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Annual Review of Physiology

Volume 80, 2018

Titin Gene and Protein Functions in Passive and Active Muscle

Abstract

The thin and thick filaments of muscle sarcomeres are interconnected by the giant protein titin, which is a scaffolding filament, signaling platform, and provider of passive tension and elasticity in myocytes. This review summarizes recent insight into the mechanisms behind how titin gene mutations cause hereditary cardiomyopathy and how titin protein is mechanically active in skeletal and cardiac myocytes. A main theme is the evolving role of titin as a modulator of contraction. Topics include strain-sensing via titin in the sarcomeric A-band as the basis for length-dependent activation, titin elastic recoil and refolding of titin domains as an energy source, and Ca2+-dependent stiffening of titin stretched during eccentric muscle contractions. Findings suggest that titin stiffness is a principal regulator of the contractile behavior of striated muscle. Physiological or pathological changes to titin stiffness therefore affect contractility. Taken together, titin emerges as a linker element between passive and active myocyte properties.

Keyword(s): cardiac muscle, cardiomyopathy, heart failure, muscle mechanics, sarcomere, skeletal muscle
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2018-02-10
2024-05-12
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Literature Cited

  1. Hill AV. 1.  1938. The heat of shortening and dynamic constants of muscles. Proc. R. Soc. B 126:136–95 [Google Scholar]
  2. Campbell KS.2.  2011. Impact of myocyte strain on cardiac myofilament activation. Pflügers Arch 462:13–14 [Google Scholar]
  3. McDonald KS.3.  2011. The interdependence of Ca2+ activation, sarcomere length, and power output in the heart. Pflügers Arch 462:161–67 [Google Scholar]
  4. Fukuda N, Terui T, Ohtsuki I, Ishiwata S, Kurihara S. 4.  2009. Titin and troponin: central players in the Frank-Starling mechanism of the heart. Curr. Cardiol. Rev. 5:2119–24 [Google Scholar]
  5. de Tombe PP, Mateja RD, Tachampa K, Ait Mou Y, Farman GP, Irving TC. 5.  2010. Myofilament length dependent activation. J. Mol. Cell. Cardiol. 48:5851–58 [Google Scholar]
  6. Bullard B, Pastore A. 6.  2011. Regulating the contraction of insect flight muscle. J. Muscle Res. Cell Motil. 32:4–5303–13 [Google Scholar]
  7. Steiger GJ.7.  1971. Stretch activation and myogenic oscillation of isolated contractile structures of heart muscle. Pflügers Arch 330:4347–61 [Google Scholar]
  8. Kulke M, Neagoe C, Kolmerer B, Minajeva A, Hinssen H. 8.  et al. 2001. Kettin, a major source of myofibrillar stiffness in Drosophila indirect flight muscle. J. Cell Biol. 154:51045–57 [Google Scholar]
  9. Bullard B, Linke WA, Leonard K. 9.  2002. Varieties of elastic protein in invertebrate muscles. J. Muscle Res. Cell Motil. 23:5–6435–47 [Google Scholar]
  10. Krzic U, Rybin V, Leonard KR, Linke WA, Bullard B. 10.  2010. Regulation of oscillatory contraction in insect flight muscle by troponin. J. Mol. Biol. 397:1110–18 [Google Scholar]
  11. Perz-Edwards RJ, Irving TC, Baumann BA, Gore D, Hutchinson DC. 11.  et al. 2011. X-ray diffraction evidence for myosin-troponin connections and tropomyosin movement during stretch activation of insect flight muscle. PNAS 108:1120–25 [Google Scholar]
  12. Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M. 12.  et al. 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. 89:111065–72 [Google Scholar]
  13. Zou J, Tran D, Baalbaki M, Tang LF, Poon A. 13.  et al. 2015. An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of titin in zebrafish. eLife 4:e09406 [Google Scholar]
  14. Freiburg A, Trombitas K, Hell W, Cazorla O, Fougerousse F. 14.  et al. 2000. Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity. Circ. Res. 86:111114–21 [Google Scholar]
