Abstract
This review covers recent developments in the titin field. Most recent reviews have discussed titin’s role in cardiac function: here we will mainly focus on skeletal muscle, and discuss recent advances in the understanding of titin’s role in skeletal muscle function and disease.
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Bagnato P, Barone V, Giacomello E, Rossi D, Sorrentino V (2003) Binding of an ankyrin-1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles. J Cell Biol 160(2):245–253
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(11):1065–1072
Barash IA, Mathew L, Lahey M, Greaser ML, Lieber RL (2005) Muscle LIM protein plays both structural and functional roles in skeletal muscle. Am J Physiol Cell Physiol 289(5):C1312–C1320
Barash IA, Bang ML, Mathew L, Greaser ML, Chen J, Lieber RL (2007) Structural and regulatory roles of muscle ankyrin repeat protein family in skeletal muscle. Am J Physiol Cell Physiol 293(1):C218–C227
Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294(5547):1704–1708
Cazorla O, Freiburg A, Helmes M, Centner T, McNabb M, Wu Y, Trombitas K, Labeit S, Granzier H (2000) Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ Res 86(1):59–67
Cazorla O, Wu Y, Irving TC, Granzier H (2001) Titin-based modulation of calcium sensitivity of active tension in mouse skinned cardiac myocytes. Circ Res 88(10):1028–1035
Centner T, Yano J, Kimura E, McElhinny AS, Pelin K, Witt CC, Bang ML, Trombitas K, Granzier H, Gregorio CC, Sorimachi H, Labeit S (2001) Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain. J Mol Biol 306(4):717–726
Clarke BA, Drujan D, Willis MS, Murphy LO, Corpina RA, Burova E, Rakhilin SV, Stitt TN, Patterson C, Latres E, Glass DJ (2007) The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. Cell Metab 6 (5):376–385
Coen AC, Ottenheijm, Anna M. Knottnerus, Danielle Buck, Xiuju Luo, Kevin Greer, Adam Hoying, Siegfried Labeit, and Henk Granzier (2009) Tuning passive mechanics through differential splicing of titin During Skeletal Muscle Development. J Biol 97(8):2277–2286
Ehler E, Horowits R, Zuppinger C, Price RL, Perriard E, Leu M, Caroni P, Sussman M, Eppenberger HM, Perriard JC (2001) Alterations at the intercalated disk associated with the absence of muscle LIM protein. J Cell Biol 153(4):763–772
Erickson HP (1994) Reversible unfolding of fibronectin type III and immunoglobulin domains provides the structural basis for stretch and elasticity of titin and fibronectin. Proc Natl Acad Sci U S A 91(21):10114–10118
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(11):1114–1121
Friden J, Lieber RL (2003) Spastic muscle cells are shorter and stiffer than normal cells. Muscle Nerve 27(2):157–164
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. 1:147–154
Fukuzawa A, Lange S, Holt M, Vihola A, Carmignac V, Ferreiro A, Udd B, Gautel M (2008) Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band: implications for hereditary myopathies. J Cell Sci 121:1841–1851
Furukawa T, Ono Y, Tsuchiya H, Katayama Y, Bang ML, Labeit D, Labeit S, Inagaki N, Gregorio CC (2001) Specific interaction of the potassium channel beta-subunit minK with the sarcomeric protein T-cap suggests a T-tubule-myofibril linking system. J Mol Biol. 313(4):775–784
Gautel M, Leonard K, Labeit S (1993) Phosphorylation of KSP motifs in the C-terminal region of titin in differentiating myoblasts. EMBO J 12(10):3827–3834
Gerull B, Gramlich M, Atherton J, McNabb M, Trombitás K, Sasse-Klaassen S, Seidman JG, Seidman C, Granzier H, Labeit S, Frenneaux M, Thierfelder L (2002) Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 30(2):201–204
Gotthardt M, Hammer RE, Hübner N, Monti J, Witt CC, McNabb M, Richardson JA, Granzier H, Labeit S, Herz J (2003) Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure. J Biol Chem 278(8):6059–6065
Granzier H, Labeit S (2004) The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circ Res 94(3):284–295
Granzier H, Labeit S (2007) Structure-function relations of the giant elastic protein titin in striated and smooth muscle cells. Muscle & Nerve 36(6):740–755
Granzier H, Kellermayer M, Helmes M, Trombitás K (1997) Titin elasticity and mechanism of passive force development in rat cardiac myocytes probed by thin-filament extraction. Biophys J 73(4):2043–2053
