Skip to main content
Log in

Insights into myosin regulatory and essential light chains: a focus on their roles in cardiac and skeletal muscle function, development and disease

  • ORIGINAL ARTICLE
  • Published:
Journal of Muscle Research and Cell Motility Aims and scope Submit manuscript

Abstract

The activity of cardiac and skeletal muscles depends upon the ATP-coupled actin–myosin interactions to execute the power stroke and muscle contraction. The goal of this review article is to provide insight into the function of myosin II, the molecular motor of the heart and skeletal muscles, with a special focus on the role of myosin II light chain (MLC) components. Specifically, we focus on the involvement of myosin regulatory (RLC) and essential (ELC) light chains in striated muscle development, isoform appearance and their function in normal and diseased muscle. We review the consequences of isoform switching and knockout of specific MLC isoforms on cardiac and skeletal muscle function in various animal models. Finally, we discuss how dysregulation of specific RLC/ELC isoforms can lead to cardiac and skeletal muscle diseases and summarize the effects of most studied mutations leading to cardiac or skeletal myopathies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abdelaziz A, Segaric J, Bartsch H, Petzhold D, Schlegel W-P, Kott M, Seefeldt I, Klose J, Bader M, Haase H, Morano I (2004) Functional characterization of the human atrial essential myosin light chain (hALC-1) in a transgenic rat model. J Mol Med 82(4):265–274

    CAS  PubMed  Google Scholar 

  • Alamo L, Ware JS, Pinto A, Gillilan RE, Seidman JG, Seidman CE, Padron R (2017) Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes. Elife 6:e24634

    PubMed  PubMed Central  Google Scholar 

  • Arrell DK, Neverova I, Fraser H, Marban E, Van Eyk JE (2001) Proteomic analysis of pharmacologically preconditioned cardiomyocytes reveals novel phosphorylation of myosin light chain 1. Circ Res 89(6):480–487

    CAS  PubMed  Google Scholar 

  • Auckland LM, Lambert SJ, Cummins P (1986) Cardiac myosin light and heavy chain isotypes in tetralogy of Fallot. Cardiovasc Res 20(11):828–836

    CAS  PubMed  Google Scholar 

  • Aydt EM, Wolff G, Morano I (2007) Molecular modeling of the myosin-S1(A1) isoform. J Struct Biol 159(1):158–163

    CAS  PubMed  Google Scholar 

  • Babai F, Musevi-Aghdam J, Schurch W, Royal A, Gabbiani G (1990) Coexpression of alpha-sarcomeric actin, alpha-smooth muscle actin and desmin during myogenesis in rat and mouse embryos I. Skelet Muscle Differ 44(2):132–142

    CAS  Google Scholar 

  • Barth PG, Wanders RJ, Ruitenbeek W, Roe C, Scholte HR, van der Harten H, van Moorsel J, Duran M, Dingemans KP (1998) Infantile fibre type disproportion, myofibrillar lysis and cardiomyopathy: a disorder in three unrelated Dutch families. Neuromuscul Disord 8(5):296–304

    CAS  PubMed  Google Scholar 

  • Biressi S, Tagliafico E, Lamorte G, Monteverde S, Tenedini E, Roncaglia E, Ferrari S, Ferrari S, Cusella-De Angelis MG, Tajbakhsh S, Cossu G (2007) Intrinsic phenotypic diversity of embryonic and fetal myoblasts is revealed by genome-wide gene expression analysis on purified cells. Dev Biol 304(2):633–651

    CAS  PubMed  Google Scholar 

  • Bober E, Lyons GE, Braun T, Cossu G, Buckingham M, Arnold HH (1991) The muscle regulatory gene, Myf-6, has a biphasic pattern of expression during early mouse development. J Cell Biol 113(6):1255–1265

    CAS  PubMed  Google Scholar 

  • Bruneau BG (2002) Transcriptional regulation of vertebrate cardiac morphogenesis. Circ Res 90(5):509–519

    PubMed  Google Scholar 

  • Bruneau BG (2013) Signaling and transcriptional networks in heart development and regeneration. Cold Spring Harb Perspect Biol 5(3):a008292

    PubMed  PubMed Central  Google Scholar 

  • Buck SH, Konyn PJ, Palermo J, Robbins J, Moss RL (1999) Altered kinetics of contraction of mouse atrial myocytes expressing ventricular myosin regulatory light chain. Am J Physiol 276(4 Pt 2):H1167–H1171

    CAS  PubMed  Google Scholar 

  • Buckingham M, Kelly R, Tajbakhsh S, Zammit P (1998) The formation and maturation of skeletal muscle in the mouse: the myosin MLC1F/3F gene as a molecular model. Acta Physiol Scand 163(3):S3–S5

    CAS  PubMed  Google Scholar 

  • Buckingham M, Meilhac S, Zaffran S (2005) Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet 6(11):826–835

    CAS  PubMed  Google Scholar 

  • Burghardt TP, Sun X, Wang Y, Ajtai K (2015) In vitro and in vivo single myosin step-sizes in striated muscle. J Muscle Res Cell Motil 36(6):463–477

