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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2002 Feb 28;357(1418):199–206. doi: 10.1098/rstb.2001.1028

Role of titin in vertebrate striated muscle.

L Tskhovrebova 1, J Trinick 1
PMCID: PMC1692937  PMID: 11911777

Abstract

Titin is a giant muscle protein with a molecular weight in the megaDalton range and a contour length of more than 1 microm. Its size and location within the sarcomere structure determine its important role in the mechanism of muscle elasticity. According to the current consensus, elasticity stems directly from more than one type of spring-like behaviour of the I-band portion of the molecule. Starting from slack length, extension of the sarcomere first causes straightening of the molecule. Further extension then induces local unfolding of a unique sequence, the PEVK region, which is named due to the preponderance of these amino-acid residues. High speeds of extension and/or high forces are likely to lead to unfolding of the beta-sandwich domains from which the molecule is mainly constructed. A release of tension leads to refolding and recoiling of the polypeptide. Here, we review the literature and present new experimental material related to the role of titin in muscle elasticity. In particular, we analyse the possible influence of the arrangement and environment of titin within the sarcomere structure on its extensible behaviour. We suggest that, due to the limited conformational space, elongation and compression of the molecule within the sarcomere occur in a more ordered way or with higher viscosity and higher forces than are observed in solution studies of the isolated protein.

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Selected References

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  1. Bennett P. M., Hodkin T. E., Hawkins C. Evidence that the tandem Ig domains near the end of the muscle thick filament form an inelastic part of the I-band titin. J Struct Biol. 1997 Oct;120(1):93–104. doi: 10.1006/jsbi.1997.3898. [DOI] [PubMed] [Google Scholar]
  2. Brady A. J. Length dependence of passive stiffness in single cardiac myocytes. Am J Physiol. 1991 Apr;260(4 Pt 2):H1062–H1071. doi: 10.1152/ajpheart.1991.260.4.H1062. [DOI] [PubMed] [Google Scholar]
  3. Carrion-Vazquez M., Oberhauser A. F., Fowler S. B., Marszalek P. E., Broedel S. E., Clarke J., Fernandez J. M. Mechanical and chemical unfolding of a single protein: a comparison. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3694–3699. doi: 10.1073/pnas.96.7.3694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cazorla O., Freiburg A., Helmes M., Centner T., McNabb M., Wu Y., Trombitás K., Labeit S., Granzier H. Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ Res. 2000 Jan 7;86(1):59–67. doi: 10.1161/01.res.86.1.59. [DOI] [PubMed] [Google Scholar]
  5. Freiburg A., Gautel M. A molecular map of the interactions between titin and myosin-binding protein C. Implications for sarcomeric assembly in familial hypertrophic cardiomyopathy. Eur J Biochem. 1996 Jan 15;235(1-2):317–323. doi: 10.1111/j.1432-1033.1996.00317.x. [DOI] [PubMed] [Google Scholar]
  6. Freiburg A., Trombitas K., Hell W., Cazorla O., Fougerousse F., Centner T., Kolmerer B., Witt C., Beckmann J. S., Gregorio C. C. Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity. Circ Res. 2000 Jun 9;86(11):1114–1121. doi: 10.1161/01.res.86.11.1114. [DOI] [PubMed] [Google Scholar]