Gregorio CC, Trombitás K, Centner T, Kolmerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Herrmann B, Granzier H, Sorimachi H, Labeit S (1998) 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 143(4):1013–1027
Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B (2002) Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 71(3):492–500
Hackman P, Marchand S, Sarparanta J, Vihola A, Pénisson-Besnier I, Eymard B, Pardal-Fernández JM, Hammouda EL-H, Richard I, Illa I, Udd B (2008) Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscul Disord 18(12):922–928
Haravuori H, Vihola A, Straub V, Auranen M, Richard I, Marchand S, Voit T, Labeit S, Somer H, Peltonen L, Beckmann JS, Udd B (2001) Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene. Neurology 56(7):869–877
Hayashi C, Ono Y, Doi N, Kitamura F, Tagami M, Mineki R, Arai T, Taguchi H, Yanagida M, Hirner S, Labeit D, Labeit S, Sorimachi H (2008) Multiple molecular interactions implicate the connectin/titin N2A region as a modulating scaffold for p94/calpain 3 activity in skeletal muscle. J Biol Chem 283(21):14801–14814
Helmes M, Trombitás K, Centner T, Kellermayer M, Labeit S, Linke WA, Granzier H (1999) Mechanically driven contour-length adjustment in rat cardiac titin’s unique N2B sequence: titin is an adjustable spring. Circ Res 84(11):1339–1352
Ikeda K, Yamamoto R, Wirschell M, Yagi T, Bower R, Porter ME, Sale WS, Kamiya R (2009) A novel ankyrin-repeat protein interacts with the regulatory proteins of inner arm dynein f (I1) of Chlamydomonas reinhardtii. Cell Motil Cytoskeleton 66(8):448–56
Kedar V, McDonough H, Arya R, Li HH, Rockman HA, Patterson C (2004) Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I. Proc Natl Acad Sci U S A 101(52):18135–18140
Kellermayer MS, Smith SB, Granzier HL, Bustamante C (1997) Folding-unfolding transitions in single titin molecules characterized with laser tweezers. Science 276 (5315):1112–1116
Kellermayer MS, Smith SB, Bustamante C, Granzier HL (2001) Mechanical fatigue in repetitively stretched single molecules of titin. Biophys J 80(2):852–863
Kemp TJ, Sadusky TJ, Saltisi F, Carey N, Moss J, Yang SY, Sassoon DA, Goldspink G, Coulton GR (2000) Identification of Ankrd2, a novel skeletal muscle gene coding for a stretch-responsive ankyrin-repeat protein. Genomics 66(3):229–241
Knöll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss HP, Chien KR. (2002) The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 111(7):943–955
Krüger M, Kohl T, Linke WA (2006) Developmental changes in passive stiffness and myofilament Ca2+ sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth. Am J Physiol Heart Circ Physiol 291(2):H496–H506
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(4):439–447
Kulke M, Fujita-Becker S, Rostkova E, Neagoe C, Labeit D, Manstein DJ, Gautel M, Linke WA (2001) Interaction between PEVK-titin and actin filaments: origin of a viscous force component in cardiac myofibrils. Circ Res 89(10):874–881
Labeit S, Kolmerer B (1995) Titins: giant proteins in charge of muscle ultrastructure and elasticity. Science 270(5234):293–296
Labeit S, Kolmerer B, Linke WA (1997) The giant protein titin. Emerging roles in physiology and pathophysiology. Circ Res 80(2):290–294
Labeit D, Watanabe K, Witt C, Fujita H, Wu Y, Lahmers S, Funck T, Labeit S, Granzier H (2003) Calcium-dependent molecular spring elements in the giant protein titin. Proc Natl Acad Sci USA 100(23):13716–13721
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):505–513
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 (5728):1599–1603
Leake MC, Wilson D, Gautel M, Simmons RM (2004) The elasticity of single titin molecules using a two-bead optical tweezers assay. Biophys J 87(2):1112–1135
Leake MC, Grützner A, Krüger M, Linke WA (2006) Mechanical properties of cardiac titin’s N2B-region by single-molecule atomic force spectroscopy. J Struct Biol 155(2):263–272
LeWinter MM, Wu Y, Labeit S, Granzier H (2007) Cardiac titin: structure, functions and role in disease. Clin Chim Acta 375(1–2):1–9
Li H, Fernandez JM (2003) Mechanical design of the first proximal Ig domain of human cardiac titin revealed by single molecule force spectroscopy. J Mol Biol 334(1):75–86
Li H, Oberhauser AF, Redick SD, Carrion-Vazquez M, Erickson HP, Fernandez JM (2001) Multiple conformations of PEVK proteins detected by single-molecule techniques. Proc Natl Acad Sci USA 98(19):10682–10686
