1996;8:86–96.PubMedCrossRefGoogle Scholar
  19. Fulton AB, Alftine C. Organization of protein and mRNA for titin and other myofibril components during myofibrillogenesis in cultured chicken skeletal muscle. Cell Struc Func 1997;22:51–58.CrossRefGoogle Scholar
  20. Funatsu T, Higuchi H, Ishiwata, S. Elastic filaments in skeletal muscle revealed by selective removal of thin filaments with plasma gelsolin. J Cell Biol 1990;110:53–62.PubMedCrossRefGoogle Scholar
  21. Funatsu T, Kono E, Higuchi H, Kimura S, Ishiwata S, Yoshioka T, Maruyama K, Tsukita S. Elastic filaments in situ in cardiac muscle: deep-etch replica analysis in combination with selective removal of actin and myosin filaments. J Cell Biol 1993;120:711–724.PubMedCrossRefGoogle Scholar
  22. Fürst DO, Osborn M, Nave R, Weber K. 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 1988;106:1563–1572.PubMedCrossRefGoogle Scholar
  23. Fürst DO, Nave R, Osborn M, Weber K. Repetitive titin epitopes with a 42 nm spacing coincide in relative position with known A-band striations also identified by major myosin-associated proteins. An immunoelectron-microscopical study on myofibrils. J Cell Sci 1989;94:119–125.PubMedGoogle Scholar
  24. Gautel M, Lakey A, Barlow DP, Holmes Z, Scales S, Leonard K, Labeit S, Mygland A, Gilhus NE, Aarli JA. Titin antibodies in myasthenia gravis: Identification of a major auto-immunogenic region of titin. Neurology 1993;43:1581–1585.PubMedCrossRefGoogle Scholar
  25. Gautel M, Goulding D, Bullard B, Weber K, Fürst DO. The central Z-disc region of titin is assembled from a novel repeat in variable copy numbers. J Cell Sci 1996;109:2747–2754.PubMedGoogle Scholar
  26. Geisterfer-Lowrance AA, Christie M, Conner DA, Ingwal JS, Schoen FJ, Seidman CE, Seidman JG. A mouse model of familial hypertrophic cardiomyopathy. Science 1996,272:731–734.PubMedCrossRefGoogle Scholar
  27. Granzier HL, Irving TC. Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophys J 1995;68:1027–1044.PubMedCrossRefGoogle Scholar
  28. Granzier H, Kellermayer M, Trombitás, K. Titin elasticity and mechanism of passive force development in rat cardiac myocytes probed by thin-filament extraction. Biophys J 1997;73:2043–2053.PubMedCrossRefGoogle Scholar
  29. Gregorio CC. Models of striated muscle thin filament assembly. Cell Struc Func 1997;22:191–195.CrossRefGoogle Scholar
  30. Gregorio CC, Fowler VM. Mechanisms of thin filament assembly in embryonic chick cardiac myocytes: tropomodulin requires tropomyosin for assembly. J Cell Biol 1995;129:683–695.PubMedCrossRefGoogle Scholar
  31. Gregorio CC, Fowler VM. Tropomodulin function and thin filament assembly in cardiac myocytes. Trends Cardiovas Med 1996;6:136–141.CrossRefGoogle Scholar
  32. Gregorio CC, Granzier H, Sorimachi H, Labeit S. Muscle assembly: a titanic achievement? Curr Opin Cell Biol 1999;11:18–25.PubMedCrossRefGoogle Scholar
  33. Gregorio CC, Trombitás K, Centner T, Kolmerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Herrmann B, Granzier H, Sorimachi H, Labeit S. The NH2 terminus of titin spans the Z-disc; Its interaction with a novel 19 kD ligand (T-cap) is required for sarcomeric integrity. J Cell Biol 1998;143:1013–1027.PubMedCrossRefGoogle Scholar