  15. Miller MK, Granzier H, Ehler E, Gregorio CC. 15.  2004. The sensitive giant: the role of titin-based stretch sensing complexes in the heart. Trends Cell Biol 14:3119–26 [Google Scholar]
  16. Linke WA.16.  2008. Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc. Res. 77:4637–48 [Google Scholar]
  17. Gautel M, Djinović-Carugo K. 17.  2016. The sarcomeric cytoskeleton: from molecules to motion. J. Exp. Biol. 219:Pt. 2135–45 [Google Scholar]
  18. Labeit S, Gautel M, Lakey A, Trinick J. 18.  1992. Towards a molecular understanding of titin. EMBO J 11:51711–16 [Google Scholar]
  19. Whiting A, Wardale J, Trinick J. 19.  1989. Does titin regulate the length of muscle thick filaments?. J. Mol. Biol. 205:1263–68 [Google Scholar]
  20. Tskhovrebova L, Bennett P, Gautel M, Trinick J. 20.  2015. Titin ruler hypothesis not refuted. PNAS 112:11E1172 [Google Scholar]
  21. Granzier HL, Hutchinson KR, Tonino P, Methawasin M, Li FW. 21.  et al. 2014. Deleting titin's I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function. PNAS 111:4014589–94 [Google Scholar]
  22. Gautel M.22.  2011. The sarcomeric cytoskeleton: who picks up the strain?. Curr. Opin. Cell Biol. 23:139–46 [Google Scholar]
  23. Zacharchenko T, von Castelmur E, Rigden DJ, Mayans O. 23.  2015. Structural advances on titin: towards an atomic understanding of multi-domain functions in myofilament mechanics and scaffolding. Biochem. Soc. Trans. 43:5850–55 [Google Scholar]
  24. Labeit S, Kolmerer B. 24.  1995. Titins: giant proteins in charge of muscle ultrastructure and elasticity. Science 270:5234293–96 [Google Scholar]
  25. Linke WA, Ivemeyer M, Mundel P, Stockmeier MR, Kolmerer B. 25.  1998. Nature of PEVK-titin elasticity in skeletal muscle. PNAS 795:148052–57 [Google Scholar]
  26. Linke WA, Rudy DE, Centner T, Gautel M, Witt C. 26.  et al. 1999. I-band titin in cardiac muscle is a three-element molecular spring and is critical for maintaining thin filament structure. J. Cell Biol. 146:3631–44 [Google Scholar]
  27. Opitz CA, Leake MC, Makarenko I, Benes V, Linke WA. 27.  2004. Developmentally regulated switching of titin size alters myofibrillar stiffness in the perinatal heart. Circ. Res. 94:7967–75 [Google Scholar]
  28. Lahmers S, Wu Y, Call DR, Labeit S, Granzier H. 28.  2004. Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ. Res. 94:4505–13 [Google Scholar]
  29. Warren CM, Krzesinski PR, Campbell KS, Moss RL, Greaser ML. 29.  2004. Titin isoform changes in rat myocardium during development. Mech. Dev. 121:111301–12 [Google Scholar]
  30. Cazorla O, Freiburg A, Helmes M, Centner T, McNabb M. 30.  et al. 2000. Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ. Res. 86:159–67 [Google Scholar]
  31. Neagoe C, Opitz CA, Makarenko I, Linke WA. 31.  2003. Gigantic variety: expression patterns of titin isoforms in striated muscles and consequences for myofibrillar passive stiffness. J. Muscle Res. Cell Motil. 24:2–3175–79 [Google Scholar]
  32. Neagoe C, Kulke M, del Monte F, Gwathmey JK, de Tombe PP. 32.  et al. 2002. Titin isoform switch in ischemic human heart disease. Circulation 106:111333–41 [Google Scholar]
  33. Prado LG, Makarenko I, Andresen C, Krüger M, Opitz CA, Linke WA. 33.  2005. Isoform diversity of giant proteins in relation to passive and active contractile properties of rabbit skeletal muscles. J. Gen. Physiol. 126:5461–80 [Google Scholar]
  34. Ottenheijm CAC, Knottnerus AM, Buck D, Luo X, Greer K. 34.  et al. 2009. Tuning passive mechanics through differential splicing of titin during skeletal muscle development. Biophys. J. 97:82277–86 [Google Scholar]
  35. Guo W, Schafer S, Greaser ML, Radke MH, Liss M. 35.  et al. 2012. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat. Med. 18:5766–73 [Google Scholar]
  36. Methawasin M, Hutchinson KR, Lee EJ, Smith JE 3rd, Saripalli C. 36.  et al. 2014. Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a beneficial effect on diastole. Circulation 129:191924–36 [Google Scholar]