Li H, Linke WA, Oberhauser AF, Carrion-Vazquez M, Kerkvliet JG, Lu H, Marszalek PE, Fernandez JM (2002) Reverse engineering of the giant muscle protein titin. Nature 418(6901):998–1002
Linke WA (2008) Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc Res 77(4):637–648
Linke WA, Ivemeyer M, Mundel P, Stockmeier MR, Kolmerer B (1998) Nature of PEVK-titin elasticity in skeletal muscle. Proc Natl Acad Sci U S A 95(14):8052–8057
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(3):631–644
Liversage AD, Holmes D, Knight PJ, Tskhovrebova L, Trinick J (2001) Titin and the sarcomere symmetry paradox. J Mol Biol 305(3):401–409
Mancini DM, Henson D, LaManca J, Levine S (1992) Respiratory muscle function and dyspnea in patients with chronic congestive heart failure. Circulation 86(3):909–918
Maruyama K (1976) Connectin, an elastic protein from myofibrils. J Biochem 80(2):405–407
Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Fürst DO, Wilmanns M, Gautel M (1998) Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature 395(6705):863–869
Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S (2003) The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules. J Mol Biol 333(5):951–964
Minajeva A, Kulke M, Fernandez JM, Linke WA (2001) Unfolding of titin domains explains the viscoelastic behavior of skeletal myofibrils. Biophys J 80(3):1442–1451
Moore AJ, Stubbings A, Swallow EB, Dusmet M, Goldstraw P, Porcher R, Moxham J, Polkey MI, Ferenczi MA (2006) Passive properties of the diaphragm in COPD. J Appl Physiol 101(5):1400–1405
Mrosek M, Labeit D, Witt S, Heerklotz H, von Castelmur E, Labeit S, Mayans O (2007) Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin. FASEB J 21(7):1383–1392
Mues A, van der Ven PF, Young P, Fürst DO, Gautel M (1998) Two immunoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin. FEBS Lett 428(1–2):111–114
Mutungi G, Trinick J, Ranatunga KW (2003) Resting tension characteristics in differentiating intact rat fast- and slow-twitch muscle fibers. J Appl Physiol 95(6):2241–2247
Nagy A, Grama L, Huber T, Bianco P, Trombitás K, Granzier HL, Kellermayer MS (2005) Hierarchical extensibility in the PEVK domain of skeletal-muscle titin. Biophys J 89(1):329–336
Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M (2003) Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy. Pathol Int 53(10):653–658
Obermann WM, Gautel M, Steiner F, van der Ven PF, Weber K, Fürst DO (1996) 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 134(6):1441–1453
Obermann WM, Gautel M, Weber K, Fürst DO (1997) 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 16(2):211–220
Olsson MC, Krüger M, Meyer LH, Ahnlund L, Gransberg L, Linke WA, Larsson L (2006) Fibre type-specific increase in passive muscle tension in spinal cord-injured subjects with spasticity. J Physiol 577.1:339–352
Omens JH, Usyk TP, Li Z, McCulloch AD (2002) Muscle LIM protein deficiency leads to alterations in passive ventricular mechanics. Am J Physiol Heart Circ Physiol 282(2):H680–H687
Ono Y, Kakinuma K, Torii F, Irie A, Nakagawa K, Labeit S, Abe K, Suzuki K, Sorimachi H (2004) Possible regulation of the conventional calpain system by skeletal muscle-specific calpain, p94/calpain 3. J Biol Chem 279(4):2761–2771
Ottenheijm CA, Heunks LM, Hafmans T, van der Ven PF, Benoist C, Zhou H, Labeit S, Granzier HL, Dekhuijzen PN (2006) Titin and diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 173(5):527–534
Ottenheijm CA, Heunks LM, Dekhuijzen PN (2007) Diaphragm muscle fiber dysfunction in chronic obstructive pulmonary disease: toward a pathophysiological concept. Am J Respir Crit Care Med 175(12):1233–1240
Prado LG, Makarenko I, Andresen C, Krüger M, Opitz CA, Linke WA (2005) Isoform diversity of giant proteins in relation to passive and active contractile properties of rabbit skeletal muscles. J Gen Physiol 126(5):461–480
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(36):13385–13390
Raynaud F, Fernandez E, Coulis G, Aubry L, Vignon X, Bleimling N, Gautel M, Benyamin Y, Ouali A (2005) Calpain 1-titin interactions concentrate calpain 1 in the Z-band edges and in the N2-line region within the skeletal myofibril. FEBS J 272(10):2578–2590
Rief M, Gautel M, Oesterhelt F, Fernandez JM, Gaub HE (1997) Reversible unfolding of individual titin immunoglobulin domains by AFM. Science 276(5315):1109–1112