  34. Gregorio CC, Weber A, Bondad M, Pennise CR, Fowler VM. Requirement of pointed-end capping by tropomodulin to maintain actin filament length in embryonic chick cardiac myocytes. Nature 1995,377:83–86.PubMedCrossRefGoogle Scholar
  35. Helmes M, Trombitás K, Centner T, Kellermayer M, Labeit S, Linke WA, Granzier H. Mechanically driven contour-length adjustment in rat cardiac titin’s unique N2B sequence: titin is an adjustable spring. Circ Res 1999;84:1339–1352.PubMedCrossRefGoogle Scholar
  36. Herskowitz I. Functional inactivation of genes by dominant negative mutations. Nature 1987;329:219–222.PubMedCrossRefGoogle Scholar
  37. Hill CS, Lemanski LF. Immunoelectron microscopic localization of alpha actinin and actin in embryonic hamster heart cells. Euro J Cell Biol 1985;39:300–312.Google Scholar
  38. Hiruma T, Hirakow R. An ultrastructural topographical study on myofibrillogenesis in the heart of the chick embryo during pulsation onset period. Dev Dyn 1985;196:291–299.Google Scholar
  39. Holtzer H, Hijikata T, Lin ZX, Zhang, ZQ, Holtzer S, Protasi F, Franzini-Armstrong C, Sweeney HL. Independent assembly of 1.6μm long bipolar MHC filaments and I-Z-I bodies. Cell Struc Func 1997;22:83–93.CrossRefGoogle Scholar
  40. Horowits R, Kempner ES, Bisher ME, and Podolski RJ. A physiological role for titin and nebulin in skeletal muscle. Nature 1986;323:160–164.PubMedCrossRefGoogle Scholar
  41. Horowits R, Luo G, Zhang JZ, Herrera AH. Nebulin and nebulin-related proteins in striated muscle. Adv Biophys 1996;33:143–150.PubMedCrossRefGoogle Scholar
  42. Houmeida A, Holt J, Tskhovrebova L, Trinick J. Studies of the interaction between titin and myosin. J Cell Biol 1995;131:1471–1481.PubMedCrossRefGoogle Scholar
  43. Imanaka-Yoshida K. Myofibrillogenesis in precardiac mesoderm expiant culture. Cell Struct Func 1997;22:45–49.CrossRefGoogle Scholar
  44. Jin JP. Cloned rat cardiac titin class I and class II motifs. Expression, purification, characterization, and interaction with F-actin. J Biol Chem 1995;270:6908–6916.PubMedGoogle Scholar
  45. Jones WK, Grupp IL, Doetschman T, Grupp G, Osinska H, Hewett TE, Boivin G, Gulick J, Ng WA, Robbins J. Ablation of the murine alpha myosin heavy chain gene leads to dosage effects and functional deficits in the heart. J Clin Invest 1996;98:1906–1917.PubMedCrossRefGoogle Scholar
  46. Kass-Eisler A, Leinwand L. DNA and Adenovirus-mediated gene transfer into cardiac muscle. Methods Cell Biol 1998;52:423–437.CrossRefGoogle Scholar
  47. Keller TCS. Molecular bungees. Nature 1997;387:233–235.PubMedCrossRefGoogle Scholar
  48. Kinbara K, Ishiura S, Tomioka S, Sorimachi H, Jeong S, Amano S, Kawasaki H, Kolmerer B, Kimura S, Labeit S, Suzuki K. Purification of native p94, a muscle-specific calpain, and characterization of its autolysis. Biochem J 1998;335:589–596.PubMedGoogle Scholar
  49. Kolmerer B, Olivieri N, Witt CC, Herrmann BG, Labeit S. Genomic organization of the M-line titin and its tissue-specific expression in two distinct isoforms. J Mol Biol 1996;256:556–563.PubMedCrossRefGoogle Scholar
  50. Kumar A, Crawford K, Close L, Madison M, Lorenz J, Doetschman T, Pawlowski S, Duffy J, Neumann J, Robbins J, Boivin G. P., O’Toole BA, Lessard JL. Rescue of cardiac alpha-actin deficient mice by enteric smooth muscle gamma-actin. Proc Natl Acad Sci USA 1997;94:4406–4411.PubMedCrossRefGoogle Scholar