  37. Krüger M, Sachse C, Zimmermann WH, Eschenhagen T, Klede S, Linke WA. 37.  2008. Thyroid hormone regulates developmental titin isoform transitions via the phosphatidylinositol-3-kinase/AKT pathway. Circ. Res. 102:4439–47 [Google Scholar]
  38. Krüger M, Babicz K, Frieling-Salewsky M, Linke WA. 38.  2010. Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy. J. Mol. Cell. Cardiol. 48:5910–16 [Google Scholar]
  39. Zhu C, Yin Z, Ren J, McCormick RJ, Ford SP, Guo W. 39.  2015. RBM20 is an essential factor for thyroid hormone-regulated titin isoform transition. J. Mol. Cell Biol. 7:188–90 [Google Scholar]
  40. Linke WA, Fernandez JM. 40.  2002. Cardiac titin: molecular basis of elasticity and cellular contribution to elastic and viscous stiffness components in myocardium. J. Muscle Res. Cell Motil. 23:5–6483–97 [Google Scholar]
  41. Granzier H, Labeit S. 41.  2007. Structure–function relations of the giant elastic protein titin in striated and smooth muscle cells. Muscle Nerve 36:6740–55 [Google Scholar]
  42. Linke WA, Hamdani N. 42.  2014. Gigantic business: titin properties and function through thick and thin. Circ. Res. 114:61052–68 [Google Scholar]
  43. Grützner A, Garcia-Manyes S, Kötter S, Badilla CL, Fernandez JM, Linke WA. 43.  2009. Modulation of titin-based stiffness by disulfide bonding in the cardiac titin N2-B unique sequence. Biophys. J. 97:3825–34 [Google Scholar]
  44. Alegre-Cebollada J, Kosuri P, Giganti D, Eckels E, Rivas-Pardo JA. 44.  et al. 2014. S-glutathionylation of cryptic cysteines enhances titin elasticity by blocking protein folding. Cell 156:61235–46 [Google Scholar]
  45. Yamasaki R, Wu Y, McNabb M, Greaser M, Labeit S, Granzier H. 45.  2002. Protein kinase A phosphorylates titin's cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes. Circ. Res. 90:111181–88 [Google Scholar]
  46. Krüger M, Kötter S, Grützner A, Lang P, Andresen C. 46.  et al. 2009. Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ. Res. 104:187–94 [Google Scholar]
  47. Hidalgo CG, Hudson B, Bogomolovas J, Zhu Y, Anderson B. 47.  et al. 2009. PKC phosphorylation of titin's PEVK element: a novel and conserved pathway for modulating myocardial stiffness. Circ. Res. 105:7631–8 [Google Scholar]
  48. Hamdani N, Krysiak J, Kreusser MM, Neef S, dos Remedios CG. 48.  et al. 2013. Crucial role for Ca2+/calmodulin-dependent protein kinase-II in regulating diastolic stress of normal and failing hearts via titin phosphorylation. Circ. Res. 112:4664–74 [Google Scholar]
  49. Hamdani N, Herwig M, Linke WA. 49.  2017. Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes. Biophys. Rev. 9:3225–37 [Google Scholar]
  50. Beckendorf L, Linke WA. 50.  2015. Emerging importance of oxidative stress in regulating striated muscle elasticity. J. Muscle Res. Cell Motil. 36:125–36 [Google Scholar]
  51. Makarenko I, Opitz CA, Leake MC, Neagoe C, Kulke M. 51.  et al. 2004. Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts. Circ. Res. 95:7708–16 [Google Scholar]
  52. Nagueh SF, Shah G, Wu Y, Torre-Amione G, King NM. 52.  et al. 2004. Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 110:2155–62 [Google Scholar]
  53. Borbély A, Falcao-Pires I, van Heerebeek L, Hamdani N, Édes I. 53.  et al. 2009. Hypophosphorylation of the stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ. Res. 104:6780–6 [Google Scholar]
  54. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P. 54.  et al. 2012. Truncations of titin causing dilated cardiomyopathy. N. Engl. J. Med. 366:7619–28 [Google Scholar]
  55. Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J. 55.  et al. 2015. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci. Transl. Med. 7:270270ra6 [Google Scholar]
  56. Schafer S, de Marvao A, Adami E, Fiedler LR, Ng B. 56.  et al. 2017. Titin-truncating variants affect heart function in disease cohorts and the general population. Nat. Genet. 49:146–53 [Google Scholar]