  7. 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 Feb;120(3):711–724. doi: 10.1083/jcb.120.3.711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fürst D. O., 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 May;106(5):1563–1572. doi: 10.1083/jcb.106.5.1563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gajdosik R. L. Passive extensibility of skeletal muscle: review of the literature with clinical implications. Clin Biomech (Bristol, Avon) 2001 Feb;16(2):87–101. doi: 10.1016/s0268-0033(00)00061-9. [DOI] [PubMed] [Google Scholar]
  10. Gautel M., Mues A., Young P. Control of sarcomeric assembly: the flow of information on titin. Rev Physiol Biochem Pharmacol. 1999;138:97–137. doi: 10.1007/BFb0119625. [DOI] [PubMed] [Google Scholar]
  11. Gautel M. The super-repeats of titin/connectin and their interactions: glimpses at sarcomeric assembly. Adv Biophys. 1996;33:27–37. doi: 10.1016/s0065-227x(96)90020-9. [DOI] [PubMed] [Google Scholar]
  12. Granzier H. L., Irving T. C. Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophys J. 1995 Mar;68(3):1027–1044. doi: 10.1016/S0006-3495(95)80278-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Granzier H., Helmes M., Trombitás K. Nonuniform elasticity of titin in cardiac myocytes: a study using immunoelectron microscopy and cellular mechanics. Biophys J. 1996 Jan;70(1):430–442. doi: 10.1016/S0006-3495(96)79586-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Greaser M. Identification of new repeating motifs in titin. Proteins. 2001 May 1;43(2):145–149. doi: 10.1002/1097-0134(20010501)43:2<145::aid-prot1026>3.0.co;2-b. [DOI] [PubMed] [Google Scholar]
  15. Gregorio C. C., Trombitás K., Centner T., Kolmerer B., Stier G., Kunke K., Suzuki K., Obermayr F., Herrmann B., Granzier H. 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 Nov 16;143(4):1013–1027. doi: 10.1083/jcb.143.4.1013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gutierrez-Cruz G., Van Heerden A. H., Wang K. Modular motif, structural folds and affinity profiles of the PEVK segment of human fetal skeletal muscle titin. J Biol Chem. 2000 Nov 17;276(10):7442–7449. doi: 10.1074/jbc.M008851200. [DOI] [PubMed] [Google Scholar]
  17. Helmes M., Trombitás K., Granzier H. Titin develops restoring force in rat cardiac myocytes. Circ Res. 1996 Sep;79(3):619–626. doi: 10.1161/01.res.79.3.619. [DOI] [PubMed] [Google Scholar]
  18. Higuchi H., Nakauchi Y., Maruyama K., Fujime S. Characterization of beta-connectin (titin 2) from striated muscle by dynamic light scattering. Biophys J. 1993 Nov;65(5):1906–1915. doi: 10.1016/S0006-3495(93)81261-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Horowits R. Passive force generation and titin isoforms in mammalian skeletal muscle. Biophys J. 1992 Feb;61(2):392–398. doi: 10.1016/S0006-3495(92)81845-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Horowits R., Podolsky R. J. Thick filament movement and isometric tension in activated skeletal muscle. Biophys J. 1988 Jul;54(1):165–171. doi: 10.1016/S0006-3495(88)82941-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Horowits R. The physiological role of titin in striated muscle. Rev Physiol Biochem Pharmacol. 1999;138:57–96. doi: 10.1007/BFb0119624. [DOI] [PubMed] [Google Scholar]
  22. Houmeida A., Holt J., Tskhovrebova L., Trinick J. Studies of the interaction between titin and myosin. J Cell Biol. 1995 Dec;131(6 Pt 1):1471–1481. doi: 10.1083/jcb.131.6.1471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Improta S., Politou A. S., Pastore A. Immunoglobulin-like modules from titin I-band: extensible components of muscle elasticity. Structure. 1996 Mar 15;4(3):323–337. doi: 10.1016/s0969-2126(96)00036-6. [DOI] [PubMed] [Google Scholar]
