Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations

James A. Spudich1
1Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA

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Ababou A, Rostkova E, Mistry S, Le Masurier C, Gautel M, Pfuhl M (2008) Myosin binding protein C positioned to play a key role in regulation of muscle contraction: structure and interactions of domain C1. J Mol Biol 384:615–630. https://doi.org/10.1016/j.jmb.2008.09.065

Adhikari AS, Kooiker KB, Sarkar SS, Liu C, Bernstein D, Spudich JA, Ruppel KM (2016) Early-onset hypertrophic cardiomyopathy mutations significantly increase the velocity, force, and actin-activated ATPase activity of human beta-cardiac myosin. Cell Rep 17:2857–2864. https://doi.org/10.1016/j.celrep.2016.11.040

Adhikari AS, Trivedi DV, Sarkar SS, Song D, Kooiker KB, Bernstein D, Spudich JA, Ruppel KM (2019) Hypertrophic cardiomyopathy mutations at the folded-back sequestered β-cardiac myosin S1-S2 and S1-S1 interfaces release sequestered heads and increase myosin enzymatic activity. BioRxiv. https://doi.org/10.1101/537159

Aksel T, Choe Yu E, Sutton S, Ruppel KM, Spudich JA (2015) Ensemble force changes that result from human cardiac myosin mutations and a small-molecule effector. Cell Rep 11:910–920

Al-Khayat HA, Kensler RW, Squire JM, Marston SB, Morris EP (2013) Atomic model of the human cardiac muscle myosin filament. Proc Natl Acad Sci U S A 110:318–323. https://doi.org/10.1073/pnas.1212708110

Alamo L, Pinto A, Sulbaran G, Mavarez J, Padron R (2018) Lessons from a tarantula: new insights into myosin interacting-heads motif evolution and its implications on disease. Biophys Rev 10:1465–1477. https://doi.org/10.1007/s12551-017-0292-4

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. https://doi.org/10.7554/eLife.24634

Alamo L, Wriggers W, Pinto A, Bartoli F, Salazar L, Zhao FQ, Craig R, Padron R (2008) Three-dimensional reconstruction of tarantula myosin filaments suggests how phosphorylation may regulate myosin activity. J Mol Biol 384:780–797. https://doi.org/10.1016/j.jmb.2008.10.013

Anderson RL, Trivedi DV, Sarkar SS, Henze M, Ma W, Gong H, Rogers CS, Gorham JM, Wong FL, Morck MM, Seidman JG, Ruppel KM, Irving TC, Cooke R, Green EM, Spudich JA (2018) Deciphering the super relaxed state of human beta-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. Proc Natl Acad Sci U S A 115:E8143–E8152. https://doi.org/10.1073/pnas.1809540115

Bennett P, Craig R, Starr R, Offer G (1986) The ultrastructural location of C-protein, X-protein and H-protein in rabbit muscle. J Muscle Res Cell Motil 7:550–567

Blankenfeldt W, Thoma NH, Wray JS, Gautel M, Schlichting I (2006) Crystal structures of human cardiac beta-myosin II S2-delta provide insight into the functional role of the S2 subfragment. Proc Natl Acad Sci U S A 103:17713–17717. https://doi.org/10.1073/pnas.0606741103

Bonne G, Carrier L, Bercovici J, Cruaud C, Richard P, Hainque B, Gautel M, Labeit S, James M, Beckmann J, Weissenbach J, Vosberg HP, Fiszman M, Komajda M, Schwartz K (1995) Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nat Genet 11:438–440. https://doi.org/10.1038/ng1295-438

Buvoli M, Hamady M, Leinwand LA, Knight R (2008) Bioinformatics assessment of β-myosin mutations reveals myosin’s high sensitivity to mutations. Trends Cardiovasc Med 18:141–149. https://doi.org/10.1016/j.tcm.2008.04.001

