Abstract
The super-relaxed (SRX) state of myosin was only recently reported in striated muscle. It is characterised by a sub-population of myosin heads with a highly inhibited rate of ATP turnover. Myosin heads in the SRX state are bound to each other along the thick filament core producing a highly ordered arrangement. Upon activation, these heads project into the interfilament space where they can bind to the actin filaments. Thus far, the population and lifetimes of myosin heads in the SRX state have been characterised in rabbit cardiac, and fast and slow skeletal muscle, as well as in the skeletal muscle of the tarantula. These studies suggest that the role of SRX in cardiac and skeletal muscle regulation is tailored to their specific functions. In skeletal muscle, the SRX modulates the resting metabolic rate. Cardiac SRX represents a “reserve” of inactive myosin heads that may protect the heart during times of stress, e.g. hypoxia and ischaemia. These heads may also be called up when there is a sustained demand for increased power. The SRX in cardiac muscle provides a potential target for novel therapies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Explore related subjects
Discover the latest articles and news from researchers in related subjects, suggested using machine learning.References
Alamo L, Wriggers W, Pinto A, Bártoli F, Salazar L, Zhao F-Q, Craig R, Padrón R (2008) Three-dimensional reconstruction of tarantula myosin filaments suggests how phosphorylation may regulate myosin activity. J Mol Biol 384:780–797. doi:10.1016/j.jmb.2008.10.013
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. doi:10.1073/pnas.1212708110
Allen DG, Kentish JC (1985) The cellular basis of the length-tension relation in cardiac muscle. J Mol Cell Cardiol 17:821–840. doi:10.1016/S0022-2828(85)80097-3
Ashrafian H, Redwood C, Blair E, Watkins H (2003) Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion. Trends Genet 19:263–268. doi:10.1016/S0168-9525(03)00081-7
Barefield D, Sadayappan S (2010) Phosphorylation and function of cardiac myosin binding protein-C in health and disease. J Mol Cell Cardiol 48:866–875. doi:10.1016/j.yjmcc.2009.11.014
Brito R, Alamo L, Lundberg U, Guerrero JR, Pinto A, Sulbaran G, Gawinowicz MA, Craig R, Padron R (2011) A molecular model of phosphorylation-based activation and potentiation of tarantula muscle thick filaments. J Mol Biol 414:44–61. doi:10.1016/j.jmb.2011.09.017
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, et al (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. doi:10.1016/s0140-6736(11)61126-4
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. doi:10.1016/j.jmb.2006.12.063
Colson BA, Bekyarova T, Locher MR, Fitzsimons DP, Irving TC, Moss RL (2008) Protein kinase A–mediated phosphorylation of cMyBP-C increases proximity of myosin heads to actin in resting myocardium. Circ Res 103:244–251. doi:10.1161/circresaha.108.178996
Colson BA, Locher MR, Bekyarova T, Patel JR, Fitzsimons DP, Irving TC, Moss RL (2010) Differential roles of regulatory light chain and myosin binding protein-C phosphorylations in the modulation of cardiac force development. J Physiol 588:981–993. doi:10.1113/jphysiol.2009.183897
Colson BA, Patel JR, Chen PP, Bekyarova T, Abdalla MI, Tong CW, Fitzsimons DP, Irving TC, Moss RL (2012) Myosin binding protein-C phosphorylation is the principal mediator of protein kinase a effects on thick filament structure in myocardium. J Mol Cell Cardiol 53:609–616. doi:10.1016/j.yjmcc.2012.07.012
Cooke R (2011) The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle. Biophys Rev 3:33–45. doi:10.1007/s12551-011-0044-9
Cooke R, Pate E (1985) The effects of ADP and phosphate on the contraction of muscle fibers. Biophys J 48:789–798. doi:10.1016/S0006-3495(85)83837-6