  57. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E. 57.  et al. 2016. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:7616285–91 [Google Scholar]
  58. Shih YH, Dvornikov AV, Zhu P, Ma X, Kim M. 58.  et al. 2016. Exon- and contraction-dependent functions of titin in sarcomere assembly. Development 143:244713–22 [Google Scholar]
  59. Hinson JT, Chopra A, Nafissi N, Polacheck WJ, Benson CC. 59.  et al. 2015. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science 349:6251982–86 [Google Scholar]
  60. Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T. 60.  et al. 2016. Shared genetic predisposition in peripartum and dilated cardiomyopathies. N. Engl. J. Med. 374:3233–41 [Google Scholar]
  61. Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A. 61.  1999. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem. Biophys. Res. Commun. 262:2411–17 [Google Scholar]
  62. Peled Y, Gramlich M, Yoskovitz G, Feinberg MS, Afek A. 62.  et al. 2014. Titin mutation in familial restrictive cardiomyopathy. Int. J. Cardiol. 171:124–30 [Google Scholar]
  63. Taylor M, Graw S, Sinagra G, Barnes C, Slavov D. 63.  et al. 2011. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation 124:8876–85 [Google Scholar]
  64. Udd B, Vihola A, Sarparanta J, Richard I, Hackman P. 64.  2005. Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology 64:4636–42 [Google Scholar]
  65. Ohlsson M, Hedberg C, Brådvik B, Lindberg C, Tajsharghi H. 65.  et al. 2012. Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin. Brain 135:Pt. 61682–94 [Google Scholar]
  66. Pfeffer G, Elliott HR, Griffin H, Barresi R, Miller J. 66.  et al. 2012. Titin mutation segregates with hereditary myopathy with early respiratory failure. Brain 135:Pt. 61695–13 [Google Scholar]
  67. Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, Schmitz-Abe K, DeChene ET. 67.  et al. 2013. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology 81:141205–14 [Google Scholar]
  68. Horowits R, Kempner ES, Bisher ME, Podolsky RJ. 68.  1986. A physiological role for titin and nebulin in skeletal muscle. Nature 323:6084160–64 [Google Scholar]
  69. Horowits R, Podolsky RJ. 69.  1987. The positional stability of thick filaments in activated skeletal muscle depends on sarcomere length: evidence for the role of titin filaments. J. Cell Biol. 105:52217–23 [Google Scholar]
  70. Konhilas JP, Irving TC, de Tombe PP. 70.  2002. Length-dependent activation in three striated muscle types of the rat. J. Physiol. 544:Pt. 1225–36 [Google Scholar]
  71. Zhang X, Kampourakis T, Yan Z, Sevrieva I, Irving M, Sun Y-B. 71.  2017. Distinct contributions of the thin and thick filaments to length-dependent activation in heart muscle. eLife 6:e24081 [Google Scholar]
  72. Kobirumaki-Shimozawa F, Inoue T, Shintani SA, Oyama K, Terui T. 72.  et al. 2014. Cardiac thin filament regulation and the Frank-Starling mechanism. J. Physiol. Sci. 64:4221–32 [Google Scholar]
  73. Linari M, Brunello E, Reconditi M, Fusi L, Caremani M. 73.  et al. 2015. Force generation by skeletal muscle is controlled by mechanosensing in myosin filaments. Nature 528:7581276–79 [Google Scholar]
  74. Fusi L, Brunello E, Yan Z, Irving M. 74.  2016. Thick filament mechano-sensing is a calcium-independent regulatory mechanism in skeletal muscle. Nat. Commun. 7:13281 [Google Scholar]
  75. Ait-Mou Y, Hsu K, Farman GP, Kumar M, Greaser ML. 75.  et al. 2016. Titin strain contributes to the Frank-Starling law of the heart by structural rearrangements of both thin- and thick-filament proteins. PNAS 113:82306–11 [Google Scholar]
  76. Kumar M, Govindan S, Zhang M, Khairallah RJ, Martin JL. 76.  et al. 2015. Cardiac myosin-binding protein C and troponin-I phosphorylation independently modulate myofilament length-dependent activation. J. Biol. Chem. 290:4929241–49 [Google Scholar]