Captur G, Lopes LR, Mohun TJ, Patel V, Li C, Bassett P, Finocchiaro G, Ferreira VM, Esteban MT, Muthurangu V, Sherrid MV, Day SM, Canter CE, McKenna WJ, Seidman CE, Bluemke DA, Elliott PM, Ho CY, Moon JC (2014) Prediction of sarcomere mutations in subclinical hypertrophic cardiomyopathy. Circ Cardiovasc Imaging 7:863–871

Charron P, Dubourg O, Desnos M, Bennaceur M, Carrier L, Camproux AC, Isnard R, Hagege A, Langlard JM, Bonne G, Richard P, Hainque B, Bouhour JB, Schwartz K, Komajda M (1998) Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation 97:2230–2236

Chow ML, Shaffer JF, Harris SP, Dawson JF (2014) Altered interactions between cardiac myosin binding protein-C and alpha-cardiac actin variants associated with cardiomyopathies. Arch Biochem Biophys 550-551:28–32

Cleland JG, Teerlink JR, Senior R, Nifontov EM, Mc Murray JJ, Lang CC, Tsyrlin VA, Greenberg BH, Mayet J, Francis DP, Shaburishvili T, Monaghan M, Saltzberg M, Neyses L, Wasserman SM, Lee JH, Saikali KG, Clarke CP, Goldman JH, Wolff AA, Malik FI (2011) The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 378:676–683. https://doi.org/10.1016/S0140-6736(11)61126-4

Colegrave M, Peckham M (2014) Structural implications of beta-cardiac myosin heavy chain mutations in human disease. Anat Rec (Hoboken) 297:1670–1680. https://doi.org/10.1002/ar.22973

Colson BA, Bekyarova T, Fitzsimons DP, Irving TC, Moss RL (2007) Radial displacement of myosin cross-bridges in mouse myocardium due to ablation of myosin binding protein-C. J Mol Biol 367:36–41. https://doi.org/10.1016/j.jmb.2006.12.063

Craig R, Offer G (1976) The location of C-protein in rabbit skeletal muscle. Proc R Soc Lond B Biol Sci 192:451–461

Craig R, Padron R, Kendrick-Jones J (1987) Structural changes accompanying phosphorylation of tarantula muscle myosin filaments. J Cell Biol 105:1319–1327

Davis J, Davis LC, Correll RN, Makarewich CA, Schwanekamp JA, Moussavi-Harami F, Wang D, York AJ, Wu H, Houser SR, Seidman CE, Seidman JG, Regnier M, Metzger JM, Wu JC, Molkentin JD (2016) A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. Cell 165:1147–1159. https://doi.org/10.1016/j.cell.2016.04.002

De Lange WJ, Grimes AC, Hegge LF, Spring AM, Brost TM, Ralphe JC (2013) E258K HCM-causing mutation in cardiac MyBP-C reduces contractile force and accelerates twitch kinetics by disrupting the cMyBP-C and myosin S2 interaction. J Gen Physiol 142:241–255. https://doi.org/10.1085/jgp.201311018

Debold EP, Schmitt JP, Patlak JB, Beck SE, Moore JR, Seidman JG, Seidman C, Warshaw DM (2007) Hypertrophic and dilated cardiomyopathy mutations differentially affect the molecular force generation of mouse alpha-cardiac myosin in the laser trap assay. Am J Physiol Heart Circ Physiol 293:H284–H291

Fenn WO (1923) A quantitative comparison between the energy liberated and the work performed by the isolated sartorius muscle of the frog. J Physiol 58:175–203

Fenn WO (1924) The relation between the work performed and the energy liberated in muscular contraction. J Physiol 58:373–395

Green EM, Wakimoto H, Anderson RL, Evanchik MJ, Gorham JM, Harrison BC, Henze M, Kawas R, Oslob JD, Rodriguez HM, Song Y, Wan W, Leinwand LA, Spudich JA, McDowell RS, Seidman JG, Seidman CE (2016) A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science 351:617–621