Craig R, Offer G (1976) The location of C-protein in rabbit skeletal muscle. Proc R Soc Lond B 192:451–461
Craig R, Woodhead JL (2006) Structure and function of myosin filaments. Curr Opin Struct Biol 16:204–212. doi:10.1016/j.sbi.2006.03.006
Craig R, Padron R, Kendrick-Jones J (1987) Structural changes accompanying phosphorylation of tarantula muscle myosin filaments. J Cell Biol 105:1319–1327
Cremo CR, Neuron JM, Yount RG (1990) Interaction of myosin subfragment 1 with fluorescent ribose-modified nucleotides. a comparison of vanadate trapping and SH1-SH2 crosslinking. Biochemistry 29:3309–3319. doi:10.1021/bi00465a023
Crowther RA, Padron R, Craig R (1985) Arrangement of the heads of myosin in relaxed thick filaments from tarantula muscle. J Mol Biol 184:429–439
Ferenczi MA, Homsher E, Simmons RM, Trentham DR (1978) Reaction mechanism of the magnesium ion-dependent adenosine triphosphatase of frog muscle myosin and subfragment 1. Biochem J 171:165–175
Fukuda N, Sasaki D, Ishiwata S, Kurihara S (2001) Length dependence of tension generation in rat skinned cardiac muscle: role of titin in the Frank-Starling mechanism of the heart. Circulation 104:1639–1645
Gautel M, Zuffardi O, Freiburg A, Labeit S (1995) Phosphorylation switches specific for the cardiac isoform of myosin binding protein-C: a modulator of cardiac contraction? EMBO J 14:1952–1960
Gonzalez-Sola M, Al-Khayat HA, Behra M, Kensler RW (2014) Zebrafish cardiac muscle thick filaments: isolation technique and three-dimensional structure. Biophys J 106:1671–1680. doi:10.1016/j.bpj.2014.01.050
Gutierrez G, Pohil RJ, Narayana P (1989) Skeletal muscle O2 consumption and energy metabolism during hypoxemia. J Appl Physiol (1985) 66:2117–2123
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. doi:10.1016/j.bpj.2011.02.061
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 AF, Niedergerke R (1954) Structural changes in muscle during contraction: interference microscopy of living muscle fibres. Nature 173:971–973
Jefferies JL, Towbin JA (2010) Dilated cardiomyopathy. Lancet 375:752–762. doi:10.1016/s0140-6736(09)62023-7
Kass DA, Solaro RJ (2006) Mechanisms and use of calcium-sensitizing agents in the failing heart. Circulation 113:305–315. doi:10.1161/circulationaha.105.542407
Kensler RW, Harris SP (2008) The structure of isolated cardiac Myosin thick filaments from cardiac Myosin binding protein-C knockout mice. Biophys J 94:1707–1718. doi:10.1529/biophysj.107.115899
Kobirumaki-Shimozawa F, Inoue T, Shintani SA, Oyama K, Terui T, Minamisawa S, Ishiwata S, Fukuda N (2014) Cardiac thin filament regulation and the Frank-Starling mechanism. J Physiol Sci 64:221–232. doi:10.1007/s12576-014-0314-y
Koretz JF (1979) Effects of C-protein on synthetic myosin filament structure. Biophys J 27:433–446. doi:10.1016/s0006-3495(79)85227-3
Kushmerick MJ, Paul RJ (1976) Aerobic recovery metabolism following a single isometric tetanus in frog sartorius muscle at 0 degrees C. J Physiol 254:693–709
Levine RJ, Kensler RW, Yang Z, Stull JT, Sweeney HL (1996) Myosin light chain phosphorylation affects the structure of rabbit skeletal muscle thick filaments. Biophys J 71:898–907. doi:10.1016/s0006-3495(96)79293-7
Lowey S, Waller GS, Trybus KM (1993) Skeletal muscle myosin light chains are essential for physiological speeds of shortening. Nature 365:454–456
Malik FI et al (2011) Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science 331:1439–1443. doi:10.1126/science.1200113
McClellan G, Kulikovskaya I, Winegrad S (2001) Changes in cardiac contractility related to calcium-mediated changes in phosphorylation of myosin-binding protein C. Biophys J 81:1083–1092. doi:10.1016/S0006-3495(01)75765-7
McNamara J, Li A, MacDonald P, dos Remedios C, Cooke A (2014) Does the Super-relaxed State of Myosin Exist in the Human Heart? 18th International Biophysics Congress, Brisbane http://www.iupab2014.org/assets/IUPAB/NewFolder/iupababstracts.pdf