  51. Labeit S, Kolmerer B. Titins, giant proteins in charge of muscle ultrastructure and elasticity. Science 1995;270:293–296.PubMedCrossRefGoogle Scholar
  52. Labeit S, Kolmerer B, Linke W. The giant protein titin: emerging roles in physiology and pathophysiology. Circ Res 1997;80:290–294.PubMedCrossRefGoogle Scholar
  53. Labeit S, Gautel M, Lakey A, Trinick J. Towards a molecular understanding of titin. EMBO J 1992;11:1711–1716.PubMedGoogle Scholar
  54. Li H, Choudhary SK, Milner DJ, Munir ML, Kuisk IR, Capetanaki Y. Inhibition of desmin expression blocks myoblast fusion and interferes with the myogenic regulators MyoD and myogenin. J Cell Biol 1994;124:827:841.PubMedGoogle Scholar
  55. Lin Z, Kijikata T, Zhang Z, Choi J, Holtzer S, Sweeney HS, Holtzer H. Dispensability of the actin-binding site and spectrin repeats for targeting sarcomeric α-actinin into maturing Z-bands in vivo: implications for in vitro binding studies. Development. 1998;199:291–308.CrossRefGoogle Scholar
  56. Lin Z, Holtzer S, Schultheiss T, Murray J, Masaki T, Fischman DA, Holtzer H. Polygons and adhesion plaques and the disassembly and assembly of myofibrils in cardiac myocytes. J Cell Biol 1989;10:2355–2367.CrossRefGoogle Scholar
  57. Linke WA, Granzier H. A spring tale: new facts on titin elasticity. Biophys J 1998;75:2613–2614.PubMedCrossRefGoogle Scholar
  58. Linke WA, Ivemeyer M, Labeit S, Hinssen H, Ruegg JC, Gautel M. Actin-titin interaction in cardiac myofibrils: probing a physiological role. Biophys J 1997;73:905–919.PubMedCrossRefGoogle Scholar
  59. Linke WA, Ivemeyer M, Olivieri N, Kolmerer B, Rüegg JC, Labeit S. Towards a molecular understanding of the elasticity of titin. J Mol Biol 1996;261:62–71.PubMedCrossRefGoogle Scholar
  60. Linke WA, Rudy DE, Centner T, Witt C, Labeit S, Gregorio CC. I-band titin in cardiac muscle is a three-element molecular spring and is critical for maintaining thin filament structure. J Cell Biol 1999;146:631–644.PubMedCrossRefGoogle Scholar
  61. Littlefield R, Fowler VM. Defining actin filament length in striated muscle: rulers and caps or dynamic stability? Annu Rev Dev Biol 1998;14:487–525.CrossRefGoogle Scholar
  62. Lough JW, Markwald RR. A culture model for cardiac morphogenesis. Ann NY Acad Sci 1990;588:421–424.CrossRefGoogle Scholar
  63. Luo G, Zhang JQ, Nguyen TP, Herrera AH, Paterson B, Horowits R. Complete cDNA sequence and tissue localization of N-RAP, a novel nebulin-related protein of striated muscle. Cell Motil Cytoskel 1997;38:75–90.CrossRefGoogle Scholar
  64. Machado C, Sunkel CE, Andrew DJ. Human autoantibodies reveal titin as a chromosomal protein. J cell Biol 1998;141:321–333.PubMedCrossRefGoogle Scholar
  65. Manasek FJ. Embryonic development of the heart. I. A light and electron microscopic study of myocardial development in the early chick embryo. J Morphol 1968;125:329–365.PubMedCrossRefGoogle Scholar
  66. Markwald RR. Distribution and relationship of precursor Z material to organizing myofibrillar bundles in embryonic rat and hamster ventricular myocytes. J Mol Cell Cardiol 1973;5:341–350.PubMedCrossRefGoogle Scholar