Gruen M, Gautel M (1999) Mutations in beta-myosin S2 that cause familial hypertrophic cardiomyopathy (FHC) abolish the interaction with the regulatory domain of myosin-binding protein-C. J Mol Biol 286:933–949. https://doi.org/10.1006/jmbi.1998.2522

Haland TF, Almaas VM, Hasselberg NE, Saberniak J, Leren IS, Hopp E, Edvardsen T, Haugaa KH (2016) Strain echocardiography is related to fibrosis and ventricular arrhythmias in hypertrophic cardiomyopathy. Eur Heart J Cardiovasc Imaging 17:613–621. https://doi.org/10.1093/ehjci/jew005

Harris SP, Lyons RG, Bezold KL (2011) In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament. Circ Res 108:751–764

Harris SP, Rostkova E, Gautel M, Moss RL (2004) Binding of myosin binding protein-C to myosin subfragment S2 affects contractility independent of a tether mechanism. Circ Res 95:930–936. https://doi.org/10.1161/01.RES.0000147312.02673.56

Harvey PA, Leinwand LA (2011) Cellular mechanisms of cardiomyopathy. J Cell Biol 194:355–365. https://doi.org/10.1083/jcb.201101100

Ho CY, Carlsen C, Thune JJ, Havndrup O, Bundgaard H, Farrohi F, Rivero J, Cirino AL, Andersen PS, Christiansen M, Maron BJ, Orav EJ, Kober L (2009) Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy. Circ Cardiovasc Genet 2:314–321. https://doi.org/10.1161/CIRCGENETICS.109.862128

Ho CY, Day SM, Ashley EA, Michels M, Pereira AC, Jacoby D, Cirino AL, Fox JC, Lakdawala NK, Ware JS, Caleshu CA, Helms AS, Colan SD, Girolami F, Cecchi F, Seidman CE, Sajeev G, Signorovitch J, Green EM, Olivotto I (2018) Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation 138:1387–1398. https://doi.org/10.1161/CIRCULATIONAHA.117.033200

Ho CY, Lopez B, Coelho-Filho OR, Lakdawala NK, Cirino AL, Jarolim P, Kwong R, Gonzalez A, Colan SD, Seidman JG, Diez J, Seidman CE (2010) Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med 363:552–563

Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, Seidman CE, Solomon SD (2002) Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 105:2992–2997

Homburger JR, Green EM, Caleshu C, Sunitha MS, Taylor RE, Ruppel KM, Metpally RP, Colan SD, Michels M, Day SM, Olivotto I, Bustamante CD, Dewey FE, Ho CY, Spudich JA, Ashley EA (2016) Multidimensional structure-function relationships in human beta-cardiac myosin from population-scale genetic variation. Proc Natl Acad Sci U S A 113:6701–6706. https://doi.org/10.1073/pnas.1606950113

Hooijman P, Stewart MA, Cooke R (2011) A new state of cardiac myosin with very slow ATP turnover: a potential cardioprotective mechanism in the heart. Biophys J 100:1969–1976. https://doi.org/10.1016/j.bpj.2011.02.061

Irving M (2017) Regulation of contraction by the thick filaments in skeletal muscle. Biophys J 113:2579–2594. https://doi.org/10.1016/j.bpj.2017.09.037

Jacoby DLS, Owens A, Wang A, Young D, Tripuraneni R, Semigran M, Heitner S (2018) Reduction in left ventricular outflow tract gradient with mavacamten (MYK-461) in symptomatic obstructive hypertrophic cardiomyopathy patients (PIONEER-HCM). JAC 71:A644

Jia W, Shaffer JF, Harris SP, Leary JA (2010) Identification of novel protein kinase A phosphorylation sites in the M-domain of human and murine cardiac myosin binding protein-C using mass spectrometry analysis. J Proteome Res 9:1843–1853. https://doi.org/10.1021/pr901006h

Kampourakis T, Irving M (2015) Phosphorylation of myosin regulatory light chain controls myosin head conformation in cardiac muscle. J Mol Cell Cardiol 85:199–206. https://doi.org/10.1016/j.yjmcc.2015.06.002