  77. Mamidi R, Gresham KS, Stelzer JE. 77.  2014. Length-dependent changes in contractile dynamics are blunted due to cardiac myosin binding protein-C ablation. Front. Physiol. 5:461 [Google Scholar]
  78. Kampourakis T, Sun YB, Irving M. 78.  2016. Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments. PNAS 113:21E3039–47 [Google Scholar]
  79. Cazorla O, Wu Y, Irving TC, Granzier H. 79.  2001. Titin-based modulation of calcium sensitivity of active tension in mouse skinned cardiac myocytes. Circ. Res. 88:101028–35 [Google Scholar]
  80. Fukuda N, Sasaki D, Ishiwata S, Kurihara S. 80.  2001. Length dependence of tension generation in rat skinned cardiac muscle: role of titin in the Frank-Starling mechanism of the heart. Circulation 104:141639–45 [Google Scholar]
  81. Lee E-J, Peng J, Radke M, Gotthardt M, Granzier HL. 81.  2010. Calcium sensitivity and the Frank-Starling mechanism of the heart are increased in titin N2B region-deficient mice. J. Mol. Cell. Cardiol. 49:3449–58 [Google Scholar]
  82. Linke WA, Ivemeyer M, Labeit S, Hinssen H, Rüegg JC, Gautel M. 82.  1997. Actin-titin interaction in cardiac myofibrils: probing a physiological role. Biophys. J. 73:2905–19 [Google Scholar]
  83. Irving T, Wu Y, Bekyarova T, Farman GP, Fukuda N, Granzier H. 83.  2011. Thick-filament strain and interfilament spacing in passive muscle: effect of titin-based passive tension. Biophys. J. 100:61499–508 [Google Scholar]
  84. Godt RE, Maughan DW. 84.  1981. Influence of osmotic compression on calcium activation and tension in skinned muscle fibers of the rabbit. Pflügers Arch 391:4334–37 [Google Scholar]
  85. McDonald KS, Moss RL. 85.  1995. Osmotic compression of single cardiac myocytes eliminates the reduction in Ca2+ sensitivity of tension at short sarcomere length. Circ. Res. 77:1199–205 [Google Scholar]
  86. Fuchs F, Smith SH. 86.  2001. Calcium, cross-bridges, and the Frank-Starling relationship. News Physiol. Sci. 16:5–10 [Google Scholar]
  87. Konhilas JP, Irving TC, de Tombe PP. 87.  2002. Myofilament calcium sensitivity in skinned rat cardiac trabeculae: role of interfilament spacing. Circ. Res. 90:159–65 [Google Scholar]
  88. Li Y, Lang P, Linke WA. 88.  2016. Titin stiffness modifies the force-generating region of muscle sarcomeres. Sci. Rep. 6:24492 [Google Scholar]
  89. Farman GP, Gore D, Allen E, Schoenfelt K, Irving TC, de Tombe PP. 89.  2011. Myosin head orientation: a structural determinant for the Frank-Starling relationship. Am. J. Physiol. Heart Circ. Physiol. 300:6H2155–60 [Google Scholar]
  90. Patel JR, Pleitner JM, Moss RL, Greaser ML. 90.  2012. Magnitude of length-dependent changes in contractile properties varies with titin isoform in rat ventricles. Am. J. Physiol. Heart Circ. Physiol. 302:3H697–708 [Google Scholar]
  91. Terui T, Sodnomtseren M, Matsuba D, Udaka J, Ishiwata S. 91.  et al. 2008. Troponin and titin coordinately regulate length-dependent activation in skinned porcine ventricular muscle. J. Gen. Physiol. 131:3275–83 [Google Scholar]
  92. Beqqali A, Bollen IAE, Rasmussen TB, van den Hoogenhof MM, van Deutekom HWM. 92.  et al. 2016. A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank-Starling mechanism. Cardiovasc. Res. 112:1452–63 [Google Scholar]
  93. Pfuhl M, Gautel M. 93.  2012. Structure, interactions and function of the N-terminus of cardiac myosin binding protein C (MyBP-C): who does what, with what, and to whom?. J. Muscle Res. Cell Motil. 33:183–94 [Google Scholar]
  94. Sadayappan S, de Tombe PP. 94.  2014. Cardiac myosin binding protein-C as a central target of cardiac sarcomere signaling: a special mini review series. Pflügers Arch 466:2195–200 [Google Scholar]
  95. Shaffer JF, Kensler RW, Harris SP. 95.  2009. The myosin-binding protein C motif binds to F-actin in a phosphorylation-sensitive manner. J. Biol. Chem. 284:1812318–27 [Google Scholar]
