Advertisement

Journal of Muscle Research and Cell Motility

, Volume 36, Issue 6, pp 433–445 | Cite as

Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations

  • Wenrui Huang
  • Danuta Szczesna-Cordary
Review Article

Abstract

We discuss here the potential mechanisms of action associated with hypertrophic (HCM) or dilated (DCM) cardiomyopathy causing mutations in the myosin regulatory (RLC) and essential (ELC) light chains. Specifically, we focus on four HCM mutations: RLC-A13T, RLC-K104E, ELC-A57G and ELC-M173V, and one DCM RLC-D94A mutation shown by population studies to cause different cardiomyopathy phenotypes in humans. Our studies indicate that RLC and ELC mutations lead to heart disease through different mechanisms with RLC mutations triggering alterations of the secondary structure of the RLC which further affect the structure and function of the lever arm domain and impose changes in the cross bridge cycling rates and myosin force generation ability. The ELC mutations exert their detrimental effects through changes in the interaction of the N-terminus of ELC with actin altering the cross talk between the thick and thin filaments and ultimately resulting in an altered force-pCa relationship. We also discuss the effect of mutations on myosin light chain phosphorylation. Exogenous myosin light chain phosphorylation and/or pseudo-phosphorylation were explored as potential rescue tools to treat hypertrophy-related cardiac phenotypes.

Keywords

Myosin light chains Mutation Cardiomyopathy Structure Function Phosphorylation 

Abbreviations

A13T

Alanine-to-threonine mutation in myosin RLC

A57G

Alanine-to-glycine mutation in myosin ELC

ANP

Atrial natriuretic peptide

BNP

Brain natriuretic peptide

CaM

Calmodulin

CD

Circular dichroism

CO

Cardiac output

D94A

Aspartic acid-to-alanine mutation in myosin RLC

D166V

Aspartic acid-to-valine mutation in myosin RLC

DCM

Dilated cardiomyopathy

E/A ratio

Doppler transmitral blood velocities, early (E)/late (A) diastolic

ECG

Echocardiography

EF

Ejection fraction

ELC

Essential light chain of myosin (MYL3 gene)

HCM

Hypertrophic cardiomyopathy

IFS

Interfilament lattice spacing

IVS

Inter-ventricular septum

H&E

Hematoxylin and eosin

HF

Heart failure

K104E

Lysine-to-glutamic acid mutation in myosin RLC

LV

Left ventricle

M173V

Methionine-to-valine mutation in myosin ELC

MHC

Myosin heavy chain

MLC

Myosin light chain

MLCK

Myosin light chain kinase

MyBP-C

Myosin binding protein-C

NTg

Non-transgenic

PV

Pressure volume

R58Q

Arginine-to-glutamine mutation in myosin RLC

RLC

Regulatory light chain of myosin (MYL2 gene)

S15D

Serine-to-aspartic acid mutation to mimic phosphorylation

SCD

Sudden cardiac death

SR

Sarcoplasmic reticulum

SW

Stroke work

SV

Stroke volume

Tg

Transgenic

Tm

Tropomyosin

Tn

Troponin

WT

Wild-type

Notes

Acknowledgments

The authors thank Michelle Jones for critical reading of the manuscript. This work was supported in part by grants from the National Institutes of Health HL108343 and HL123255 (D.S-C.); and the American Heart Association 12PRE12030412 (W.H.). The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Center for Research Resources or the NIH.