Kampourakis T, Yan Z, Gautel M, Sun YB, Irving M (2014) Myosin binding protein-C activates thin filaments and inhibits thick filaments in heart muscle cells. Proc Natl Acad Sci U S A 111:18763–18768. https://doi.org/10.1073/pnas.1413922112

Kampourakis T, Zhang X, Sun YB, Irving M (2018) Omecamtiv mercabil and blebbistatin modulate cardiac contractility by perturbing the regulatory state of the myosin filament. J Physiol 596:31–46. https://doi.org/10.1113/JP275050

Kawana M, Sarkar SS, Sutton S, Ruppel KM, Spudich JA (2017) Biophysical properties of human beta-cardiac myosin with converter mutations that cause hypertrophic cardiomyopathy. Sci Adv 3:e1601959. https://doi.org/10.1126/sciadv.1601959

Kawas RF, Anderson RL, Ingle SRB, Song Y, Sran AS, Rodriguez HM (2017) A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle. J Biol Chem 292:16571–16577. https://doi.org/10.1074/jbc.M117.776815

Konno T, Chang S, Seidman JG, Seidman CE (2010) Genetics of hypertrophic cardiomyopathy. Curr Opin Cardiol 25:205–209. https://doi.org/10.1097/HCO.0b013e3283375698

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. https://doi.org/10.1016/j.jmb.2014.10.023

Lee KH, Sulbaran G, Yang S, Mun JY, Alamo L, Pinto A, Sato O, Ikebe M, Liu X, Korn ED, Sarsoza F, Bernstein SI, Padron R, Craig R (2018) Interacting-heads motif has been conserved as a mechanism of myosin II inhibition since before the origin of animals. Proc Natl Acad Sci U S A 115:E1991–E2000. https://doi.org/10.1073/pnas.1715247115

Lee SPA EA, Homburger J, Caleshu C, Green EM, Jacoby D, Colan SD, Arteaga-Fernández E, Day SM, Girolami F, Olivotto I, Michels M, Ho CY, Perez MV (2018) Incident atrial fibrillation is associated with MYH7 sarcomeric gene variation in hypertrophic cardiomyopathy. Results from the international sarcomeric human cardiomyopathy registry. Circ Heart Fail 11:1–11. https://doi.org/10.1161/circheartfailure.118.005191

Liu C, Kawana M, Song D, Ruppel KM, Spudich JA (2018) Controlling load-dependent kinetics of beta-cardiac myosin at the single-molecule level. Nat Struct Mol Biol 25:505–514. https://doi.org/10.1038/s41594-018-0069-x

Liu Y, White HD, Belknap B, Winkelmann DA, Forgacs E (2015) Omecamtiv mecarbil modulates the kinetic and motile properties of porcine beta-cardiac myosin. Biochemistry 54:1963–1975. https://doi.org/10.1021/bi5015166

Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, Anderson RL, Sueoka SH, Lee KH, Finer JT, Sakowicz R, Baliga R, Cox DR, Garard M, Godinez G, Kawas R, Kraynack E, Lenzi D, Lu PP, Muci A, Niu C, Qian X, Pierce DW, Pokrovskii M, Suehiro I, Sylvester S, Tochimoto T, Valdez C, Wang W, Katori T, Kass DA, Shen YT, Vatner SF, Morgans DJ (2011) Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science 331:1439–1443. https://doi.org/10.1126/science.1200113

Maron BJ, Maron MS (2013) Hypertrophic cardiomyopathy. Lancet 381:242–255. https://doi.org/10.1016/S0140-6736(12)60397-3

Marston S, Copeland O, Jacques A, Livesey K, Tsang V, McKenna WJ, Jalilzadeh S, Carballo S, Redwood C, Watkins H (2009) Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circ Res 105:219–222. https://doi.org/10.1161/CIRCRESAHA.109.202440

McNamara JW, Li A, Lal S, Bos JM, Harris SP, van der Velden J, Ackerman MJ, Cooke R, Dos Remedios CG (2017) MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy. PLoS One 12:e0180064. https://doi.org/10.1371/journal.pone.0180064