  67. Martin XJ, Wynne DG, Glennon PE, Moorman A, Boheler KR. Regulation of expression of contractile proteins with cardiac hypertrophy and failure. Mol Cell Biochem 1996;157:181–189.PubMedCrossRefGoogle Scholar
  68. Maruyama K. Connectin/titin, giant elastic protein of muscle. Faseb J 1997;11:341–345.PubMedGoogle Scholar
  69. Maruyama K, Matsubara R, Natori Y, Nonomura S, Kimura S, Ohashi K, Murakami F, Handa S, Eguchi G. Connectin, an elastic protein of muscle. J Biochem 1977;82:317–337.PubMedGoogle Scholar
  70. Maruyama K, Yoshioka T, Higuchi H, Ohashi K, Kimura S, Natori R. Connectin filaments link thick filaments and Z-lines in frog skeletal muscle as revealed by immunoelectron microscopy. J Cell Biol 1985;101:2167–2172.PubMedCrossRefGoogle Scholar
  71. Mayans O, van der Ven P, Wilm M, Mues A, Young P, Fürst DO, Wilmanns M, Gautel M. Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature 1998;395:863–869.PubMedCrossRefGoogle Scholar
  72. McKenna N, Meigs JB, Wang YL. Identical distribution of fluorescently labeled brain and muscle actins in living cardiac fibroblasts and myocytes. J Cell Biol 1985a;100:292–296.PubMedCrossRefGoogle Scholar
  73. McKenna N, Meigs JB, Wang YL. Exchangeability of alpha-actin in living cardiac fibroblasts and muscle cells. J Cell Biol 1985b;101:2223–2232.PubMedCrossRefGoogle Scholar
  74. Michele DE, Albayya P, Metzger JM. Thin filament protein dynamics in fully differentiated adult cardiac myocytes: toward a model of sarcomere maintenance. J Cell Biol 1999;145:1483–1495.PubMedCrossRefGoogle Scholar
  75. Millevoi S, Trombitás K, Kostin S, Schaper J, Pelin K, Kolmerer B, Granzier H, Labeit S. Characterization of Nebulette and Nebulin and emerging concepts of their roles for vertebrate Z-discs. J Mol Biol 1998;282:111–123.PubMedCrossRefGoogle Scholar
  76. Mittal B, Sanger JM, Sänger JW. Visualization of myosin in living cells. J Cell Biol 1987;105:1753–1760.PubMedCrossRefGoogle Scholar
  77. Moncman CL, Wang K. Nebulette: a 107 kD nebulin-like protein in cardiac muscle. Cell Motil Cyto 1995;32:205–225.CrossRefGoogle Scholar
  78. Mues A, van der Ven PF, Young P, Fürst DO, Gautel M. Two immunoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin. FEBS Lett 1998;428:111–114.PubMedCrossRefGoogle Scholar
  79. Ng WA, Doetschman T, Lessard JL. Muscle isoactin expression during in vitro differentiation of murine embryonic stem cells. Pediatr Res 1997;41:285–292.PubMedCrossRefGoogle Scholar
  80. Obermann WM, Gautel M, Weber K, Fürst DO. Molecular structure of the sarcomeric M band: mapping of titin and myosin binding domains in myomesin and the identification of a potential regulatory phosphorylation site in myomesin. EMBO J 1997;16:211–220.PubMedCrossRefGoogle Scholar
  81. Obermann WMJ, Gautel M, Steiner F, van der Ven PFM, Weber K, Fürst DO. The structure of the sarcomeric M band: localization of defined domains of myomesin, M protein, and the 250 kD carboxy terminal region of titin by immunoelectron microscopy. J Cell Biol 1996;134:1441–1453.PubMedCrossRefGoogle Scholar
  82. Ohtsuka H, Yajima H, Kimura S, Maruyama K. Binding of the N terminal fragment of connectin/ titin to alpha-actinin as revealed by yeast two-hybrid systems. FEBS Lett 1997;401:65–67.PubMedCrossRefGoogle Scholar