  24. Kellermayer M. S., Smith S. B., Bustamante C., Granzier H. L. Complete unfolding of the titin molecule under external force. J Struct Biol. 1998;122(1-2):197–205. doi: 10.1006/jsbi.1998.3988. [DOI] [PubMed] [Google Scholar]
  25. Kellermayer M. S., Smith S. B., Granzier H. L., Bustamante C. Folding-unfolding transitions in single titin molecules characterized with laser tweezers. Science. 1997 May 16;276(5315):1112–1116. doi: 10.1126/science.276.5315.1112. [DOI] [PubMed] [Google Scholar]
  26. Labeit S., Gautel M., Lakey A., Trinick J. Towards a molecular understanding of titin. EMBO J. 1992 May;11(5):1711–1716. doi: 10.1002/j.1460-2075.1992.tb05222.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Labeit S., Kolmerer B. Titins: giant proteins in charge of muscle ultrastructure and elasticity. Science. 1995 Oct 13;270(5234):293–296. doi: 10.1126/science.270.5234.293. [DOI] [PubMed] [Google Scholar]
  28. Linke W. A., Granzier H. A spring tale: new facts on titin elasticity. Biophys J. 1998 Dec;75(6):2613–2614. doi: 10.1016/S0006-3495(98)77706-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Linke W. A., Ivemeyer M., Labeit S., Hinssen H., Rüegg J. C., Gautel M. Actin-titin interaction in cardiac myofibrils: probing a physiological role. Biophys J. 1997 Aug;73(2):905–919. doi: 10.1016/S0006-3495(97)78123-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Linke W. A., Ivemeyer M., Mundel P., Stockmeier M. R., Kolmerer B. Nature of PEVK-titin elasticity in skeletal muscle. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8052–8057. doi: 10.1073/pnas.95.14.8052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Linke W. A., Ivemeyer M., Olivieri N., Kolmerer B., Rüegg J. C., Labeit S. Towards a molecular understanding of the elasticity of titin. J Mol Biol. 1996 Aug 9;261(1):62–71. doi: 10.1006/jmbi.1996.0441. [DOI] [PubMed] [Google Scholar]
  32. Linke W. A., Rudy D. E., Centner T., Gautel M., Witt C., Labeit S., Gregorio C. C. I-band titin in cardiac muscle is a three-element molecular spring and is critical for maintaining thin filament structure. J Cell Biol. 1999 Aug 9;146(3):631–644. doi: 10.1083/jcb.146.3.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Linke W. A., Stockmeier M. R., Ivemeyer M., Hosser H., Mundel P. Characterizing titin's I-band Ig domain region as an entropic spring. J Cell Sci. 1998 Jun;111(Pt 11):1567–1574. doi: 10.1242/jcs.111.11.1567. [DOI] [PubMed] [Google Scholar]
  34. Linke W. A. Stretching molecular springs: elasticity of titin filaments in vertebrate striated muscle. Histol Histopathol. 2000 Jul;15(3):799–811. doi: 10.14670/HH-15.799. [DOI] [PubMed] [Google Scholar]
  35. Liversage A. D., Holmes D., Knight P. J., Tskhovrebova L., Trinick J. Titin and the sarcomere symmetry paradox. J Mol Biol. 2001 Jan 19;305(3):401–409. doi: 10.1006/jmbi.2000.4279. [DOI] [PubMed] [Google Scholar]
  36. Lu H., Schulten K. The key event in force-induced unfolding of Titin's immunoglobulin domains. Biophys J. 2000 Jul;79(1):51–65. doi: 10.1016/S0006-3495(00)76273-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ma K., Kan L., Wang K. Polyproline II helix is a key structural motif of the elastic PEVK segment of titin. Biochemistry. 2001 Mar 27;40(12):3427–3438. doi: 10.1021/bi0022792. [DOI] [PubMed] [Google Scholar]
  38. Magid A., Law D. J. Myofibrils bear most of the resting tension in frog skeletal muscle. Science. 1985 Dec 13;230(4731):1280–1282. doi: 10.1126/science.4071053. [DOI] [PubMed] [Google Scholar]