McNamara JW, Li A, Smith NJ, Lal S, Graham RM, Kooiker KB, van Dijk SJ, Remedios CG, Harris SP, Cooke R (2016) Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes. J Mol Cell Cardiol 94:65–71. https://doi.org/10.1016/j.yjmcc.2016.03.009

Moore JR, Leinwand L, Warshaw DM (2012) Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor. Circ Res 111:375–385. https://doi.org/10.1161/circresaha.110.223842

Nag S, Sommese RF, Ujfalusi Z, Combs A, Langer S, Sutton S, Leinwand LA, Geeves MA, Ruppel KM, Spudich JA (2015) Contractility parameters of human beta-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function. Sci Adv 1:e1500511. https://doi.org/10.1126/sciadv.1500511

Nag S, Trivedi DV, Sarkar SS, Adhikari AS, Sunitha MS, Sutton S, Ruppel KM, Spudich JA (2017) The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations. Nat Struct Mol Biol 24:525–533. https://doi.org/10.1038/nsmb.3408

Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE (2002) Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 105:446–451

Offer G, Moos C, Starr R (1973) A new protein of the thick filaments of vertebrate skeletal myofibrils. Extractions, purification and characterization. J Mol Biol 74:653–676

Padron R, Pante N, Sosa H, Kendrick-Jones J (1991) X-ray diffraction study of the structural changes accompanying phosphorylation of tarantula muscle. J Muscle Res Cell Motil 12:235–241

Planelles-Herrero VJ, Hartman JJ, Robert-Paganin J, Malik FI, Houdusse A (2017) Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil. Nat Commun 8:190. https://doi.org/10.1038/s41467-017-00176-5

Rall JA (2014) Mechanism of muscular contraction. Perspectives in physiology, vol X111. Springer, New York, NY

Ratti J, Rostkova E, Gautel M, Pfuhl M (2011) Structure and interactions of myosin-binding protein C domain C0: cardiac-specific regulation of myosin at its neck? J Biol Chem 286:12650–12658. https://doi.org/10.1074/jbc.M110.156646

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 261:50–58

Robert-Paganin J, Auguin D, Houdusse A (2018) Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition. Nat Commun 9:4019. https://doi.org/10.1038/s41467-018-06191-4

Rohde JA, Roopnarine O, Thomas DD, Muretta JM (2018) Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin. Proc Natl Acad Sci U S A 115:E7486–E7494. https://doi.org/10.1073/pnas.1720342115

Rohde JA, Thomas DD, Muretta JM (2017) Heart failure drug changes the mechanoenzymology of the cardiac myosin powerstroke. Proc Natl Acad Sci U S A 114:E1796–E1804. https://doi.org/10.1073/pnas.1611698114

Sarkar SS, Trivedi DV, Morck MM, Adhikari AS, Pasha SN, Ruppel KM, Spudich JA (2019) The molecular basis of hypercontractility caused by the hypertrophic cardiomyopathy mutations R403Q and R663H. BioRxiv https://doi.org/10.1101/543413

Seidman CE, Seidman JG (2000) Hypertrophic cardiomyopathy. In: Scriver CR, Beaudet AL, Valle D, Sly WS, Childs KW, Vogelstein B (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York City, pp 5532–5452

Seidman JG, Seidman CE (2001) The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell 104:557–567. https://doi.org/10.1016/S0092-8674(01)00242-2

Semsarian C, Ingles J, Maron MS, Maron BJ (2015) New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol 65:1249–1254. https://doi.org/10.1016/j.jacc.2015.01.019

Shaffer JF, Kensler RW, Harris SP (2009) The myosin-binding protein C motif binds to F-actin in a phosphorylation-sensitive manner. J Biol Chem 284:12318–12327. https://doi.org/10.1074/jbc.M808850200