    CAS  PubMed  Google Scholar 

  • Cadete VJ, Sawicka J, Jaswal JS, Lopaschuk GD, Schulz R, Szczesna-Cordary D, Sawicki G (2012) Ischemia/reperfusion-induced myosin light chain 1 phosphorylation increases its degradation by matrix metalloproteinase 2. FEBS J 279(13):2444–2454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Caforio AL, Rossi B, Risaliti R, Siciliano G, Marchetti A, Angelini C, Crea F, Mariani M, Muratorio A (1989) Type 1 fiber abnormalities in skeletal muscle of patients with hypertrophic and dilated cardiomyopathy: evidence of subclinical myogenic myopathy. J Am Coll Cardiol 14(6):1464–1473

    CAS  PubMed  Google Scholar 

  • Charron F, Nemer M (1999) GATA transcription factors and cardiac development. Semin Cell Dev Biol 10(1):85–91

    CAS  PubMed  Google Scholar 

  • Chaudhuri T, Mukherjea M, Sachdev S, Randall JD, Sarkar S (2005) Role of the fetal and alpha/beta exons in the function of fast skeletal troponin T isoforms: correlation with altered Ca2+ regulation associated with development. J Mol Biol 352(1):58–71

    CAS  PubMed  Google Scholar 

  • Chen J, Kubalak SW, Minamisawa S, Price RL, Becker KD, Hickey R, Ross J Jr, Chien KR (1998) Selective requirement of myosin light chain 2v in embryonic heart function. J Biol Chem 273(2):1252–1256

    CAS  PubMed  Google Scholar 

  • Chen Z, Huang W, Dahme T, Rottbauer W, Ackerman MJ, Xu X (2008) Depletion of zebrafish essential and regulatory myosin light chains reduces cardiac function through distinct mechanisms. Cardiovasc Res 79(1):97–108

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dunnigan A, Pierpont ME, Smith SA, Breningstall G, Benditt DG, Benson DW Jr (1984) Cardiac and skeletal myopathy associated with cardiac dysrhythmias. Am J Cardiol 53(6):731–737

    CAS  PubMed  Google Scholar 

  • Dunnigan A, Staley NA, Smith SA, Pierpont ME, Judd D, Benditt DG, Benson DW Jr (1987) Cardiac and skeletal muscle abnormalities in cardiomyopathy: comparison of patients with ventricular tachycardia or congestive heart failure. J Am Coll Cardiol 10(3):608–618

    CAS  PubMed  Google Scholar 

  • Ebashi S (1974) Regulatory mechanism of muscle contraction with special reference to the Ca-troponin-tropomyosin system. Essays Biochem 10:1–36

    CAS  PubMed  Google Scholar 

  • Edmondson DG, Lyons GE, Martin JF, Olson EN (1994) Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis. Development 120(5):1251–1263

    CAS  PubMed  Google Scholar 

  • Eldin P, Le Cunff M, Vosberg HP, Mornet D, Leger JJ (1994) Mapping of the actomyosin interfaces. Proc Natl Acad Sci USA 91(7):2772–2776

    CAS  PubMed  Google Scholar 

  • England J, Loughna S (2013) Heavy and light roles: myosin in the morphogenesis of the heart. Cell Mol Life Sci 70(7):1221–1239

    CAS  PubMed  Google Scholar 

  • Evans W (1949) Familial cardiomegaly. Br Heart J 11(1):68–82

    CAS  PubMed  PubMed Central  Google Scholar 

  • Faerman A, Shani M (1993) The expression of the regulatory myosin light chain 2 gene during mouse embryogenesis. Development 118(3):919–929

    CAS  PubMed  Google Scholar 

  • Fewell JG, Hewett TE, Sanbe A, Klevitsky R, Hayes E, Warshaw D, Maughan D, Robbins J (1998) Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice. J Clin Invest 101(12):2630–2639

    CAS  PubMed  PubMed Central  Google Scholar 

  • Flavigny J, Richard P, Isnard R, Carrier L, Charron P, Bonne G, Forissier JF, Desnos M, Dubourg O, Komajda M, Schwartz K, Hainque B (1998) Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy. J Mol Med (Berl) 76(3–4):208–214

    CAS  Google Scholar 

  • Fodor WL, Darras B, Seharaseyon J, Falkenthal S, Francke U, Vanin EF (1989) Human ventricular/slow twitch myosin alkali light chain gene characterization, sequence, and chromosomal location. J Biol Chem 264(4):2143–2149

    CAS  PubMed  Google Scholar 

  • Furst DO, Osborn M, Weber K (1989) Myogenesis in the mouse embryo: differential onset of expression of myogenic proteins and the involvement of titin in myofibril assembly. J Cell Biol 109(2):517–527

    CAS  PubMed  Google Scholar 

  • Gaunt RT, Lecutier MA (1956) Familial cardiomegaly. Br Heart J 18(2):251–258

    CAS  PubMed  PubMed Central  Google Scholar 

  • Geeves MA (2002) Molecular motors: stretching the lever-arm theory. Nature 415(6868):129–131

    CAS  PubMed  Google Scholar 

  • Geeves MA, Holmes KC (2005) The molecular mechanism of muscle contraction. Adv Protein Chem 71:161–193

