Abstract
Cardiac sarcomeres are composed of overlapping actin-thin filaments and myosin-thick filaments. Efficient muscle contraction is dependent on the proper overlap of thick and thin filaments; therefore filament lengths are tightly regulated. The actin-thin filament is a polar structure with a distinct barbed end (at the Z-disc) and pointed end (at the M-line). Capping proteins bind to and regulate thin filament lengths at the ends of the filament. For instance, tropomodulin 1 (Tmod1) caps (blocks the incorporation and dissociation of G-actin) the pointed end of the thin filament, while CapZ caps the barbed end. Leiomodin 2 (Lmod2), a close family member of Tmod1, also binds to the pointed end but it elongates thin filaments. Lmod2 and Tmod1 compete to bind to the pointed end, which fine tunes thin filament length. While capping/elongation proteins play a critical role in length regulation, other proteins have been proposed to contribute. For instance, tropomyosin plays a vital role in stabilizing the thin filament. In addition, cyclase-associated protein 2 (CAP2) has been proposed to regulate thin filament length by severing filamentous actin and sequestering globular actin. Actin-monomer-binding proteins may also work in conjunction with capping proteins to regulate length. Due to the critical role these proteins play in maintaining lengths, it is not surprising that alterations or mutations in many of these proteins result in the development of human cardiomyopathies. Current research is focused on dissecting the role that alterations in thin filament length have in both normal heart function and the development of disease.
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References
Arimura T, Nakamura T, Hiroi S, Satoh M, Takahashi M, Ohbuchi N, Ueda K, Nouchi T, Yamaguchi N, Akai J (2000) Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy. Hum Genet 107:440–451
Babcock GG, Fowler VM (1994) Isoform-specific interaction of tropomodulin with skeletal muscle and erythrocyte tropomyosins. J Biol Chem 269:27510–27518
Bai J, Hartwig JH, Perrimon N (2007) SALS, a WH2-domain-containing protein, promotes sarcomeric actin filament elongation from pointed ends during Drosophila muscle growth. Dev Cell 13:828–842
Bang M-L, Li X, Littlefield R, Bremner S, Thor A, Knowlton KU, Lieber RL, Chen J (2006) Nebulin-deficient mice exhibit shorter thin filament lengths and reduced contractile function in skeletal muscle. J Cell Biol 173:905–916
Barron-Casella EA, Torres MA, Scherer SW, Heng HH, Tsui L-C, Casella JF (1995) Sequence analysis and chromosomal localization of human Cap Z Conserved residues within the actin-binding domain may link Cap Z to gelsolin/severin and profilin protein families. J Biol Chem 270:21472–21479
Blanchard EM, Iizuka K, Christe M, Conner DA, Geisterfer-Lowrance A, Schoen FJ, Maughan DW, Seidman CE, Seidman J (1997) Targeted ablation of the murine α-tropomyosin gene. Circ Res 81:1005–1010
Bliss KT, Tsukada T, Novak SM, Dorovkov MV, Shah SP, Nworu C, Kostyukova AS, Gregorio CC (2014) Phosphorylation of tropomodulin1 contributes to the regulation of actin filament architecture in cardiac muscle. FASEB J. 28:3987–3995
Broschat K (1990) Tropomyosin prevents depolymerization of actin filaments from the pointed end. J Biol Chem 265:21323–21329
Broschat KO, Weber A, Burgess DR (1989) Tropomyosin stabilizes the pointed end of actin filaments by slowing depolymerization. Biochemistry 28:8501–8506
Burgoyne T, Muhamad F, Luther PK (2008) Visualization of cardiac muscle thin filaments and measurement of their lengths by electron tomography. Cardiovasc Res 77:707–712
Burkholder TJ, Lieber RL (2001) Sarcomere length operating range of vertebrate muscles during movement. J Exp Biol 204:1529–1536
Cahill TJ, Ashrafian H, Watkins H (2013) Genetic cardiomyopathies causing heart failure. Circ Res 113:660–675
Caldwell JE, Heiss SG, Mermall V, Cooper JA (1989) Effects of CapZ, an actin-capping protein of muscle, on the polymerization of actin. Biochemistry 28:8506–8514