References

  1. Abraham TP et al (2009) Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice. Cardiovasc Res 82:84–92. doi: 10.1093/cvr/cvp016 PubMedCentralCrossRefPubMedGoogle Scholar
  2. Alcalai R, Seidman JG, Seidman CE (2008) Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics. J Cardiovasc Electrophysiol 19:104–110PubMedGoogle Scholar
  3. Alvarez-Acosta L et al (2014) Regulatory light chain (MYL2) mutations in familial hypertrophic cardiomyopathy. J Cardiovasc Dis 2:82–90Google Scholar
  4. Andersen PS et al (2001) Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations. J Med Genet 38:e43. doi: 10.1136/jmg.38.12.e43 PubMedCentralCrossRefPubMedGoogle Scholar
  5. Andersen PS et al (2009) Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives. Hum Mutat 30:363–370. doi: 10.1002/humu.20862 CrossRefPubMedGoogle Scholar
  6. 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 89:480–487CrossRefPubMedGoogle Scholar
  7. Aydt EM, Wolff G, Morano I (2007) Molecular modeling of the myosin-S1(A1) isoform. J Struct Biol 159:158–163CrossRefPubMedGoogle Scholar
  8. Chang AN et al (2015) Constitutive phosphorylation of cardiac myosin regulatory light chain in vivo. J Biol Chem. doi: 10.1074/jbc.M115.642165 Google Scholar
  9. Dellefave L, McNally EM (2011) The genetics of dilated cardiomyopathy. Curr Opin Cardiol 25:198–204. doi: 10.1097/HCO.0b013e328337ba52 CrossRefGoogle Scholar
  10. Ding P, Huang J, Battiprolu PK, Hill JA, Kamm KE, Stull JT (2010) Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo. J Biol Chem 285:40819–40829. doi: 10.1074/jbc.M110.160499 PubMedCentralCrossRefPubMedGoogle Scholar
  11. Fewell JG, Osinska H, Klevitsky R, Ng W, Sfyris G, Bahrehmand F, Robbins J (1997) A treadmill exercise regimen for identifying cardiovascular phenotypes in transgenic mice. Am J Physiol 273:H1595–H1605PubMedGoogle Scholar
  12. Garcia-Pavia P et al (2011) Genetic basis of end-stage hypertrophic cardiomyopathy. Eur J Heart Fail 13:1193–1201. doi: 10.1093/eurjhf/hfr110 CrossRefPubMedGoogle Scholar
  13. Geeves MA (2002) Molecular motors: stretching the lever-arm theory. Nature 415:129–131. doi: 10.1038/415129a CrossRefPubMedGoogle Scholar
  14. Gomes AV, Venkatraman G, Potter JD (2005) The miscommunicative cardiac cell: when good proteins go bad. Ann N Y Acad Sci 1047:30–37. doi: 10.47/1/30 CrossRefPubMedGoogle Scholar
  15. 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:H1643–H1654. doi: 10.1152/ajpheart.00931.2006 CrossRefPubMedGoogle Scholar
  16. Hershberger RE, Hedges DJ, Morales A (2013) Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 10:531–547. doi: 10.1038/nrcardio.2013.105 CrossRefPubMedGoogle Scholar
  17. Hidalgo C, Saripalli C, Granzier HL (2014) Effect of exercise training on post-translational and post-transcriptional regulation of titin stiffness in striated muscle of wild type and IG KO mice. Arch Biochem Biophys 552–553:100–107. doi: 10.1016/j.abb.2014.02.010 CrossRefPubMedGoogle Scholar
  18. Hougs L et al (2005) One third of Danish hypertrophic cardiomyopathy patients have mutations in MYH7 rod region. Eur J Hum Genet 13:161–165CrossRefPubMedGoogle Scholar
  19. Huang W (2015) Molecular Mechanisms of Myosin Light Chain Mutation-Induced Cardiomyopathies Open Access Dissertations Paper 1373Google Scholar
  20. Huang J, Shelton JM, Richardson JA, Kamm KE, Stull JT (2008) Myosin regulatory light chain phosphorylation attenuates cardiac hypertrophy. J Biol Chem 283:19748–19756. doi: 10.1074/jbc.M802605200 PubMedCentralCrossRefPubMedGoogle Scholar
  21. Huang W et al (2014) Hypertrophic cardiomyopathy associated Lys104Glu mutation in the myosin regulatory light chain causes diastolic disturbance in mice. J Mol Cell Cardiol 74:318–329. doi: 10.1016/j.yjmcc.2014.06.0111 PubMedCentralCrossRefPubMedGoogle Scholar
  22. Huang W et al (2015) Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain. FEBS J 282:2379–2393. doi: 10.1111/febs.13286 CrossRefPubMedGoogle Scholar