Shih WM, Gryczynski Z, Lakowicz JR, Spudich JA (2000) A FRET-based sensor reveals large ATP hydrolysis-induced conformational changes and three distinct states of the molecular motor myosin. Cell 102:683–694

Sirigu S, Hartman JJ, Planelles-Herrero VJ, Ropars V, Clancy S, Wang X, Chuang G, Qian X, Lu PP, Barrett E, Rudolph K, Royer C, Morgan BP, Stura EA, Malik FI, Houdusse AM (2016) Highly selective inhibition of myosin motors provides the basis of potential therapeutic application. Proc Natl Acad Sci U S A 113:E7448–E7455. https://doi.org/10.1073/pnas.1609342113

Sommese RF, Sung J, Nag S, Sutton S, Deacon JC, Choe E, Leinwand LA, Ruppel K, Spudich JA (2013) Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human beta-cardiac myosin motor function. Proc Natl Acad Sci U S A 110:12607–12612. https://doi.org/10.1073/pnas.1309493110

Spudich JA (2015) The myosin mesa and a possible unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy. Biochem Soc Trans 43:64–72. https://doi.org/10.1042/BST20140324

Spudich JA, Aksel T, Bartholomew SR, Nag S, Kawana M, Yu EC, Sarkar SS, Sung J, Sommese RF, Sutton S, Cho C, Adhikari AS, Taylor R, Liu C, Trivedi D, Ruppel KM (2016) Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human beta-cardiac myosin. J Exp Biol 219:161–167. https://doi.org/10.1242/jeb.125930

Starr R, Offer G (1971) Polypeptide chains of intermediate molecular weight in myosin preparations. FEBS Lett 15:40–44

Starr R, Offer G (1978) The interaction of C-protein with heavy meromyosin and subfragment-2. Biochem J 171:813–816

Sung J, Nag S, Mortensen KI, Vestergaard CL, Sutton S, Ruppel K, Flyvbjerg H, Spudich JA (2015) Harmonic force spectroscopy measures load-dependent kinetics of individual human beta-cardiac myosin molecules. Nat Commun 6:7931. https://doi.org/10.1038/ncomms8931

Swenson AM, Tang W, Blair CA, Fetrow CM, Unrath WC, Previs MJ, Campbell KS, Yengo CM (2017) Omecamtiv mecarbil enhances the duty ratio of human beta-cardiac myosin resulting in increased calcium sensitivity and slowed force development in cardiac muscle. J Biol Chem 292:3768–3778. https://doi.org/10.1074/jbc.M116.748780

Teerlink JR, Clarke CP, Saikali KG, Lee JH, Chen MM, Escandon RD, Elliott L, Bee R, Habibzadeh MR, Goldman JH, Schiller NB, Malik FI, Wolff AA (2011) Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study. Lancet 378:667–675. https://doi.org/10.1016/S0140-6736(11)61219-1

Teerlink JR, Felker GM, McMurray JJ, Solomon SD, Adams KF Jr, Cleland JG, Ezekowitz JA, Goudev A, Macdonald P, Metra M, Mitrovic V, Ponikowski P, Serpytis P, Spinar J, Tomcsanyi J, Vandekerckhove HJ, Voors AA, Monsalvo ML, Johnston J, Malik FI, Honarpour N, Investigators C-H (2016) Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet 388:2895–2903. https://doi.org/10.1016/S0140-6736(16)32049-9

Toepfer C, Caorsi V, Kampourakis T, Sikkel MB, West TG, Leung MC, Al-Saud SA, MacLeod KT, Lyon AR, Marston SB, Sellers JR, Ferenczi MA (2013) Myosin regulatory light chain (RLC) phosphorylation change as a modulator of cardiac muscle contraction in disease. J Biol Chem 288:13446–13454. https://doi.org/10.1074/jbc.M113.455444

Trivedi DV, Adhikari AS, Sarkar SS, Ruppel KM, Spudich JA (2018) Hypertrophic cardiomyopathy and the myosin mesa: viewing an old disease in a new light. Biophys Rev 10:27–48. https://doi.org/10.1007/s12551-017-0274-6