Casella J, Maack D, Lin S (1986) Purification and initial characterization of a protein from skeletal muscle that caps the barbed ends of actin filaments. J Biol Chem 261:10915–10921
Casella JF, Craig SW, Maack DJ, Brown AE (1987) Cap Z (36/32), a barbed end actin-capping protein, is a component of the Z-line of skeletal muscle. J Cell Biol 105:371–379
Chandra M, Mamidi R, Ford S, Hidalgo C, Witt C, Ottenheijm C, Labeit S, Granzier H (2009) Nebulin alters cross-bridge cycling kinetics and increases thin filament activation: novel mechanism for increasing tension and reducing tension cost. J Biol Chem 284:30889–30896
Chereau D, Boczkowska M, Skwarek-Maruszewska A, Fujiwara I, Hayes DB, Rebowski G, Lappalainen P, Pollard TD, Dominguez R (2008) Leiomodin is an actin filament nucleator in muscle cells. Science 320:239–243
Chu X, Chen J, Reedy MC, Vera C, Sung K-LP, Sung LA (2003) E-Tmod capping of actin filaments at the slow-growing end is required to establish mouse embryonic circulation. Am J Physiol Heart Circ Physiol 284:H1827–H1838
Conley CA, Fritz-Six KL, Almenar-Queralt A, Fowler VM (2001) Leiomodins: larger members of the tropomodulin (Tmod) gene family. Genomics 73:127–139
Cooke R (2004) The sliding filament model 1972–2004. J Gen Physiol 123:643–656
Dorovkov M, Beznosov S, Shah S, Kotlyanskaya L, Kostyukova A (2008) Effect of mutations imitating the phosphorylation by TRPM7 kinase on the function of the N-terminal domain of tropomodulin. Biophysics 53:500–504
Dube S, Panebianco L, Matoq AA, Chionuma HN, Denz CR, Poiesz BJ, Dube DK (2014) Expression of TPM1, a novel sarcomeric isoform of the TPM1 gene, in mouse heart and skeletal muscle. Mol Biol Int 2014:896068
Fowler VM (1987) Identification and purification of a novel Mr 43,000 tropomyosin-binding protein from human erythrocyte membranes. J Biol Chem 262:12792–12800
Fowler VM (1996) Regulation of actin filament length in erythrocytes and striated muscle. Curr Opin Cell Biol 8:86–96
Fowler VM, Greenfield NJ, Moyer J (2003) Tropomodulin contains two actin filament pointed end-capping domains. J Biol Chem 278:40000–40009
Fritz-Six KL, Cox PR, Fischer RS, Xu B, Gregorio CC, Zoghbi HY, Fowler VM (2003) Aberrant myofibril assembly in tropomodulin1 null mice leads to aborted heart development and embryonic lethality. J Cell Biol 163:1033–1044
Gaikis L, Stewart D, Johnson R, Pyle WG (2013) Identifying a role of the actin capping protein CapZ in β‐adrenergic receptor signalling. Acta Physiol 207:173–182
Garcia-Pavia P, Cobo-Marcos M, Guzzo-Merello G, Gomez-Bueno M, Bornstein B, Lara-Pezzi E, Segovia J, Alonso-Pulpon L (2013) Genetics in dilated cardiomyopathy. Biomark Med 7:517–533
Garg A, O’Rourke J, Long C, Doering J, Ravenscroft G, Bezprozvannaya S, Nelson BR, Beetz N, Li L, Chen S (2014) KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy. J Clin Invest 124:3529–3539
Gokhin DS, Fowler VM (2013) A two-segment model for thin filament architecture in skeletal muscle. Nat Rev Mol Cell Biol 14:113–119
Gokhin DS, Bang M-L, Zhang J, Chen J, Lieber RL (2009) Reduced thin filament length in nebulin-knockout skeletal muscle alters isometric contractile properties. Am J Physiol Cell Physiol 296:C1123–C1132
Granzier H, Akster HA, Ter Keurs H (1991) Effect of thin filament length on the force-sarcomere length relation of skeletal muscle. Am J Physiol Cell Physiol 260:C1060–C1070
Gregorio CC, Fowler VM (1995) Mechanisms of thin filament assembly in embryonic chick cardiac myocytes: tropomodulin requires tropomyosin for assembly. J Cell Biol 129:683–695
Gregorio CC, Weber A, Bondad M, Pennise CR, Fowler VM (1995) Requirement of pointed-end capping by tropomodulin to maintain actin filament length in embryonic chick cardiac myocytes. Nature 377:83–86
Hart MC, Cooper JA (1999) Vertebrate isoforms of actin capping protein β have distinct functions in vivo. J Cell Biol 147:1287–1298
Hart MC, Korshunova YO, Cooper JA (2000) Mapping of the mouse actin capping protein beta subunit gene. BMC Genomics 1:1