  23. Kamisago M et al (2000) Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 343:1688–1696. doi: 10.1056/nejm200012073432304 CrossRefPubMedGoogle Scholar
  24. Kamm KE, Stull JT (2011) Signaling to myosin regulatory light chain in sarcomeres. J Biol Chem 286:9941–9947. doi: 10.1074/jbc.R110.198697 PubMedCentralCrossRefPubMedGoogle Scholar
  25. Kaski JP et al (2009) Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. Circ Cardiovasc Genet 2:436–441CrossRefPubMedGoogle Scholar
  26. 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 387:706–725. doi: 10.1016/j.jmb.2009.02.006 PubMedCentralCrossRefPubMedGoogle Scholar
  27. Kazmierczak K, Muthu P, Huang W, Jones M, Wang Y, Szczesna-Cordary D (2012) Myosin regulatory light chain mutation found in hypertrophic cardiomyopathy patients increases isometric force production in transgenic mice. Biochem J 442:95–103. doi: 10.1042/BJ20111145 CrossRefPubMedGoogle Scholar
  28. Kazmierczak K et al (2013) Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 305:H575–H589. doi: 10.1152/ajpheart.00107.2013 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 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. doi: 10.3389/fphys.2014.00353 PubMedCentralCrossRefPubMedGoogle Scholar
  30. Kerrick WGL, Kazmierczak K, Xu Y, Wang Y, Szczesna-Cordary D (2009) Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic. FASEB J 23:855–865. doi: 10.1096/fj.08-118182 PubMedCentralCrossRefPubMedGoogle Scholar
  31. Kuster DW et al (2014) Release kinetics of circulating cardiac myosin binding protein-C following cardiac injury. Am J Physiol Heart Circ Physiol 306:H547–H556. doi: 10.1152/ajpheart.00846.2013 PubMedCentralCrossRefPubMedGoogle Scholar
  32. Lee W et al (2001) Different expressivity of a ventricular essential myosin light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy. Am Heart J 141:184–189CrossRefPubMedGoogle Scholar
  33. Lee K, Harris SP, Sadayappan S, Craig R (2015) Orientation of myosin binding protein c in the cardiac muscle sarcomere determined by domain-specific immuno-EM. J Mol Biol 427:274–286. doi: 10.1016/j.jmb.2014.10.023 PubMedCentralCrossRefPubMedGoogle Scholar
  34. Lossie J et al (2014) Molecular mechanism regulating myosin and cardiac functions by ELC. Biochem Biophys Res Commun 450:464–469. doi: 10.1016/j.bbrc.2014.05.142 CrossRefPubMedGoogle Scholar
  35. Marian AJ, Roberts R (1998) Molecular genetic basis of hypertrophic cardiomyopathy: genetic markers for sudden cardiac death. J Cardiovasc Electrophysiol 9:88–99CrossRefPubMedGoogle Scholar
  36. Maron BJ, Bonow RO, Seshagiri TNR, Roberts WC, Epstein SE (1982) Hypertrophic cardiomyopathy with ventricular septal hypertrophy localized to the apical region of the left ventricle (apical hypertrophic cardiomyopathy). Am J Cardiol 49:1838–1848CrossRefPubMedGoogle Scholar
  37. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE (1995) Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation 92:785–789CrossRefPubMedGoogle Scholar
  38. Marston SB (2011) How do mutations in contractile proteins cause the primary familial cardiomyopathies? J Cardiovasc Transl Res 4:245–255. doi: 10.1007/s12265-011-9266-2 CrossRefPubMedGoogle Scholar
  39. Meder B et al (2009) A single serine in the carboxyl terminus of cardiac essential myosin light chain-1 controls cardiomyocyte contractility in vivo. Circ Res 104:650–659. doi: 10.1161/circresaha.108.186676 CrossRefPubMedGoogle Scholar
  40. Millat G et al (2011) Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy. Eur J Med Genet 54:e570–e575CrossRefPubMedGoogle Scholar
  41. Morano I (1999) Tuning the human heart molecular motors by myosin light chains. J Mol Med 77:544–555. doi: 10.1007/s001099900031 CrossRefPubMedGoogle Scholar
  42. Morita H et al (2008) Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med 358:1899–1908PubMedCentralCrossRefPubMedGoogle Scholar