  83. Ojala J, Choudhury M, Bag J. Inhibition of troponin C production without affecting other muscle protein synthesis by the antisense oligonucleotide. Antisense Nucleic Acid Drug Dev 1997;7:31–8.PubMedCrossRefGoogle Scholar
  84. Okagaki T, Weber FE, Fischman DA, Vaughan KT, Mikawa T, Reinach FC. The major myosin-binding domain of skeletal muscle MyBP-C (Cprotein) resides in the COOH-terminal, immunoglobulin C2 motif. J Cell Biol 1993;123:619–626.PubMedCrossRefGoogle Scholar
  85. Peckham M, Young P, Gautel M. Constitutive and variable regions of Z-disc titin/connectin in myofibril formation: a dominant-negative screen. Cell Struc Func 1997;22:95–101.CrossRefGoogle Scholar
  86. Rethinasamy P, Muthuchamy M, Hewett T, Boivin G, Wolska BM, Evans C, Solaro RJ, Wieczorek DF. Molecular and physiological effects of alpha-tropomyosin ablation in the mouse. Circ Res 1998;82:116–123.PubMedCrossRefGoogle Scholar
  87. Rhee D, Sanger JM, Sänger JW. The premyofibril: evidence for its role in myofibrillogenesis. Cell Motil Cytoskel1994;28:1–24.CrossRefGoogle Scholar
  88. Robbins J, Gulick J, Sanchez A, Howies P, Doetschman T. Mouse embryonic stem cells express the cardiac myosin heavy chain genes during development in vitro. J Biol Chem 1990;265:11905–11909.PubMedGoogle Scholar
  89. Rudy DE, Yatskievych TA, Antin PB, Gregorio CC. Investigation of the assembly of thick, thin and titin filaments in chick precardiac explants. Mol Biol Cell 1999;10:980.Google Scholar
  90. Sanger JW, Mittal B, Sanger JW. Analysis of myofiber structure and assembly using fluorescently labeled contractile proteins. J Cell Biol 1984;98:825–833.PubMedCrossRefGoogle Scholar
  91. Sanger JM, Mittal B, Pochapin MB, Sanger JW. Myofibrillogeneis in living cells microinjected with fluorescently labeled alpha-actinin. J Cell Biol 1986;102:2053–2066.PubMedCrossRefGoogle Scholar
  92. Schafer DA, Hug C, Cooper JA. Inhibition of CapZ during myofibrillogenesis alters assembly of actin filaments. J Cell Biol 1995;128:61–70.PubMedCrossRefGoogle Scholar
  93. Schultheiss T, Lin Z, Lu M-H, Murray J, Fischman DA, Weber K, Masaki M, Imamura M, Holtzer H. Differential distribution of subsets of myofibrillar proteins in cardiac nonstriated and striated myofibrils. J Cell Biol 1990;110:1159–1172.PubMedCrossRefGoogle Scholar
  94. Shimada Y, Komiyama M, Begum S, Maruyama K. Development of connectin/titin and nebulin in striated muscles of chicken. Adv Biophys 1996;33:223–234.PubMedCrossRefGoogle Scholar
  95. Shiraishi I, Takamatsu T, Fujita S. Three-dimensional observation with a confocal scanning laser microscope of fibronectin immunolabeling during cardiac looping in the chick embryo. Anat Embryol 1995;191:183–189.PubMedCrossRefGoogle Scholar
  96. Shiraishi I, Simpson DG, Carver W, Price R, Hirozane T, Terracio L, Borg TK. Vinculin is an essential component for normal myofibrillar arrangement in fetal mouse cardiac myocytes. J Mol Cell Cardiol 1997;29:2041–2052.PubMedCrossRefGoogle Scholar
  97. Shiraishi I, Takamatsu T, Fujita S. 3-D observation of N-cadherin expression during cardiac myofibrillogenesis of the chick embryo using a confocal laser scanning microscope. Anat Embryol 1993;187:115–120.PubMedCrossRefGoogle Scholar