Hartman TJ, Martin JL, Solaro RJ, Samarel AM, Russell B (2009) CapZ dynamics are altered by endothelin-1 and phenylephrine via PIP2-and PKC-dependent mechanisms. Am J Physiol Cell Physiol 296:C1034–C1039
Horowits R (2006) Nebulin regulation of actin filament lengths: new angles. Trends Cell Biol 16:121–124
Hurst S, Howes E, Coadwell J, Jones R (1998) Expression of a testis‐specific putative actin‐capping protein associated with the developing acrosome during rat spermiogenesis. Mol Reprod Dev 49:81–91
Huxley H (1985) The crossbridge mechanism of muscular contraction and its implications. J Exp Biol 115:17–30
Huxley H, Hanson J (1954) Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation. Nature 173:973–976
Huxley A, Niedergerke R (1954) Interference microscopy of living muscle fibres. Nature 173:13
Isenberg G, Aebi U, Pollard TD (1980) An actin-binding protein from Acanthamoeba regulates actin filament polymerization and interactions. Nature 288:455–459
Ishikawa R, Yamashiro S, Matsumura F (1989) Differential modulation of actin-severing activity of gelsolin by multiple isoforms of cultured rat cell tropomyosin. Potentiation of protective ability of tropomyosins by 83-kDa nonmuscle caldesmon. J Biol Chem 264:7490–7497
Kazmierski ST, Antin PB, Witt CC, Huebner N, McElhinny AS, Labeit S, Gregorio CC (2003) The complete mouse nebulin gene sequence and the identification of cardiac nebulin. J Mol Biol 328:835–846
Khaitlina S, Fitz H, Hinssen H (2013) The interaction of gelsolin with tropomyosin modulates actin dynamics. FEBS J 280:4600–4611
Kho AL, Perera S, Alexandrovich A, Gautel M (2012) The sarcomeric cytoskeleton as a target for pharmacological intervention. Curr Opin Pharmacol 12:347–354
Kim T, Cooper JA, Sept D (2010) The interaction of capping protein with the barbed end of the actin filament. J Mol Biol 404:794–802
Kobayashi T, Solaro RJ (2005) Calcium, thin filaments, and the integrative biology of cardiac contractility. Annu Rev Physiol 67:39–67
Kostyukova A, Maeda K, Yamauchi E, Krieger I, Maéda Y (2000) Domain structure of tropomodulin. Eur J Biochem 267:6470–6475
Kostyukova AS, Tiktopulo EI, Maéda Y (2001) Folding properties of functional domains of tropomodulin. Biophys J 81:345–351
Kostyukova AS, Rapp BA, Choy A, Greenfield NJ, Hitchcock-DeGregori SE (2005) Structural requirements of tropomodulin for tropomyosin binding and actin filament capping. Biochemistry 44:4905–4910
Kostyukova AS, Choy A, Rapp BA (2006) Tropomodulin binds two tropomyosins: a novel model for actin filament capping. Biochemistry 45:12068–12075
Kruger M, Wright J, Wang K (1991) Nebulin as a length regulator of thin filaments of vertebrate skeletal muscles: correlation of thin filament length, nebulin size, and epitope profile. J Cell Biol 115:97–107
Lakdawala NK, Funke BH, Baxter S, Cirino AL, Roberts AE, Judge DP, Johnson N, Mendelsohn NJ, Morel C, Care M (2012) Genetic testing for dilated cardiomyopathy in clinical practice. J Card Fail 18:296–303
Lawlor MW, Ottenheijm CA, Lehtokari V-L, Cho K, Pelin K, Wallgren-Pettersson C, Granzier H, Beggs AH (2011) Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy. Skelet muscle 1:23
Lin Y-H, Li J, Swanson ER, Russell B (2013) CapZ and actin capping dynamics increase in myocytes after a bout of exercise and abates in hours after stimulation ends. J Appl Physiol 114:1603–1609
Littlefield R, Fowler V (1998) Defining actin filament length in striated muscle: rulers and caps or dynamic stability? Annu Rev Cell Dev Biol 14:487–525
Littlefield R, Fowler VM (2002) Measurement of thin filament lengths by distributed deconvolution analysis of fluorescence images. Biophys J 82:2548–2564
Littlefield R, Almenar-Queralt A, Fowler VM (2001) Actin dynamics at pointed ends regulates thin filament length in striated muscle. Nat Cell Biol 3:544–551
Maiellaro-Rafferty K, Wansapura J, Mendsaikhan U, Osinska H, James J, Taylor M, Robbins J, Kranias E, Towbin J, Purevjav E (2013) Altered regional cardiac wall mechanics are associated with differential cardiomyocyte calcium handling due to nebulette mutations in preclinical inherited dilated cardiomyopathy. J Mol Cell Cardiol 60:151–160