Russell MW et al. (2002) Identification, tissue expression and chromosomal localization of human Obscurin-MLCK, a member of the titin and Dbl families of myosin light chain kinases. Gene 282 (1–2):237–246
Sarkar A, Caamano S, and Fernandez JM (2005) The elasticity of individual titin PEVK exons measured by single molecule atomic force microscopy. J Biol Chem 280 (8):6261–6264
Toursel T, Stevens L, Granzier H, Mounier Y (2002) Passive tension of rat skeletal soleus muscle fibers: effects of unloading conditions. J Appl Physiol 92(4):1465–1472
Trombitás K, Greaser M, French G, Granzier H (1998a) PEVK extension of human soleus muscle titin revealed by immunolabeling with the anti-titin antibody 9D10. J Struct Biol 122(1–2):188–196
Trombitás K, Greaser M, Labeit S, Jin JP, Kellermayer M, Helmes M, Granzier H (1998b) Titin extensibility in situ: entropic elasticity of permanently folded and permanently unfolded molecular segments. J Cell Biol 140(4):853–859
Trombitás K, Freiburg A, Centner T, Labeit S, Granzier H (1999) Molecular dissection of N2B cardiac titin’s extensibility. Biophys J 77(6):3189–3196
Trombitás K, Wu Y, Labeit D, Labeit S, Granzier H (2001) Cardiac titin isoforms are coexpressed in the half-sarcomere and extend independently. Am J Physiol Heart Circ Physiol 281(4):H1793–H1799
Trombitás K, Wu Y, McNabb M, Greaser M, Kellermayer MS, Labeit S, Granzier H (2003) Molecular basis of passive stress relaxation in human soleus fibers: assessment of the role of immunoglobulin-like domain unfolding. Biophys J 85(5):3142–3153
Tskhovrebova L, Trinick J, Sleep JA, Simmons RM (1997) Elasticity and unfolding of single molecules of the giant muscle protein titin. Nature 387(6630):308–312
Udaka J, Ohmori S, Terui T, Ohtsuki I, Ishiwata S, Kurihara S, Fukuda N (2008) Disuse-induced preferential loss of the giant protein titin depresses muscle performance via abnormal sarcomeric organization. J Gen Physiol 131(1):33–41
Van den Bergh PY, Bouquiaux O, Verellen C, Marchand S, Richard I, Hackman P, Udd B (2003) Tibial muscular dystrophy in a Belgian family. Ann Neurol 54(2):248–251
van Hees HW, Ottenheijm CA, Granzier HL, Dekhuijzen PN, Heunks LM (2010) Int J Cardiol. 141(3):275–283
Wang K, McClure J, Tu A (1979) Titin: major myofibrillar components of striated muscle. Proc Natl Acad Sci USA 76(8):3698–3702
Warren CM, Krzesinski PR, Campbell KS, Moss RL, Greaser ML (2004) Titin isoform changes in rat myocardium during development. Mech Dev 121(11):1301–1312
Watanabe K, Muhle-Goll C, Kellermayer MS, Labeit S, Granzier H (2002a) Different molecular mechanics displayed by titin’s constitutively and differentially expressed tandem Ig segments. J Struct Biol 137(1–2):248–258
Watanabe K, Nair P, Labeit D, Kellermayer MS, Greaser M, Labeit S, Granzier H (2002b) Molecular mechanics of cardiac titin’s PEVK and N2B spring elements. J Biol Chem 277(13):11549–11558
Weinert S, Bergmann N, Luo X, Erdmann B, Gotthardt M (2006) M line-deficient titin causes cardiac lethality through impaired maturation of the sarcomere. J Cell Biol 173(4):559–570
Witt CC, Ono Y, Puschmann E, McNabb M, Wu Y, Gotthardt M, Witt SH, Haak M, Labeit D, Gregorio CC, Sorimachi H, Granzier H, Labeit S (2004) Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling. J Mol Biol 336(1):145–154
Yamasaki R, Berri M, Wu Y, Trombitás K, McNabb M, Kellermayer MS, Witt C, Labeit D, Labeit S, Greaser M, Granzier H (2001) Titin-actin interaction in mouse myocardium: passive tension modulation and its regulation by calcium/S100A1. Biophys J 81(4):2297–2313
Young P, Ehler E, Gautel M (2001) Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly. J Cell Biol 154(1):123–136
Zhu Y, Bogomolovas J, Labeit S, Granzier H (2009) Single molecule force spectroscopy of the cardiac titin N2B element: effects of the molecular chaperone alphaB-crystallin with disease-causing mutations. J Biol Chem 284(20):13914–13923
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Ottenheijm, C.A.C., Granzier, H. (2010). Role of Titin in Skeletal Muscle Function and Disease. In: Rassier, D. (eds) Muscle Biophysics. Advances in Experimental Medicine and Biology, vol 682. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6366-6_6
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