  39. Maruyama K. Connectin/titin, giant elastic protein of muscle. FASEB J. 1997 Apr;11(5):341–345. doi: 10.1096/fasebj.11.5.9141500. [DOI] [PubMed] [Google Scholar]
  40. Maruyama K., Kimura S., Yoshidomi H., Sawada H., Kikuchi M. Molecular size and shape of beta-connectin, an elastic protein of striated muscle. J Biochem. 1984 May;95(5):1423–1433. doi: 10.1093/oxfordjournals.jbchem.a134750. [DOI] [PubMed] [Google Scholar]
  41. Millman B. M. The filament lattice of striated muscle. Physiol Rev. 1998 Apr;78(2):359–391. doi: 10.1152/physrev.1998.78.2.359. [DOI] [PubMed] [Google Scholar]
  42. Minajeva A., Kulke M., Fernandez J. M., Linke W. A. Unfolding of titin domains explains the viscoelastic behavior of skeletal myofibrils. Biophys J. 2001 Mar;80(3):1442–1451. doi: 10.1016/S0006-3495(01)76116-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Mutungi G., Ranatunga K. W. The viscous, viscoelastic and elastic characteristics of resting fast and slow mammalian (rat) muscle fibres. J Physiol. 1996 Nov 1;496(Pt 3):827–836. doi: 10.1113/jphysiol.1996.sp021730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Nave R., Fürst D. O., Weber K. Visualization of the polarity of isolated titin molecules: a single globular head on a long thin rod as the M band anchoring domain? J Cell Biol. 1989 Nov;109(5):2177–2187. doi: 10.1083/jcb.109.5.2177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Obermann W. M., Gautel M., Weber K., Fürst D. O. 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 Jan 15;16(2):211–220. doi: 10.1093/emboj/16.2.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Politou A. S., Thomas D. J., Pastore A. The folding and stability of titin immunoglobulin-like modules, with implications for the mechanism of elasticity. Biophys J. 1995 Dec;69(6):2601–2610. doi: 10.1016/S0006-3495(95)80131-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rief M., Gautel M., Oesterhelt F., Fernandez J. M., Gaub H. E. Reversible unfolding of individual titin immunoglobulin domains by AFM. Science. 1997 May 16;276(5315):1109–1112. doi: 10.1126/science.276.5315.1109. [DOI] [PubMed] [Google Scholar]
  48. Soteriou A., Clarke A., Martin S., Trinick J. Titin folding energy and elasticity. Proc Biol Sci. 1993 Nov 22;254(1340):83–86. doi: 10.1098/rspb.1993.0130. [DOI] [PubMed] [Google Scholar]
  49. Soteriou A., Gamage M., Trinick J. A survey of interactions made by the giant protein titin. J Cell Sci. 1993 Jan;104(Pt 1):119–123. doi: 10.1242/jcs.104.1.119. [DOI] [PubMed] [Google Scholar]
  50. Trinick J. A. End-filaments: a new structural element of vertebrate skeletal muscle thick filaments. J Mol Biol. 1981 Sep 15;151(2):309–314. doi: 10.1016/0022-2836(81)90517-9. [DOI] [PubMed] [Google Scholar]
  51. Trinick J., Knight P., Whiting A. Purification and properties of native titin. J Mol Biol. 1984 Dec 5;180(2):331–356. doi: 10.1016/s0022-2836(84)80007-8. [DOI] [PubMed] [Google Scholar]
  52. Trinick J. Titin and nebulin: protein rulers in muscle? Trends Biochem Sci. 1994 Oct;19(10):405–409. doi: 10.1016/0968-0004(94)90088-4. [DOI] [PubMed] [Google Scholar]
  53. Trinick J. Titin as a scaffold and spring. Cytoskeleton. Curr Biol. 1996 Mar 1;6(3):258–260. doi: 10.1016/s0960-9822(02)00472-4. [DOI] [PubMed] [Google Scholar]
  54. Trinick J., Tskhovrebova L. Titin: a molecular control freak. Trends Cell Biol. 1999 Oct;9(10):377–380. doi: 10.1016/s0962-8924(99)01641-4. [DOI] [PubMed] [Google Scholar]