    CAS  PubMed  Google Scholar 

  • Grabarek Z (2006) Structural basis for diversity of the EF-hand calcium-binding proteins. J Mol Biol 359(3):509–525

    CAS  PubMed  Google Scholar 

  • Gregorich ZR, Cai W, Lin Z, Chen AJ, Peng Y, Kohmoto T, Ge Y (2017) Distinct sequences and post-translational modifications in cardiac atrial and ventricular myosin light chains revealed by top-down mass spectrometry. J Mol Cell Cardiol 107:13–21

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E, Sigurdsson GT, Stacey SN, Frigge ML, Holm H, Saemundsdottir J, Helgadottir HT, Johannsdottir H, Sigfusson G, Thorgeirsson G, Sverrisson JT, Gretarsdottir S, Walters GB, Rafnar T, Thjodleifsson B, Bjornsson ES, Olafsson S, Thorarinsdottir H, Steingrimsdottir T, Gudmundsdottir TS, Theodors A, Jonasson JG, Sigurdsson A, Bjornsdottir G, Jonsson JJ, Thorarensen O, Ludvigsson P, Gudbjartsson H, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Arnar DO, Magnusson OT, Kong A, Masson G, Thorsteinsdottir U, Helgason A, Sulem P, Stefansson K (2015) Large-scale whole-genome sequencing of the Icelandic population. Nat Genet 47(5):435–444

    CAS  PubMed  Google Scholar 

  • Gudbjartsson DF, Holm H, Sulem P, Masson G, Oddsson A, Magnusson OT, Saemundsdottir J, Helgadottir HT, Helgason H, Johannsdottir H, Gretarsdottir S, Gudjonsson SA, Njolstad I, Lochen ML, Baum L, Ma RC, Sigfusson G, Kong A, Thorgeirsson G, Sverrisson JT, Thorsteinsdottir U, Stefansson K, Arnar DO (2017) A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation. Eur Heart J 38(1):27–34

    CAS  PubMed  Google Scholar 

  • Gulick J, Hewett TE, Klevitsky R, Buck SH, Moss RL, Robbins J (1997) Transgenic remodeling of the regulatory myosin light chains in the mammalian heart. Circ Res 80(5):655–664

    CAS  PubMed  Google Scholar 

  • Haase H, Dobbernack G, Tunnemann G, Karczewski P, Cardoso C, Petzhold D, Schlegel W-P, Lutter S, Pierschalek P, Behlke J, Morano I (2006) Minigenes encoding N-terminal domains of human cardiac myosin light chain-1 improve heart function of transgenic rats. FASEB J. 20(7):865–873

    CAS  PubMed  Google Scholar 

  • Hartshorne DJ, Mrwa U (1982) Regulation of smooth muscle actomyosin. Blood Vessels 19(1):1–18

    CAS  PubMed  Google Scholar 

  • Hasty P, Bradley A, Morris JH, Edmondson DG, Venuti JM, Olson EN, Klein WH (1993) Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Nature 364(6437):501–506

    CAS  PubMed  Google Scholar 

  • Henry GD, Winstanley MA, Dalgarno DC, Scott GM, Levine BA, Trayer IP (1985) Characterization of the actin-binding site on the alkali light chain of myosin. Biochim Biophys Acta 830(3):233–243

    CAS  PubMed  Google Scholar 

  • Hernandez OM, Jones M, Guzman G, Szczesna-Cordary D (2007) Myosin essential light chain in health and disease. Am J Physiol Heart Circ Physiol 292(4):H1643–H1654

    CAS  PubMed  Google Scholar 

  • Hinterberger TJ, Sassoon DA, Rhodes SJ, Konieczny SF (1991) Expression of the muscle regulatory factor MRF4 during somite and skeletal myofiber development. Dev Biol 147(1):144–156

    CAS  PubMed  Google Scholar 

  • Hootsmans WJ, Meerschwam IS (1971) Electromyography in patients with hypertrophic obstructive cardiomyopathy. Neurology 21(8):810–816

    CAS  PubMed  Google Scholar 

  • Houdusse A, Cohen C (1996) Structure of the regulatory domain of scallop myosin at 2 A resolution: implications for regulation. Structure 4(1):21–32

    CAS  PubMed  Google Scholar 

  • Huang C, Sheikh F, Hollander M, Cai C, Becker D, Chu PH, Evans S, Chen J (2003) Embryonic atrial function is essential for mouse embryogenesis, cardiac morphogenesis and angiogenesis. Development 130(24):6111–6119

    CAS  PubMed  Google Scholar 

  • Huxley AF (1957) A hypothesis for the mechanism of contraction of muscle. Prog Biophys Biophys Chem 7:255–318

    CAS  PubMed  Google Scholar 

  • Huxley HE (1969) The mechanism of muscular contraction. Science 164(3886):1356–1366

    CAS  PubMed  Google Scholar 

  • Huxley HE (1985) The crossbridge mechanism of muscular contraction and its implications. J Exp Biol 115(1):17–30