  43. Muthu P et al (2011) Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction FASEB journal : official publication of the Federation of American Societies for. Exp Biol 25:4394–4405. doi: 10.1096/fj.11-191973 Google Scholar
  44. Muthu P, Huang W, Kazmierczak K, Szczesna-Cordary D (2012) 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, chap. 17. InTech, Croatia, pp 383–408. doi: 10.5772/29012 Google Scholar
  45. Olivotto I et al (2008) Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc 83:630–638CrossRefPubMedGoogle Scholar
  46. Olson TM, Karst ML, Whitby FG, Driscoll DJ (2002) Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation 105:2337–2340CrossRefPubMedGoogle Scholar
  47. Perriard JC, Hirschy A, Ehler E (2003) Dilated cardiomyopathy: a disease of the intercalated disc? Trends Cardiovasc Med 13:30–38CrossRefPubMedGoogle Scholar
  48. Petzhold D, Lossie J, Keller S, Werner S, Haase H, Morano I (2011) Human essential myosin light chain isoforms revealed distinct myosin binding, sarcomeric sorting, and inotropic activity. Cardiovasc Res 90:513–520. doi: 10.1093/cvr/cvr026
  49. 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 449:284–288. doi: 10.1016/j.bbrc.2014.05.040 CrossRefPubMedGoogle Scholar
  50. Piran S, Liu P, Morales A, Hershberger RE (2012) Where genome meets phenome: rationale for integrating genetic and protein biomarkers in the diagnosis and management of dilated cardiomyopathy and heart failure. J Am Coll Cardiol 60:283–289CrossRefPubMedGoogle Scholar
  51. Poetter K et al (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 13:63–69CrossRefPubMedGoogle Scholar
  52. Rayment I (1996) The structural basis of the myosin ATPase activity. J Biol Chem 271:15850–15853. doi: 10.1074/jbc.271.27.15850 CrossRefPubMedGoogle Scholar
  53. Rayment I et al (1993) Three-dimensional structure of myosin subfragment-1: a molecular motor. Science 261:50–58. doi: 10.1126/science.8316857 CrossRefPubMedGoogle Scholar
  54. Richard P et al. (2003) Hypertrophic cardiomyopathy: Distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 107:2227–2232, and erratum (2004) 2109(2225):3258Google Scholar
  55. Robinson JM, Wang Y, Kerrick WG, Kawai R, Cheung HC (2002) Activation of striated muscle: nearest-neighbor regulatory-unit and cross-bridge influence on myofilament kinetics. J Mol Biol 322:1065–1088CrossRefPubMedGoogle Scholar
  56. Sadayappan S, Gulick J, Klevitsky R, Lorenz JN, Sargent M, Molkentin JD, Robbins J (2009) Cardiac myosin binding protein-C phosphorylation in a {beta}-myosin heavy chain background. Circulation 119:1253–1262PubMedCentralCrossRefPubMedGoogle Scholar
  57. Santos S et al (2012) High Resolution Melting: improvements in the genetic diagnosis of Hypertrophic Cardiomyopathy in a Portuguese cohort. BMC Med Gen 13:17. doi: 10.1186/1471-2350-13-17 CrossRefGoogle Scholar
  58. Schaub MC, Hefti MA, Zuellig RA, Morano I (1998) Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms. Cardiovasc Res 37:381–404CrossRefPubMedGoogle Scholar
  59. Schonberger J, Seidman CE (2001) Many roads lead to a broken heart: the genetics of dilated cardiomyopathy. Am J Hum Genet 69:249–260PubMedCentralCrossRefPubMedGoogle Scholar
  60. Scruggs SB, Solaro RJ (2011) The significance of regulatory light chain phosphorylation in cardiac physiology. Arch Biochem Biophys 510:129–134PubMedCentralCrossRefPubMedGoogle Scholar
  61. Scruggs SB et al (2009) Ablation of ventricular myosin regulatory light chain phosphorylation in mice causes cardiac dysfunction in situ and affects neighboring myofilament protein phosphorylation. J Biol Chem 284:5097–5106PubMedCentralCrossRefPubMedGoogle Scholar
  62. Sheikh F et al (2012) Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease. J Clin Invest 122:1209–1221. doi: 10.1172/JCI61134 PubMedCentralCrossRefPubMedGoogle Scholar
  63. Sutoh K (1982) An actin-binding site on the 20 K fragment of myosin subfragment 1. Biochemistry 21:4800–4804CrossRefPubMedGoogle Scholar