  98. Simpson DG, Decker ML, Clark WA, Decker RS. Contractile activity and cell-cell contact regulate myofibrillar organization in cultured cardiac myocytes. J Cell Biol 1993;123:323–336.PubMedCrossRefGoogle Scholar
  99. Sorimachi H, Kinbara K, Kimura S, Takahashi M, Ishiura S, Sasagawa N, Sorimachi N, Shimada H, Tagawa K, Maruyama K, Suzuki K. Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence. J Biol Chem 1995;270:31158–31162.PubMedCrossRefGoogle Scholar
  100. Sorimachi H, Freiburg A, Kolmerer B, Ishiura S, Stier G, Gregorio CC, Linke WA, Suzuki K, Labeit SL. Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs. J Mol Biol 1997;270:688–695.PubMedCrossRefGoogle Scholar
  101. Soteriou A, Gamage M, Trinick J. A survey of the interactions made by titin. J Cell Sci 1993;104:119–123.PubMedGoogle Scholar
  102. Squire JM. Architecture and function in the muscle sarcomere. Curr Opin Struct Biol 1997;7:247–257.PubMedCrossRefGoogle Scholar
  103. Sussman MA, Baquè UC-S, Daniels MP, Price RL, Simpson D, Terracio L, Kedes L. Altered expression of tropomodulin in cardiomyocytes disrupts the sarcomeric structure of myofibrils. Circ Res 1998;82:94–105.PubMedCrossRefGoogle Scholar
  104. Tardiff JC, Factor SM, Tompkins BD, Hewett TE, Palmer BM, Moore RL, Schwartz S, Robbins J, Leinwand LA. A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. J Clin Invest 1998;101:2800–2811.PubMedCrossRefGoogle Scholar
  105. Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg H-P, Seidman JG, Seidman C. Beta-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 1994;77:701–712.PubMedCrossRefGoogle Scholar
  106. Tokuyasu KT, Maher PA. Immunocytochemical studies of cardiac myofibrillogenesis in early chick embryos. I. Presence of immunofluorescent titin spots in premyofibrillar stages. J Cell Biol 1987a;105:2781–2793.PubMedCrossRefGoogle Scholar
  107. Tokuyasu KT, Maher PA. Immunocytochemical studies of cardiac myofibrillogenesis in early chick embryos. II. Generation of alpha-actinin dots within titin spots at the time of the first myofibril formation. J Cell Biol 1987b;105:2795–2801.PubMedCrossRefGoogle Scholar
  108. Trinick J. Titin and nebulin protein rulers in muscle? Trends Biochem Sci 1994;19:405–408.PubMedCrossRefGoogle Scholar
  109. Trinick J. Cytoskeleton: titin as a scaffold and spring. Curr Biol 1996;6:258–260.PubMedCrossRefGoogle Scholar
  110. Trombitás K, Granzier H. Actin removal from cardiac myocytes shows that near the Z-line titin attaches to actin while under tension. Am J Physiol 1997;273:C662–C670.PubMedGoogle Scholar
  111. Turnacioglu KK, Mittal B, Dabiri GA, Sanger JM, Sanger, JW. An N-terminal fragment of titin coupled to green fluorescent protein localizes to the Z-bands in living muscle cells: overexpression leads to myofibril disassembly. Mol Biol Cell 1997;8:705–717.PubMedGoogle Scholar
  112. Valle G, Faulkner G, De Antoni A, Pacchioni B, Pallavicini A, Pandolofo D, Tiso N, Toppo S, Trevisan S, Lanfranchi G. Telethonin, a novel sarcomeric protein of heart and skeletal muscle. FEBS Lett 1997;415:163–168.PubMedCrossRefGoogle Scholar