Martin AF (1981) Turnover of cardiac troponin subunits. Kinetic evidence for a precursor pool of troponin-I. J Biol Chem 256:964–968
McElhinny AS, Kolmerer B, Fowler VM, Labeit S, Gregorio CC (2001) The N-terminal end of nebulin interacts with tropomodulin at the pointed ends of the thin filaments. J Biol Chem 276:583–592
McElhinny AS, Schwach C, Valichnac M, Mount-Patrick S, Gregorio CC (2005) Nebulin regulates the assembly and lengths of the thin filaments in striated muscle. J Cell Biol 170:947–957
McKeown CR, Nowak RB, Moyer J, Sussman MA, Fowler VM (2008) Tropomodulin1 is required in the heart but not the yolk sac for mouse embryonic development. Circ Res 103:1241–1248
Millevoi S, Trombitas K, Kolmerer B, Kostin S, Schaper J, Pelin K, Granzier H, Labeit S (1998) Characterization of nebulette and nebulin and emerging concepts of their roles for vertebrate Z-discs. J Mol Biol 282:111–123
Moncman CL, Wang K (1995) Nebulette: a 107 kD nebulin‐like protein in cardiac muscle. Cell Motil Cytoskeleton 32:205–225
Moncman CL, Wang K (2002) Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function. Exp Cell Res 273:204–218
Nishida E, Maekawa S, Sakai H (1984) Cofilin, a protein in porcine brain that binds to actin filaments and inhibits their interactions with myosin and tropomyosin. Biochemistry 23:5307–5313
Ono S, Ono K (2002) Tropomyosin inhibits ADF/cofilin-dependent actin filament dynamics. J Cell Biol 156:1065–1076
Ottenheijm CA, Witt CC, Stienen GJ, Labeit S, Beggs AH, Granzier H (2009) Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency. Hum Mol Genet 18:2359–2369
Ottenheijm CA, Hooijman P, DeChene ET, Stienen GJ, Beggs AH, Granzier H (2010) Altered myofilament function depresses force generation in patients with nebulin-based nemaline myopathy (NEM2). J Struct Biol 170:334–343
Ottenheijm CA, Buck D, de Winter JM, Ferrara C, Piroddi N, Tesi C, Jasper JR, Malik FI, Meng H, Stienen GJ (2013) Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy. Brain 136:1718–1731
Page SG, Huxley H (1963) Filament lengths in striated muscle. J Cell Biol 19:369–390
Pappas CT, Bhattacharya N, Cooper JA, Gregorio CC (2008) Nebulin interacts with CapZ and regulates thin filament architecture within the Z-disc. Mol Biol Cell 19:1837–1847
Pappas CT, Krieg PA, Gregorio CC (2010) Nebulin regulates actin filament lengths by a stabilization mechanism. J Cell Biol 189:859–870
Pappas CT, Bliss KT, Zieseniss A, Gregorio CC (2011) The Nebulin family: an actin support group. Trends Cell Biol 21:29–37
Peche V, Shekar S, Leichter M, Korte H, Schröder R, Schleicher M, Holak T, Clemen C, Ramanath-Y B, Pfitzer G (2007) CAP2, cyclase-associated protein 2, is a dual compartment protein. Cell Mol Life Sci 64:2702–2715
Peche VS, Holak TA, Burgute BD, Kosmas K, Kale SP, Wunderlich FT, Elhamine F, Stehle R, Pfitzer G, Nohroudi K (2013) Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy. Cell Mol Life Sci 70:527–543
Purevjav E, Varela J, Morgado M, Kearney DL, Li H, Taylor MD, Arimura T, Moncman CL, McKenna W, Murphy RT, Labeit S, Vatta M, Bowles NE, Kimura A, Boriek AM, Towbin JA (2010) Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis. J Am Coll Cardiol 56:1493–1502
Pyle WG, Hart MC, Cooper JA, Sumandea MP, de Tombe PP, Solaro RJ (2002) Actin capping protein an essential element in protein kinase signaling to the myofilaments. Circ Res 90:1299–1306
Pyle WG, La Rotta G, de Tombe PP, Sumandea MP, Solaro RJ (2006) Control of cardiac myofilament activation and PKC-betaII signaling through the actin capping protein, CapZ. J Mol Cell Cardiol 41:537–543
Rao JN, Madasu Y, Dominguez R (2014) Mechanism of actin filament pointed-end capping by tropomodulin. Science 345:463–467
Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M (2003) Hypertrophic cardiomyopathy distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 107:2227–2232