    CAS  PubMed  Google Scholar 

  • Isaacs H, Muncke G (1975) Idiopathic cardiomyopathy and skeletal muscle abnormality. Am Heart J 90(6):767–773

    CAS  PubMed  Google Scholar 

  • Kabaeva ZT, Perrot A, Wolter B, Dietz R, Cardim N, Correia JM, Schulte HD, Aldashev AA, Mirrakhimov MM, Osterziel KJ (2002) Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy. Eur J Hum Genet 10(11):741–748

    CAS  PubMed  Google Scholar 

  • Kazmierczak K, Xu Y, Jones M, Guzman G, Hernandez OM, Kerrick WGL, Szczesna-Cordary D (2009) The role of the N-terminus of the myosin essential light chain in cardiac muscle contraction. J Mol Biol 387(3):706–725

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kazmierczak K, Paulino EC, Huang W, Muthu P, Liang J, Yuan CC, Rojas AI, Hare JM, Szczesna-Cordary D (2013) Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 305(4):H575–H589

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kazmierczak K, Yuan C-C, Liang J, Huang W, Rojas AI, Szczesna-Cordary D (2014) Remodeling of the heart in hypertrophy in animal models with myosin essential light chain mutations. Front Physiol 5:353

    PubMed  PubMed Central  Google Scholar 

  • Kazmierczak K, Liang J, Yuan CC, Yadav S, Sitbon YH, Walz K, Ma W, Irving TC, Cheah JX, Gomes AV, Szczesna-Cordary D (2019) Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain. FASEB J 33(3):3152–3166

    CAS  PubMed  Google Scholar 

  • Kelly R, Alonso S, Tajbakhsh S, Cossu G, Buckingham M (1995) Myosin light chain 3F regulatory sequences confer regionalized cardiac and skeletal muscle expression in transgenic mice. J Cell Biol 129(2):383–396

    CAS  PubMed  Google Scholar 

  • Kelly RG, Zammit PS, Schneider A, Alonso S, Biben C, Buckingham ME (1997) Embryonic and fetal myogenic programs act through separate enhancers at the MLC1F/3F locus. Dev Biol 187(2):183–199

    CAS  PubMed  Google Scholar 

  • Kitajima S, Takagi A, Inoue T, Saga Y (2000) MesP1 and MesP2 are essential for the development of cardiac mesoderm. Development 127(15):3215–3226

    CAS  PubMed  Google Scholar 

  • Koshiba-Takeuchi K, Mori AD, Kaynak BL, Cebra-Thomas J, Sukonnik T, Georges RO, Latham S, Beck L, Henkelman RM, Black BL, Olson EN, Wade J, Takeuchi JK, Nemer M, Gilbert SF, Bruneau BG (2009) Reptilian heart development and the molecular basis of cardiac chamber evolution. Nature 461(7260):95–98

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kubalak SW, Miller-Hance WC, O’Brien TX, Dyson E, Chien KR (1994) Chamber specification of atrial myosin light chain-2 expression precedes septation during murine cardiogenesis. J Biol Chem 269(24):16961–16970

    CAS  PubMed  Google Scholar 

  • Kurabayashi M, Komuro I, Tsuchimochi H, Takaku F, Yazaki Y (1988) Molecular cloning and characterization of human atrial and ventricular myosin alkali light chain cDNA clones. J Biol Chem 263(27):13930–13936

    CAS  PubMed  Google Scholar 

  • Kwon H, Goodwin EB, Nyitray L, Berliner E, O’Neall-Hennessey E, Melandri FD, Szent-Gyorgyi AG (1990) Isolation of the regulatory domain of scallop myosin: role of the essential light chain in calcium binding. PNAS 87(12):4771–4775

    CAS  PubMed  Google Scholar 

  • Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP (1993) Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development 119(3):969

    CAS  PubMed  Google Scholar 

  • Lochner A, Hewlett RH, O’Kennedy A, van der Walt JJ, Tiedt FA, Hoffman H, de Graaf AS, Przybojewski JZ, Torrington M (1981) A study of a family with inherited disease of cardiac and skeletal muscle. Part II. Skeletal muscle morphology and mitochondrial oxidative phosphorylation. S Afr Med J 59(13):453–461

    CAS  PubMed  Google Scholar 

  • Lowey S, Saraswat LD, Liu H, Volkmann N, Hanein D (2007) Evidence for an interaction between the SH3 domain and the N-terminal extension of the essential light chain in class II myosins. J Mol Biol 371(4):902–913

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lyons GE, Ontell M, Cox R, Sassoon D, Buckingham M (1990a) The expression of myosin genes in developing skeletal muscle in the mouse embryo. J Cell Biol 111(4):1465–1476

    CAS  PubMed  Google Scholar 

  • Lyons GE, Schiaffino S, Sassoon D, Barton P, Buckingham M (1990b) Developmental regulation of myosin gene expression in mouse cardiac muscle. J Cell Biol 111(6 Pt 1):2427–2436

    CAS  PubMed  Google Scholar 

  • Lyons I, Parsons LM, Hartley L, Li R, Andrews JE, Robb L, Harvey RP (1995) Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev 9(13):1654–1666