  64. Sweeney HL, Bowman BF, Stull JT (1993) Myosin light chain phosphorylation in vertebrate striated muscle: regulation and function. Am J Physiol 264:C1085–C1095PubMedGoogle Scholar
  65. Szczesna D (2003) Regulatory light chains of striated muscle myosin. Structure, function and malfunction. Curr Drug Targets Cardiovasc Haematol Disord 3:187–197. doi: 10.2174/1568006033481474 CrossRefPubMedGoogle Scholar
  66. Szczesna D et al (2001) Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation. J Biol Chem 276:7086–7092. doi: 10.1074/jbc.M009823200 CrossRefPubMedGoogle Scholar
  67. Szczesna-Cordary D, Guzman G, Ng SS, Zhao J (2004) Familial hypertrophic cardiomyopathy-linked alterations in Ca2+ binding of human cardiac myosin regulatory light chain affect cardiac muscle contraction. J Biol Chem 279:3535–3542CrossRefPubMedGoogle Scholar
  68. Szczesna-Cordary D et al (2007) Myosin regulatory light chain E22 K mutation results in decreased cardiac intracellular calcium and force transients FASEB journal : official publication of the Federation of American Societies for. Exp Biol 21:3974–3985. doi: 10.1096/fj.07-8630com Google Scholar
  69. Szczesna-Cordary D, Morimoto S, Gomes AV, Moore JR (2012) Cardiomyopathies: classification, clinical characterization, and functional phenotypes. Biochemistry research international 2012:870942. doi: 10.1155/2012/870942 PubMedCentralCrossRefPubMedGoogle Scholar
  70. Timson DJ (2003) Fine tuning the myosin motor: the role of the essential light chain in striated muscle myosin. Biochimie 85:639–645CrossRefPubMedGoogle Scholar
  71. Trayer HR, Trayer IP (1985) Differential binding of rabbit fast muscle myosin light chain isoenzymes to regulated actin. FEBS Lett 180:170–173CrossRefPubMedGoogle Scholar
  72. van der Velden J et al (2003a) The effect of myosin light chain 2 dephosphorylation on Ca2+-sensitivity of force is enhanced in failing human hearts. Cardiovasc Res 57:505–514. doi: 10.1016/s0008-6363(02)00662-4 CrossRefPubMedGoogle Scholar
  73. van der Velden J et al (2003b) Increased Ca2+-sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins. Cardiovasc Res 57:37–47. doi: 10.1016/s0008-6363(02)00606-5 CrossRefPubMedGoogle Scholar
  74. Wang Y, Xu Y, Kerrick WGL, Wang Y, Guzman G, Diaz-Perez Z, Szczesna-Cordary D (2006) Prolonged Ca2+ and force transients in myosin RLC transgenic mouse fibers expressing malignant and benign FHC mutations. J Mol Biol 361:286–299. doi: 10.1016/j.jmb.2006.06.018 CrossRefPubMedGoogle Scholar
  75. Warren SA et al (2012) Myosin light chain phosphorylation is critical for adaptation to cardiac stress. Circulation 126:2575–2588. doi: 10.1161/CIRCULATIONAHA.112.116202 PubMedCentralCrossRefPubMedGoogle Scholar
  76. Wijnker PJ, Murphy AM, Stienen GJ, van der Velden J (2014) Troponin I phosphorylation in human myocardium in health and disease. Neth Heart J 22:463–469. doi: 10.1007/s12471-014-0590-4 PubMedCentralCrossRefPubMedGoogle Scholar
  77. Winstanley MA, Trayer HR, Trayer IP (1977) Role of the myosin light chains in binding to actin. FEBS Lett 77:239–242CrossRefPubMedGoogle Scholar
  78. Xie X, Harrison DH, Schlichting I, Sweet RM, Kalabokis VN, Szent-Gyorgyi AG, Cohen C (1994) Structure of the regulatory domain of scallop myosin at 2.8 A resolution. Nature 368:306–312CrossRefPubMedGoogle Scholar
  79. Xu Q, Dewey S, Nguyen S, Gomes AV (2010) Malignant and benign mutations in familial cardiomyopathies: insights into mutations linked to complex cardiovascular phenotypes. J Mol Cell Cardiol 48:899–909CrossRefPubMedGoogle Scholar
  80. Yuan CC et al (2015) Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice. Proc Natl Acad Sci USA. doi: 10.1073/pnas.1505819112 Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Molecular and Cellular PharmacologyUniversity of Miami Miller School of MedicineMiamiUSA

Personalised recommendations