Robinson TF, Winegrad S (1977) Variation of thin filament length in heart muscles. Nature 267:74–75
Schevzov G, Vrhovski B, Bryce NS, Elmir S, Qiu MR, O’Neill GM, Yang N, Verrills NM, Kavallaris M, Gunning PW (2005) Tissue-specific tropomyosin isoform composition. J Histochem Cytochem: official journal of the Histochemistry Society 53:557–570
Skwarek-Maruszewska A, Boczkowska M, Zajac AL, Kremneva E, Svitkina T, Dominguez R, Lappalainen P (2010) Different localizations and cellular behaviors of leiomodin and tropomodulin in mature cardiomyocyte sarcomeres. Mol Biol Cell 21:3352–3361
Spudich JA (2014) Hypertrophic and dilated cardiomyopathy: four decades of basic research on muscle lead to potential therapeutic approaches to these devastating genetic diseases. Biophys J 106:1236–1249
Sussman MA, Baqué S, Uhm CS, Daniels MP, Price RL, Simpson D, Terracio L, Kedes L (1998a) Altered expression of tropomodulin in cardiomyocytes disrupts the sarcomeric structure of myofibrils. Circ Res 82:94–105
Sussman MA, Welch S, Cambon N, Klevitsky R, Hewett TE, Price R, Witt SA, Kimball TR (1998b) Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice. J Clin Invest 101:51–61
Szent-Györgyi AG (2004) The early history of the biochemistry of muscle contraction. J Gen Physiol 123:631–641
Tardiff JC (2011) Thin filament mutations: developing an integrative approach to a complex disorder. Circ Res 108:765–782
Tsukada T, Pappas CT, Moroz N, Antin PB, Kostyukova AS, Gregorio CC (2010) Leiomodin-2 is an antagonist of tropomodulin-1 at the pointed end of the thin filaments in cardiac muscle. J Cell Sci 123:3136–3145
Wang K, Wright J (1988) Architecture of the sarcomere matrix of skeletal muscle: immunoelectron microscopic evidence that suggests a set of parallel inextensible nebulin filaments anchored at the Z line. J Cell Biol 107:2199–2212
Wear MA, Yamashita A, Kim K, Maéda Y, Cooper JA (2003) How capping protein binds the barbed end of the actin filament. Curr Biol 13:1531–1537
Weber A, Pennise CR, Babcock GG, Fowler VM (1994) Tropomodulin caps the pointed ends of actin filaments. J Cell Biol 127:1627–1635
Weber A, Pennise CR, Fowler VM (1999) Tropomodulin increases the critical concentration of barbed end-capped actin filaments by converting ADP.Pi-actin to ADP-actin at all pointed filament ends. J Biol Chem 274:34637–34645
Williams W (2011) Huxley’s model of muscle contraction with compliance. J Elast 105:365–380
Willott RH, Gomes AV, Chang AN, Parvatiyar MS, Pinto JR, Potter JD (2010) Mutations in Troponin that cause HCM, DCM AND RCM: what can we learn about thin filament function? J Mol Cell Cardiol 48:882–892
Witt CC, Burkart C, Labeit D, McNabb M, Wu Y, Granzier H, Labeit S (2006) Nebulin regulates thin filament length, contractility, and Z-disk structure in vivo. EMBO J 25:3843–3855
Yamashiro S, Cox EA, Baillie DL, Hardin JD, Ono S (2008) Sarcomeric actin organization is synergistically promoted by tropomodulin, ADF/cofilin, AIP1 and profilin in C. elegans. J Cell Sci 121:3867–3877
Yamashiro S, Gokhin DS, Kimura S, Nowak RB, Fowler VM (2012) Tropomodulins: pointed‐end capping proteins that regulate actin filament architecture in diverse cell types. Cytoskeleton 69:337–370
Yamashita A, Maeda K, Maéda Y (2003) Crystal structure of CapZ: structural basis for actin filament barbed end capping. EMBO J 22:1529–1538
Yang FH, Pyle WG (2012) Reduced cardiac CapZ protein protects hearts against acute ischemia–reperfusion injury and enhances preconditioning. J Mol Cell Cardiol 52:761–772
Acknowledgments
This work was funded by NIH grant HL123078 (C.C.G) and a predoctoral fellowship from the American Heart Association Western States Affiliate (13PRE14340043 to C.A.H).
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Henderson, C.A., Gregorio, C.C. (2015). Dynamics of Actin in the Heart: Defining Thin Filament Length. In: Ehler, E. (eds) Cardiac Cytoarchitecture. Springer, Cham. https://doi.org/10.1007/978-3-319-15263-9_4
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