  113. Vigoreaux JO. The muscle Z-band: lessons in stress management J Muscle Res Cell Motil 1994;15:237–255.PubMedGoogle Scholar
  114. Vikstrom KL, Factor SM, Leinwand LA. Mice expressing mutant myosing heavy chains are a model for familial hyptertrophic cardiomyopathy. Mol Med 1996,2:556–567.PubMedGoogle Scholar
  115. Wagner RW. The state of the art in antisense research. Nat Med 1995;1:1116–1118.PubMedCrossRefGoogle Scholar
  116. Wang K, McClure J, Tu A. Titin: Major myofibrillar component of striated muscle. Proc Natl Acad Sci USA 1979;76:3698–3702.PubMedCrossRefGoogle Scholar
  117. Wang K. Titin/connectin and nebulin: giant protein rulers of muscle structure and function. Adv Biophys 1996;33:123–134.PubMedCrossRefGoogle Scholar
  118. Wang K, Knipfer M, Huang Q, van Heerden A, Hsu LC, Gutierrez G, Quian X, Stedman H. Human skeletal muscle nebulin sequence encodes a blueprint for thin filament architecture. Sequence motifs and affinity profiles of tandem repeats and terminal SH3. J Biol Chem 1996;271:4304–4314.PubMedCrossRefGoogle Scholar
  119. Wang SM, Greaser ML, Schultz E, Bulinski JC, Lin JJ, Lessard JL. Studies on cardiac myofibrillogenesis with antibodies to titin, actin, tropomyosin, and myosin. J Cell Biol 1988;107:1075–1083.PubMedCrossRefGoogle Scholar
  120. Westfall MV, Pasyk KA, Yule DI, Samuelson LC, Metzger JM. Ultrastructure and cell-cell coupling of cardiac myocytes differentiating in embryonic stem cell cultures. Cell Motil Cytoskel 1997;36:43–54.CrossRefGoogle Scholar
  121. Whiting A, Wardale J, Trinick J. Does titin regulate the length of muscle thick filaments? J Mol Biol 1989,205:263–268.PubMedCrossRefGoogle Scholar
  122. Wobus AM, Kaomei G, Shan J, Wellner MC, Rohwedel J, Guanju J, Fleischmann B, Katus HA, Hescheler J, Franz WM. Retinoic acid accelerates embryonic stem cell-derived cardiac differentiation and enhances development of ventricular cardiomyocytes. J Mol Cell Cardiol 1997;29:1525–1539.PubMedCrossRefGoogle Scholar
  123. Yajima H, Ohtsuka H, Kawamura Y, Kume H, Maruyama T, Abe H, Kimura S, Maruyama K. A 11.5 kb 5’-terminal cDNA sequence of chicken breast muscle connectin/titin reveals its Z-line binding region. Biochem Biophys Res Commun 1996;223:160–164.PubMedCrossRefGoogle Scholar
  124. Yang Q, Sanbe A, Osinska H, Hewett TE, Klevitsky R, Robbins J. A mouse model of myosin binding protein C human familial hypertrophie cardiomyopathy. J Clin Invest 1998;102:1292–300.PubMedCrossRefGoogle Scholar
  125. Yatskievych TA, Ladd A, Antin PB. Induction of cardiac myogenesis in avian pregastrula epiblast: the role of the hypoblast and activin. Development 1997;124:2561–2570.PubMedGoogle Scholar
  126. Young P, Ferguson C, Banuelos S, Gautel M. Molecular structure of the sarcomeric Z-disc: two types of titin interactions lead to an asymmetrical sorting of alpha-actinin. EMBO J 1998;17:1614–1624.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Abigail S. McElhinny
    • 1
  • Siegfried Labeit
    • 2
  • Carol C. Gregorio
    • 1
    • 3
  1. 1.Department of Cell Biology and AnatomyUniversity of ArizonaTucsonUSA
  2. 2.European Molecular Biology LaboratoryHeidelbergGermany
  3. 3.Department of Molecular and Cellular BiologyUniversity of ArizonaTucsonUSA

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