  96. Kampourakis T, Yan Z, Gautel M, Sun Y-B, Irving M. 96.  2014. Myosin binding protein-C activates thin filaments and inhibits thick filaments in heart muscle cells. PNAS 111:5218763–68 [Google Scholar]
  97. Mun JY, Previs MJ, Yu HY, Gulick J, Tobacman LS. 97.  et al. 2014. Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism. PNAS 111:62170–75 [Google Scholar]
  98. Minajeva A, Neagoe C, Kulke M, Linke WA. 98.  2002. Titin-based contribution to shortening velocity of rabbit skeletal myofibrils. J. Physiol. 540:Pt. 1177–88 [Google Scholar]
  99. Opitz CA, Kulke M, Leake MC, Neagoe C, Hinssen H. 99.  et al. 2003. Damped elastic recoil of the titin spring in myofibrils of human myocardium. PNAS 100:2212688–93 [Google Scholar]
  100. Edman KA.100.  1979. The velocity of unloaded shortening and its relation to sarcomere length and isometric force in vertebrate muscle fibres. J. Physiol. 291:143–59 [Google Scholar]
  101. Claflin DR, Morgan DL, Julian FJ. 101.  1989. Effects of passive tension on unloaded shortening speed of frog single muscle fibers. Biophys. J. 56:5967–77 [Google Scholar]
  102. de Tombe PP, ter Keurs HE. 102.  1992. An internal viscous element limits velocity of sarcomere shortening in mammalian myocardium. J. Physiol. 454:619–42 [Google Scholar]
  103. Sweitzer NK, Moss RL. 103.  1993. Determinants of loaded shortening velocity in single cardiac myocytes permeabilized with alpha-hemolysin. Circ. Res. 73:61150–62 [Google Scholar]
  104. Llewellyn ME, Barretto RPJ, Delp SL, Schnitzer MJ. 104.  2008. Minimally invasive high-speed imaging of sarcomere contractile dynamics in mice and humans. Nature 454:7205784–88 [Google Scholar]
  105. Cromie MJ, Sanchez GN, Schnitzer MJ, Delp SL. 105.  2013. Sarcomere lengths in human extensor carpi radialis brevis measured by microendoscopy. Muscle Nerve 48:2286–92 [Google Scholar]
  106. Moo EK, Fortuna R, Sibole SC, Abusara Z, Herzog W. 106.  2016. In vivo sarcomere lengths and sarcomere elongations are not uniform across an intact muscle. Front. Physiol. 7:187 [Google Scholar]
  107. Linke WA, Ivemeyer M, Mundel P, Stockmeier MR, Kolmerer B. 107.  1998. Nature of PEVK-titin elasticity in skeletal muscle. PNAS 795:148052–57 [Google Scholar]
  108. Linke WA, Stockmeier MR, Ivemeyer M, Hosser H, Mundel P. 108.  1998. Characterizing titin's I-band Ig domain region as an entropic spring. J. Cell Sci. 111:Pt. 111567–74 [Google Scholar]
  109. Rief M, Gautel M, Oesterhelt F, Fernandez JM, Gaub HE. 109.  1997. Reversible unfolding of individual titin immunoglobulin domains by AFM. Science 276:53151109–12 [Google Scholar]
  110. Li H, Linke WA, Oberhauser AF, Carrion-Vazquez M, Kerkvliet JG. 110.  et al. 2002. Reverse engineering of the giant muscle protein titin. Nature 418:6901998–1002 [Google Scholar]
  111. Kellermayer MS, Smith SB, Granzier HL, Bustamante C. 111.  1997. Folding-unfolding transitions in single titin molecules characterized with laser tweezers. Science 276:53151112–16 [Google Scholar]
  112. Tskhovrebova L, Trinick J, Sleep JA, Simmons RM. 112.  1997. Elasticity and unfolding of single molecules of the giant muscle protein titin. Nature 387:6630308–12 [Google Scholar]
  113. Erickson HP.113.  1994. Reversible unfolding of fibronectin type III and immunoglobulin domains provides the structural basis for stretch and elasticity of titin and fibronectin. PNAS 91:2110114–18 [Google Scholar]
  114. Minajeva A, Kulke M, Fernandez JM, Linke WA. 114.  2001. Unfolding of titin domains explains the viscoelastic behavior of skeletal myofibrils. Biophys. J. 80:31442–51 [Google Scholar]
  115. Sotomayor M, Schulten K. 115.  2007. Single-molecule experiments in vitro and in silico. Science 316:58281144–48 [Google Scholar]
  116. Linke WA, Granzier H. 116.  1998. A spring tale: new facts on titin elasticity. Biophys. J. 75:62613–14 [Google Scholar]
  117. Rivas-Pardo JA, Eckels EC, Popa I, Kosuri P, Linke WA, Fernández JM. 117.  2016. Work done by titin protein folding assists muscle contraction. Cell Rep 14:61339–47 [Google Scholar]