    CAS  PubMed  Google Scholar 

  • Meder B, Laufer C, Hassel D, Just S, Marquart S, Vogel B, Hess A, Fishman MC, Katus HA, Rottbauer W (2009) A single serine in the carboxyl terminus of cardiac essential myosin light chain-1 controls cardiomyocyte contractility in vivo. Circ Res 104(5):650–659

    CAS  PubMed  Google Scholar 

  • Messina G, Biressi S, Monteverde S, Magli A, Cassano M, Perani L, Roncaglia E, Tagliafico E, Starnes L, Campbell CE, Grossi M, Goldhamer DJ, Gronostajski RM, Cossu G (2010) Nfix regulates fetal-specific transcription in developing skeletal muscle. Cell 140(4):554–566

    CAS  PubMed  Google Scholar 

  • Michael JJ, Gollapudi SK, Ford SJ, Kazmierczak K, Szczesna-Cordary D, Chandra M (2013) Deletion of 1-43 amino acids in cardiac myosin essential light chain blunts length dependency of Ca(2+) sensitivity and cross-bridge detachment kinetics. Am J Physiol Heart Circ Physiol 304(2):H253–H259

    CAS  PubMed  Google Scholar 

  • Miller MS, Palmer BM, Ruch S, Martin LA, Farman GP, Wang Y, Robbins J, Irving TC, Maughan DW (2005) The essential light chain N-terminal extension alters force and fiber kinetics in mouse cardiac muscle. J Biol Chem 280(41):34427–34434

    CAS  PubMed  Google Scholar 

  • Milligan RA, Whittaker M, Safer D (1990) Molecular structure of F-actin and location of surface binding sites. Nature 348(6298):217–221

    CAS  PubMed  Google Scholar 

  • Morano I, Ritter O, Bonz A, Timek T, Vahl CF, Michel G (1995) Myosin light chain-actin interaction regulates cardiac contractility. Circ Res 76(5):720–725

    CAS  PubMed  Google Scholar 

  • Morano M, Zacharzowski U, Maier M, Lange PE, Alexi-Meskishvili V, Haase H, Morano I (1996) Regulation of human heart contractility by essential myosin light chain isoforms. J Clin Invest 98(2):467–473

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murre C, McCaw PS, Baltimore D (1989) A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56(5):777–783

    CAS  PubMed  Google Scholar 

  • Muthu P, Wang L, Yuan CC, Kazmierczak K, Huang W, Hernandez OM, Kawai M, Irving TC, Szczesna-Cordary D (2011) Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction. FASEB J 25(12):4394–4405

    CAS  PubMed  PubMed Central  Google Scholar 

  • Muthu P, Huang W, Kazmierczak K, Szczesna-Cordary D (2012a) Functional consequences of mutations in the myosin regulatory light chain associated with hypertrophic cardiomyopathy. In: Veselka J (ed) Cardiomyopathies—from Basic research to clinical management. InTech, Croatia, pp 383–408

    Google Scholar 

  • Muthu P, Kazmierczak K, Jones M, Szczesna-Cordary D (2012b) The effect of myosin RLC phosphorylation in normal and cardiomyopathic mouse hearts. J Cell Mol Med 16(4):911–919

    CAS  PubMed  PubMed Central  Google Scholar 

  • Muthu P, Liang J, Schmidt W, Moore JR, Szczesna-Cordary D (2014) In vitro rescue study of a malignant familial hypertrophic cardiomyopathy phenotype by pseudo-phosphorylation of myosin regulatory light chain. Arch Biochem Biophys 552–553:29–39

    PubMed  Google Scholar 

  • O’Brien TX, Lee KJ, Chien KR (1993) Positional specification of ventricular myosin light chain 2 expression in the primitive murine heart tube. Proc Natl Acad Sci USA 90(11):5157–5161

    PubMed  Google Scholar 

  • Ontell MP, Sopper MM, Lyons G, Buckingham M, Ontell M (1993) Modulation of contractile protein gene expression in fetal murine crural muscles: emergence of muscle diversity. Dev Dyn 198(3):203–213

    CAS  PubMed  Google Scholar 

  • Orr N, Arnaout R, Gula LJ, Spears DA, Leong-Sit P, Li Q, Tarhuni W, Reischauer S, Chauhan VS, Borkovich M, Uppal S, Adler A, Coughlin SR, Stainier DY, Gollob MH (2016) A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation. Nat Commun 7:11303

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ott MO, Bober E, Lyons G, Arnold H, Buckingham M (1991) Early expression of the myogenic regulatory gene, myf-5, in precursor cells of skeletal muscle in the mouse embryo. Development 111(4):1097–1107

    CAS  PubMed  Google Scholar 

  • Palmer B (2005) Thick filament proteins and performance in human heart failure. Heart Fail Rev 10(3):187–197

    CAS  PubMed  Google Scholar 

  • Pawloski Dahm CM, Song G, Kirkpatrick DL, Palermo J, Gulick J, Dorn GW 2nd, Robbins J, Walsh RA (1998) Effects of total replacement of atrial myosin light chain-2 with the ventricular isoform in atrial myocytes of transgenic mice. Circulation 97(15):1508–1513