  55. Trombitás K., Freiburg A., Centner T., Labeit S., Granzier H. Molecular dissection of N2B cardiac titin's extensibility. Biophys J. 1999 Dec;77(6):3189–3196. doi: 10.1016/S0006-3495(99)77149-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Trombitás K., Greaser M. L., Pollack G. H. Interaction between titin and thin filaments in intact cardiac muscle. J Muscle Res Cell Motil. 1997 Jun;18(3):345–351. doi: 10.1023/a:1018626210300. [DOI] [PubMed] [Google Scholar]
  57. Trombitás K., Greaser M., Labeit S., Jin J. P., Kellermayer M., Helmes M., Granzier H. Titin extensibility in situ: entropic elasticity of permanently folded and permanently unfolded molecular segments. J Cell Biol. 1998 Feb 23;140(4):853–859. doi: 10.1083/jcb.140.4.853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Trombitás K., Redkar A., Centner T., Wu Y., Labeit S., Granzier H. Extensibility of isoforms of cardiac titin: variation in contour length of molecular subsegments provides a basis for cellular passive stiffness diversity. Biophys J. 2000 Dec;79(6):3226–3234. doi: 10.1016/S0006-3495(00)76555-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tskhovrebova L., Trinick J. Direct visualization of extensibility in isolated titin molecules. J Mol Biol. 1997 Jan 17;265(2):100–106. doi: 10.1006/jmbi.1996.0717. [DOI] [PubMed] [Google Scholar]
  60. Tskhovrebova L., Trinick J. Extensibility in the titin molecule and its relation to muscle elasticity. Adv Exp Med Biol. 2000;481:163–178. doi: 10.1007/978-1-4615-4267-4_10. [DOI] [PubMed] [Google Scholar]
  61. Tskhovrebova L., Trinick J. Flexibility and extensibility in the titin molecule: analysis of electron microscope data. J Mol Biol. 2001 Jul 20;310(4):755–771. doi: 10.1006/jmbi.2001.4700. [DOI] [PubMed] [Google Scholar]
  62. Tskhovrebova L., Trinick J., Sleep J. A., Simmons R. M. Elasticity and unfolding of single molecules of the giant muscle protein titin. Nature. 1997 May 15;387(6630):308–312. doi: 10.1038/387308a0. [DOI] [PubMed] [Google Scholar]
  63. Wang K., McCarter R., Wright J., Beverly J., Ramirez-Mitchell R. 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. 1991 Aug 15;88(16):7101–7105. doi: 10.1073/pnas.88.16.7101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Wang K., McCarter R., Wright J., Beverly J., Ramirez-Mitchell R. Viscoelasticity of the sarcomere matrix of skeletal muscles. The titin-myosin composite filament is a dual-stage molecular spring. Biophys J. 1993 Apr;64(4):1161–1177. doi: 10.1016/S0006-3495(93)81482-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Wang K., Ramirez-Mitchell R., Palter D. Titin is an extraordinarily long, flexible, and slender myofibrillar protein. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3685–3689. doi: 10.1073/pnas.81.12.3685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Wang K. Titin/connectin and nebulin: giant protein rulers of muscle structure and function. Adv Biophys. 1996;33:123–134. [PubMed] [Google Scholar]
  67. Witt C. C., Olivieri N., Centner T., Kolmerer B., Millevoi S., Morell J., Labeit D., Labeit S., Jockusch H., Pastore A. A survey of the primary structure and the interspecies conservation of I-band titin's elastic elements in vertebrates. J Struct Biol. 1998;122(1-2):206–215. doi: 10.1006/jsbi.1998.3993. [DOI] [PubMed] [Google Scholar]
  68. Wu Y., Cazorla O., Labeit D., Labeit S., Granzier H. Changes in titin and collagen underlie diastolic stiffness diversity of cardiac muscle. J Mol Cell Cardiol. 2000 Dec;32(12):2151–2162. doi: 10.1006/jmcc.2000.1281. [DOI] [PubMed] [Google Scholar]

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