Tyska MJ, Hayes E, Giewat M, Seidman CE, Seidman JG, Warshaw DM (2000) Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy. Circ Res 86:737–744

Ujfalusi Z, Vera CD, Mijailovich SM, Svicevic M, Yu EC, Kawana M, Ruppel KM, Spudich JA, Geeves MA, Leinwand LA (2018) Dilated cardiomyopathy myosin mutants have reduced force-generating capacity. J Biol Chem 293:9017–9029. https://doi.org/10.1074/jbc.RA118.001938

van Dijk SJ, Bezold KL, Harris SP (2014) Earning stripes: myosin binding protein-C interactions with actin. Pflugers Arch 466:445–450

van Dijk SJ, Dooijes D, dos Remedios C, Michels M, Lamers JM, Winegrad S, Schlossarek S, Carrier L, ten Cate FJ, Stienen GJ, van der Velden J (2009) Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction. Circulation 119:1473–1483

Waldmuller S, Erdmann J, Binner P, Gelbrich G, Pankuweit S, Geier C, Timmermann B, Haremza J, Perrot A, Scheer S, Wachter R, Schulze-Waltrup N, Dermintzoglou A, Schonberger J, Zeh W, Jurmann B, Brodherr T, Borgel J, Farr M, Milting H, Blankenfeldt W, Reinhardt R, Ozcelik C, Osterziel KJ, Loeffler M, Maisch B, Regitz-Zagrosek V, Schunkert H, Scheffold T, German Competence Network Heart F (2011) Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure. Eur J Heart Fail 13:1185–1192. https://doi.org/10.1093/eurjhf/hfr074

Walsh R, Rutland C, Thomas R, Loughna S (2010) Cardiomyopathy: a systematic review of disease-causing mutations in myosin heavy chain 7 and their phenotypic manifestations. Cardiology 115:49–60

Watkins H, Conner D, Thierfelder L, Jarcho JA, MacRae C, McKenna WJ, Maron BJ, Seidman JG, Seidman CE (1995) Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat Genet 11:434–437. https://doi.org/10.1038/ng1295-434

Wendt T, Taylor D, Messier T, Trybus KM, Taylor KA (1999) Visualization of head-head interactions in the inhibited state of smooth muscle myosin. J Cell Biol 147:1385–1390

Wendt T, Taylor D, Trybus KM, Taylor K (2001) Three-dimensional image reconstruction of dephosphorylated smooth muscle heavy meromyosin reveals asymmetry in the interaction between myosin heads and placement of subfragment 2. Proc Natl Acad Sci U S A 98:4361–4366. https://doi.org/10.1073/pnas.071051098

Wilson C, Naber N, Pate E, Cooke R (2014) The myosin inhibitor blebbistatin stabilizes the super-relaxed state in skeletal muscle. Biophys J 107:1637–1646. https://doi.org/10.1016/j.bpj.2014.07.075

Woodhead JL, Zhao FQ, Craig R (2013) Structural basis of the relaxed state of a Ca2+-regulated myosin filament and its evolutionary implications. Proc Natl Acad Sci U S A 110:8561–8566. https://doi.org/10.1073/pnas.1218462110

Woodhead JL, Zhao FQ, Craig R, Egelman EH, Alamo L, Padron R (2005) Atomic model of a myosin filament in the relaxed state. Nature 436:1195–1199. https://doi.org/10.1038/nature03920

Woody MS, Greenberg MJ, Barua B, Winkelmann DA, Goldman YE, Ostap EM (2018) Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke. Nat Commun 9:3838. https://doi.org/10.1038/s41467-018-06193-2

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 48:899–909. https://doi.org/10.1016/j.yjmcc.2010.03.005

Zhao FQ, Padron R, Craig R (2008) Blebbistatin stabilizes the helical order of myosin filaments by promoting the switch 2 closed state. Biophys J 95:3322–3329. https://doi.org/10.1529/biophysj.108.137067