    CAS  PubMed  Google Scholar 

  • Petzhold D, Simsek B, Meißner R, Mahmoodzadeh S, Morano I (2014) Distinct interactions between actin and essential myosin light chain isoforms. Biochem Biophys Res Commun 449(3):284–288

    CAS  PubMed  Google Scholar 

  • Poetter K, Jiang H, Hassanzadeh S, Master SR, Chang A, Dalakas MC, Rayment I, Sellers JR, Fananapazir L, Epstein ND (1996) Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat Genet 13(1):63–69

    CAS  PubMed  Google Scholar 

  • Poggesi C, Ho CY (2014) Muscle dysfunction in hypertrophic cardiomyopathy: what is needed to move to translation? J Muscle Res Cell Motil 35(1):37–45

    CAS  PubMed  PubMed Central  Google Scholar 

  • Przybojewski JZ, Hoffman H, de Graaf AS, van der Walt JJ, Tiedt FA, O’Kennedy A, Torrington M, Lochner A, Hewlett R (1981) A study of a family with inherited disease of cardiac and skeletal muscle. Part I Clinical, electrocardiographic, echocardiographic, haemodynamic, electrophysiological and electron microscopic studies. S Afr Med J 59(11):363–373

    CAS  PubMed  Google Scholar 

  • Rarick HM, Opgenorth TJ, von Geldern TW, Wu-Wong JR, Solaro RJ (1996) An essential myosin light chain peptide induces supramaximal stimulation of cardiac myofibrillar ATPase activity. J Biol Chem 271(43):27039–27043

    CAS  PubMed  Google Scholar 

  • Ravenscroft G, Zaharieva IT, Bortolotti CA, Lambrughi M, Pignataro M, Borsari M, Sewry CA, Phadke R, Haliloglu G, Ong R, Goullee H, Whyte T, Consortium UK, Manzur A, Talim B, Kaya U, Osborn DPS, Forrest ARR, Laing NG, Muntoni F (2018) Bi-allelic mutations in MYL1 cause a severe congenital myopathy. Hum Mol Genet 27(24):4263–4272

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rayment I, Rypniewski WR, Schmidt-Base K, Smith R, Tomchick DR, Benning MM, Winkelmann DA, Wesenberg G, Holden HM (1993) Three-dimensional structure of myosin subfragment-1: a molecular motor. Science 261(5117):50–58

    CAS  PubMed  Google Scholar 

  • Rehman I, Rehman A (2018) Anatomy, Thorax. Heart StatPearls, Treasure Island (FL)

    Google Scholar 

  • Rottbauer W, Wessels G, Dahme T, Just S, Trano N, Hassel D, Burns CG, Katus HA, Fishman MC (2006) Cardiac myosin light chain-2. A novel essential component of thick-myofilament assembly and contractility of the heart. Circ Res 99(3):323–331

    CAS  PubMed  Google Scholar 

  • Saga Y, Miyagawa-Tomita S, Takagi A, Kitajima S, Miyazaki J, Inoue T (1999) MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. Development 126(15):3437–3447

    CAS  PubMed  Google Scholar 

  • Sanbe A, Gulick J, Fewell J, Robbins J (2001) Examining the in vivo role of the amino terminus of the essential myosin light chain. J Biol Chem 276(35):32682–32686

    CAS  PubMed  Google Scholar 

  • Sassoon D, Lyons G, Wright WE, Lin V, Lassar A, Weintraub H, Buckingham M (1989) Expression of two myogenic regulatory factors myogenin and MyoD1 during mouse embryogenesis. Nature 341(6240):303–307

    CAS  PubMed  Google Scholar 

  • Schaub MC, Tuchschmid CR, Srihari T, Hirzel HO (1984) Myosin isoenzymes in human hypertrophic hearts Shift in atrial myosin heavy chains and in ventricular myosin light chains. Eur Heart J 5(Suppl F):85–93

    CAS  PubMed  Google Scholar 

  • Scheid LM, Mosqueira M, Hein S, Kossack M, Juergensen L, Mueller M, Meder B, Fink RH, Katus HA, Hassel D (2016) Essential light chain S195 phosphorylation is required for cardiac adaptation under physical stress. Cardiovasc Res 111(1):44–55

    CAS  PubMed  Google Scholar 

  • Schiaffino S, Reggiani C (1996) Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Physiol Rev 76(2):371–423

    CAS  PubMed  Google Scholar 

  • Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG (1998) Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281(5373):108–111

    CAS  PubMed  Google Scholar 

  • Scruggs SB, Reisdorph R, Armstrong ML, Warren CM, Reisdorph N, Solaro RJ, Buttrick PM (2010) A novel, in-solution separation of endogenous cardiac sarcomeric proteins and identification of distinct charged variants of regulatory light chain. Mol Cell Proteomics 9(9):1804–1818

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shafiq SA, Sande MA, Carruthers RR, Killip T, Milhorat AT (1972) Skeletal muscle in idiopathic cardiomyopathy. J Neurol Sci 15(3):303–320