  118. Mártonfalvi Z, Bianco P, Linari M, Caremani M, Nagy A. 118.  et al. 2014. Low-force transitions in single titin molecules reflect a memory of contractile history. J. Cell Sci. 127:Pt. 4858–70 [Google Scholar]
  119. Mártonfalvi Z, Bianco P, Naftz K, Ferenczy GG, Kellermayer M. 119.  2017. Force generation by titin folding. Protein Sci 26:71380–90 [Google Scholar]
  120. Kötter S, Unger A, Hamdani N, Lang P, Vorgerd M. 120.  et al. 2014. Human myocytes are protected from titin aggregation-induced stiffening by small heat shock proteins. J. Cell Biol. 204:2187–202 [Google Scholar]
  121. Olsson MC, Krüger M, Meyer LH, Ahnlund L, Gransberg L. 121.  et al. 2006. Fibre type-specific increase in passive muscle tension in spinal cord-injured subjects with spasticity. J. Physiol. 577:Pt. 1339–52 [Google Scholar]
  122. Trombitas K, Wu Y, McNabb M, Greaser M, Kellermayer MS. 122.  et al. 2003. Molecular basis of passive stress relaxation in human soleus fibers: assessment of the role of immunoglobulin-like domain unfolding. Biophys. J. 85:53142–53 [Google Scholar]
  123. Bianco P, Reconditi M, Piazzesi G, Lombardi V. 123.  2016. Is muscle powered by springs or motors?. J. Muscle Res. Cell Motil. 37:4–5165–67 [Google Scholar]
  124. Bullard B, Ferguson C, Minajeva A, Leake MC, Gautel M. 124.  et al. 2004. Association of the chaperone αB-crystallin with titin in heart muscle. J. Biol. Chem. 279:97917–24 [Google Scholar]
  125. Donlin LT, Andresen C, Just S, Rudensky E, Pappas CT. 125.  et al. 2012. Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization. Genes Dev 26:2114–19 [Google Scholar]
  126. Berkovich R, Hermans RI, Popa I, Stirnemann G, Garcia-Manyes S. 126.  et al. 2012. Rate limit of protein elastic response is tether dependent. PNAS 109:3614416–21 [Google Scholar]
  127. Herzog W, Schappacher G, DuVall M, Leonard TR, Herzog JA. 127.  2016. Residual force enhancement following eccentric contractions: a new mechanism involving titin. Physiology 31:4300–12 [Google Scholar]
  128. Lindstedt S, Nishikawa K. 128.  2017. Huxleys’ missing filament: form and function of titin in vertebrate striated muscle. Annu. Rev. Physiol. 79:145–66 [Google Scholar]
  129. Rassier DE.129.  2017. Sarcomere mechanics in striated muscles: from molecules to sarcomeres to cells. Am. J. Physiol. Cell Physiol. 313:2C134–45 [Google Scholar]
  130. Edman KAP, Elzinga G, Noble MIM. 130.  1982. Residual force enhancement after stretch of contracting frog single muscle fibers. J. Gen. Physiol. 80:5769–84 [Google Scholar]
  131. Abbott BC, Aubert XM. 131.  1952. The force exerted by active striated muscle during and after change of length. J. Physiol. 117:77–86 [Google Scholar]
  132. Tatsumi R, Maeda K, Hattori A, Takahashi K. 132.  2001. Calcium binding to an elastic portion of connectin/titin filaments. J. Muscle Res. Cell Motil. 22:2149–62 [Google Scholar]
  133. Labeit D, Watanabe K, Witt C, Fujita H, Wu Y. 133.  et al. 2003. Calcium-dependent molecular spring elements in the giant protein titin. PNAS 100:2313716–21 [Google Scholar]
  134. Fujita H, Labeit D, Gerull B, Labeit S, Granzier HL. 134.  2004. Titin isoform-dependent effect of calcium on passive myocardial tension. Am. J. Physiol. Heart Circ. Physiol. 287:6H2528–34 [Google Scholar]
  135. Bagni MA, Cecchi G, Colombini B, Colomo F. 135.  2002. A non-cross-bridge stiffness in activated frog muscle fibers. Biophys. J. 82:63118–27 [Google Scholar]
  136. Bagni MA, Colombini B, Geiger P, Berlinguer Palmini R, Cecchi G. 136.  2004. Non-cross-bridge calcium-dependent stiffness in frog muscle fibers. Am. J. Physiol. Cell Physiol. 286:6C1353–57 [Google Scholar]
  137. Campbell KS, Moss RL. 137.  2002. History-dependent mechanical properties of permeabilized rat soleus muscle fibers. Biophys. J. 82:2929–43 [Google Scholar]