    Google Scholar 

  • Shi QW, Danilczyk U, Wang JX, See YP, Williams WG, Trusler GA, Beaulieu R, Rose V, Jackowski G (1991) Expression of ventricular myosin subunits in the atria of children with congenital heart malformations. Circ Res 69(6):1601–1607

    CAS  PubMed  Google Scholar 

  • Smith ER, Heffernan LP, Sangalang VE, Vaughan LM, Flemington CS (1976) Voluntary muscle involvement in hypertrophic cardiomyopathy. A study of eleven patients. Ann Intern Med 85(5):566–572

    CAS  PubMed  Google Scholar 

  • Sobieszek A (1977) Ca-linked phosphorylation of a light chain of vertebrate smooth-muscle myosin. Eur J Biochem 73(2):477–483

    CAS  PubMed  Google Scholar 

  • Spudich James A (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(6):1236–1249

    CAS  PubMed  PubMed Central  Google Scholar 

  • Srivastava D, Cserjesi P, Olson EN (1995) A subclass of bHLH proteins required for cardiac morphogenesis. Science 270(5244):1995–1999

    CAS  PubMed  Google Scholar 

  • Steimle JD, Moskowitz IP (2017) TBX5: a key regulator of heart development. Curr Top Dev Biol 122:195–221

    CAS  PubMed  Google Scholar 

  • Stuart CA, Stone WL, Howell ME, Brannon MF, Hall HK, Gibson AL, Stone MH (2016) Myosin content of individual human muscle fibers isolated by laser capture microdissection. Am J Physiol Cell Physiol 310(5):C381–C389

    PubMed  Google Scholar 

  • Sutoh K (1982) Identification of myosin-binding sites on the actin sequence. Biochemistry 21(15):3654–3661

    CAS  PubMed  Google Scholar 

  • Sutsch G, Brunner UT, von Schulthess C, Hirzel HO, Hess OM, Turina M, Krayenbuehl HP, Schaub MC (1992) Hemodynamic performance and myosin light chain-1 expression of the hypertrophied left ventricle in aortic valve disease before and after valve replacement. Circ Res 70(5):1035–1043

    CAS  PubMed  Google Scholar 

  • Sweeney HL (1995) Function of the N terminus of the myosin essential light chain of vertebrate striated muscle. Biophys J 68(4):112S–118S

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sweeney HL, Bowman BF, Stull JT (1993) Myosin light chain phosphorylation in vertebrate striated muscle: regulation and function. Am J Physiol 264(5 Pt 1):C1085–C1095

    CAS  PubMed  Google Scholar 

  • Szczesna D, Ghosh D, Li Q, Gomes AV, Guzman G, Arana C, Zhi G, Stull JT, Potter JD (2001) Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation. J Biol Chem 276(10):7086–7092

    CAS  PubMed  Google Scholar 

  • Szczesna-Cordary D (2003) Regulatory light chains of striated muscle myosin. Structure, function and malfunction. Curr Drug Targets Cardiovasc Haematol Disord 3(2):187–197

    Google Scholar 

  • Taylor KC, Buvoli M, Korkmaz EN, Buvoli A, Zheng Y, Heinze NT, Cui Q, Leinwand LA, Rayment I (2015) Skip residues modulate the structural properties of the myosin rod and guide thick filament assembly. Proc Natl Acad Sci USA 112(29):E3806–E3815

    CAS  PubMed  Google Scholar 

  • Teekakirikul P, Padera RF, Seidman JG, Seidman CE (2012) Hypertrophic cardiomyopathy: translating cellular cross talk into therapeutics. J Cell Biol 199(3):417–421

    CAS  PubMed  PubMed Central  Google Scholar 

  • Timson DJ (2003) Fine tuning the myosin motor: the role of the essential light chain in striated muscle myosin. Biochimie 85(7):639–645

    CAS  PubMed  Google Scholar 

  • Timson DJ, Trayer HR, Smith KJ, Trayer IP (1999) Size and charge requirements for kinetic modulation and actin binding by alkali 1-type myosin essential light chains. J Biol Chem 274(26):18271–18277

    CAS  PubMed  Google Scholar 

  • Tirosh-Finkel L, Elhanany H, Rinon A, Tzahor E (2006) Mesoderm progenitor cells of common origin contribute to the head musculature and the cardiac outflow tract. Development 133(10):1943–1953

    CAS  PubMed  Google Scholar 

  • Trayer IP, Trayer HR, Levine BA (1987) Evidence that the N-terminal region of A1-light chain of myosin interacts directly with the C-terminal region of actin. A proton magnetic resonance study. Eur J Biochem 164(1):259–266

    CAS  PubMed  Google Scholar 

  • Trybus KM (1994) Role of myosin light chains. J Muscle Res Cell Motil 15(6):587–594

    CAS  PubMed  Google Scholar 

  • Van Horn R, Crow MT (1989) Fast myosin heavy chain expression during the early and late embryonic stages of chicken skeletal muscle development. Dev Biol 134(2):279–288

    PubMed  Google Scholar 

  • VanBuren P, Waller GS, Harris DE, Trybus KM, Warshaw DM, Lowey S (1994) The essential light chain is required for full force production by skeletal muscle myosin. Proc Natl Acad Sci USA 91(26):12403–12407

    CAS  PubMed  Google Scholar 

  • Villalobo A, Gonzalez-Munoz M, Berchtold MW (2019) Proteins with calmodulin-like domains: structures and functional roles. Cell Mol Life Sci 76:2299–2328

    CAS  PubMed  Google Scholar 

  • Wang Y, Szczesna-Cordary D, Craig R, Diaz-Perez Z, Guzman G, Miller T, Potter JD (2007) Fast skeletal muscle regulatory light chain is required for fast and slow skeletal muscle development. FASEB J 21(9):2205–2214

    CAS  PubMed  Google Scholar 

  • Wang Y, Ajtai K, Burghardt TP (2013) The Qdot-labeled actin super-resolution motility assay measures low-duty cycle muscle myosin step size. Biochemistry 52(9):1611–1621

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Ajtai K, Burghardt TP (2014) Ventricular myosin modifies in vitro step-size when phosphorylated. J Mol Cell Cardiol 72:231–237

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Ajtai K, Kazmierczak K, Szczesna-Cordary D, Burghardt TP (2016) N-terminus of cardiac myosin essential light chain modulates myosin step-size. Biochemistry 55(1):186–198

    CAS  PubMed  Google Scholar 

  • Wang L, Geist J, Grogan A, Hu LR, Kontrogianni-Konstantopoulos A (2018a) Thick filament protein network, functions, and disease association. Compr Physiol 8(2):631–709

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Yuan CC, Kazmierczak K, Szczesna-Cordary D, Burghardt TP (2018b) Single cardiac ventricular myosins are autonomous motors. Open Biol 8(4):170240

    PubMed  PubMed Central  Google Scholar 

  • Warmke J, Yamakawa M, Molloy J, Falkenthal S, Maughan D (1992) Myosin light chain-2 mutation affects flight, wing beat frequency, and indirect flight muscle contraction kinetics in Drosophila. J Cell Biol 119(6):1523–1539

    CAS  PubMed  Google Scholar 

  • Weintraub H (1993) The MyoD family and myogenesis: redundancy, networks, and thresholds. Cell 75(7):1241–1244

    CAS  PubMed  Google Scholar 

  • Weterman MA, Barth PG, van Spaendonck-Zwarts KY, Aronica E, Poll-The BT, Brouwer OF, van Tintelen JP, Qahar Z, Bradley EJ, de Wissel M, Salviati L, Angelini C, van den Heuvel L, Thomasse YE, Backx AP, Nurnberg G, Nurnberg P, Baas F (2013) Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy. Brain 136(Pt 1):282–293

    PubMed  Google Scholar 

  • Winstanley MA, Trayer HR, Trayer IP (1977) Role of the myosin light chains in binding to actin. FEBS Lett 77(2):239–242

    CAS  PubMed  Google Scholar 

  • Yadav S, Kazmierczak K, Liang J, Sitbon YH, Szczesna-Cordary D (2019a) Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain. FEBS J 286(1):151–168

    CAS  PubMed  Google Scholar 

  • Yadav S, Sitbon YH, Kazmierczak K, Szczesna-Cordary D (2019b) Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains. Pflugers Arch 471:683–699

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yu YT, Breitbart RE, Smoot LB, Lee Y, Mahdavi V, Nadal-Ginard B (1992) Human myocyte-specific enhancer factor 2 comprises a group of tissue-restricted MADS box transcription factors. Genes Dev 6(9):1783–1798

    CAS  PubMed  Google Scholar 

  • Yuan CC, Muthu P, Kazmierczak K, Liang J, Huang W, Irving TC, Kanashiro-Takeuchi RM, Hare JM, Szczesna-Cordary D (2015) Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice. Proc Natl Acad Sci USA 112(30):E4138–E4146

    CAS  PubMed  Google Scholar 

  • Yuan CC, Kazmierczak K, Liang J, Kanashiro-Takeuchi R, Irving TC, Gomes AV, Wang Y, Burghardt TP, Szczesna-Cordary D (2017) Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice. Cardiovasc Res 113(10):1124–1136

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan CC, Kazmierczak K, Liang J, Zhou Z, Yadav S, Gomes AV, Irving TC, Szczesna-Cordary D (2018) Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice. Proc Natl Acad Sci USA 115(10):E2338–E2347

    CAS  PubMed  Google Scholar 

  • Zhou Z, Huang W, Liang J, Szczesna-Cordary D (2016) Molecular and functional effects of a splice site mutation in the MYL2 gene associated with cardioskeletal myopathy and early cardiac death in infants. Front Physiol 7:240

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Institutes of Health R01-HL123255 (DSC), and the American Heart Association 17PRE33650085 (SY).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Danuta Szczesna‐Cordary.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sitbon, Y.H., Yadav, S., Kazmierczak, K. et al. Insights into myosin regulatory and essential light chains: a focus on their roles in cardiac and skeletal muscle function, development and disease. J Muscle Res Cell Motil 41, 313–327 (2020). https://doi.org/10.1007/s10974-019-09517-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10974-019-09517-x

Keywords

Navigation