  138. Nocella M, Cecchi G, Bagni MA, Colombini B. 138.  2014. Force enhancement after stretch in mammalian muscle fiber: no evidence of cross-bridge involvement. Am. J. Physiol. Cell Physiol. 307:12C1123–29 [Google Scholar]
  139. Rassier DE, Leite FS, Nocella M, Cornachione AS, Colombini B, Bagni MA. 139.  2015. Non-crossbridge forces in activated striated muscles: a titin dependent mechanism of regulation?. J. Muscle Res. Cell Motil. 36:137–45 [Google Scholar]
  140. Campbell SG, Campbell KS. 140.  2011. Mechanisms of residual force enhancement in skeletal muscle: insights from experiments and mathematical models. Biophys. Rev. 3:4199–207 [Google Scholar]
  141. Leonard TR, Herzog W. 141.  2010. Regulation of muscle force in the absence of actin-myosin-based cross-bridge interaction. Am. J. Physiol. Cell Physiol. 299:1C14–20 [Google Scholar]
  142. Powers K, Schappacher-Tilp G, Jinha A, Leonard T, Nishikawa K, Herzog W. 142.  2014. Titin force is enhanced in actively stretched skeletal muscle. J. Exp. Biol. 217:Pt. 203629–36 [Google Scholar]
  143. Schappacher-Tilp G, Leonard T, Desch G, Herzog W. 143.  2015. A novel three-filament model of force generation in eccentric contraction of skeletal muscles. PLOS ONE 10:3e0117634 [Google Scholar]
  144. Heidlauf T, Klotz T, Rode C, Altan E, Bleiler C. 144.  et al. 2016. A multi-scale continuum model of skeletal muscle mechanics predicting force enhancement based on actin-titin interaction. Biomech. Model. Mechanobiol. 15:61423–37 [Google Scholar]
  145. Nishikawa KC, Monroy JA, Uyeno TE, Yeo SH, Pai DK, Lindstedt SL. 145.  2012. Is titin a ‘winding filament’? A new twist on muscle contraction. Proc. R. Soc. B 279:1730981–90 [Google Scholar]
  146. Kellermayer MS, Granzier HL. 146.  1996. Calcium-dependent inhibition of in vitro thin-filament motility by native titin. FEBS Lett 380:3281–86 [Google Scholar]
  147. Kulke M, Fujita-Becker S, Rostkova E, Neagoe C, Labeit D. 147.  et al. 2001. Interaction between PEVK-titin and actin filaments: origin of a viscous force component in cardiac myofibrils. Circ. Res. 89:10874–81 [Google Scholar]
  148. Yamasaki R, Berri M, Wu Y, Trombitás K, McNabb M. 148.  et al. 2001. Titin-actin interaction in mouse myocardium: passive tension modulation and its regulation by calcium/S100A1. Biophys. J. 81:42297–313 [Google Scholar]
  149. Linke WA, Kulke M, Li H, Fujita-Becker S, Neagoe C. 149.  et al. 2002. PEVK domain of titin: an entropic spring with actin-binding properties. J. Struct. Biol. 137:1–2194–205 [Google Scholar]
  150. Fukushima H, Chung CS, Granzier H. 150.  2010. Titin-Isoform dependence of titin-actin interaction and its regulation by S100A1/Ca2+ in skinned myocardium. J. Biomed. Biotechnol. 2010:727239 [Google Scholar]
  151. Nagy A, Cacciafesta P, Grama L, Kengyel A, Málnási-Csizmadia A, Kellermayer MS. 151.  2004. Differential actin binding along the PEVK domain of skeletal muscle titin. J. Cell Sci. 117:5781–89 [Google Scholar]
  152. Gramlich M, Pane LS, Zhou Q, Chen Z, Murgia M. 152.  et al. 2015. Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy. EMBO Mol. Med. 7:5562–76 [Google Scholar]
  153. Granzier HL, Radke MH, Peng J, Westermann D, Nelson OL. 153.  et al. 2009. Truncation of titin's elastic PEVK region leads to cardiomyopathy with diastolic dysfunction. Circ. Res. 105:6557–64 [Google Scholar]
  154. Bishu K, Hamdani N, Mohammed SF, Kruger M, Ohtani T. 154.  et al. 2011. Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo. Circulation 124:252882–91 [Google Scholar]
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Titin Gene and Protein Functions in Passive and Active Muscle
Annual Review of Physiology 80, 389 (2018); https://doi.org/10.1146/annurev-physiol-021317-121234
/content/journals/10.1146/annurev-physiol-021317-121234
/content/journals/10.1146/annurev-physiol-021317-121234
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