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. doi:10.1161/CIRCRESAHA.110.223842
Moos C, Mason CM, Besterman JM, Feng I, Nan M, Dubin JH (1978) The binding of skeletal muscle C-protein to F-actin, and its relation to the interaction of actin with myosin subfragment-1. J Mol Biol 124:571–586
Moss RL, Fitzsimons DP (2010) Regulation of contraction in mammalian striated muscles–the plot thick-ens. J Gen Physiol 136:21–27. doi:10.1085/jgp.201010471
Myburgh KH, Franks-Skiba K, Cooke R (1995) Nucleotide turnover rate measured in fully relaxed rabbit skeletal muscle myofibrils. J Gen Physiol 106:957–973
Naber N, Cooke R, Pate E (2011a) EPR spectroscopy shows oriented myosin heads in relaxed muscle fibers. Biophys J 100:130a doi:10.1016/j.bpj.2010.12.914
Naber N, Cooke R, Pate E (2011b) Slow myosin ATP turnover in the super-relaxed state in tarantula muscle. J Mol Biol 411:943–950. doi:10.1016/j.jmb.2011.06.051
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
Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH (2006) obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 american heart association scientific statement on obesity and heart disease from the obesity committee of the council on nutrition, physical activity, and metabolism. Circulation 113:898–918. doi:10.1161/circulationaha.106.171016
Radke MB, Taft MH, Stapel B, Hilfiker-Kleiner D, Preller M, Manstein DJ (2014) Small molecule-mediated refolding and activation of myosin motor function. eLife 3:e01603. doi:10.7554/eLife.01603
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
Scruggs SB, Hinken AC, Thawornkaiwong A, Robbins J, Walker LA, de Tombe PP, Geenen DL, Buttrick PM, Solaro RJ (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 284:5097–5106. doi:10.1074/jbc.M807414200
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 9:1804–1818. doi:10.1074/mcp.M110.000075
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. doi:10.1074/jbc.M808850200
Shen Y-T, Malik FI, Zhao X, Depre C, Dhar SK, Abarzua P, Morgans DJ, Vatner SF (2010) Improvement of cardiac function by a cardiac myosin activator in conscious dogs with systolic heart failure. Circ Heart Fail 3:522–527
Stewart MA, Franks-Skiba K, Chen S, Cooke R (2010) Myosin ATP turnover rate is a mechanism involved in thermogenesis in resting skeletal muscle fibers. Proc Natl Acad Sci U S A 107:430–435. doi:10.1073/pnas.0909468107
Stringham JC, Southard JH, Hegge J, Triemstra L, Fields BL, Belzer FO (1992) Limitations of heart preservation by cold storage. Transplantation 53:287–294
Sulbaran G, Biasutto A, Alamo L, Riggs C, Pinto A, Mendez F, Craig R, Padron R (2013) Different head environments in tarantula thick filaments support a cooperative activation process. Biophys J 105:2114–2122. doi:10.1016/j.bpj.2013.09.001
Sweeney HL, Yang Z, Zhi G, Stull JT, Trybus KM (1994) Charge replacement near the phosphorylatable serine of the myosin regulatory light chain mimics aspects of phosphorylation. Proc Natl Acad Sci U S A 91:1490–1494
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 276:7086–7092. doi:10.1074/jbc.M009823200
Toepfer C, Caorsi V, Kampourakis T, Sikkel MB, West TG, Leung M, 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. doi:10.1074/jbc.M113.455444
van der Velden J, Papp Z, Boontje NM, Zaremba R, de Jong JW, Janssen PML, Hasenfuss G, Stienen GJM (2003) 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
Wagner FM (2011) Donor heart preservation and perfusion. Appl Cardiopulm Pathophysiol 15:198–206
Wang Y, Ajtai K, Burghardt TP (2014) Analytical comparison of natural and pharmaceutical ventricular myosin activators. Biochemistry 53:5298–5306. doi:10.1021/bi500730t
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. doi:10.1016/j.bpj.2014.07.075
Wood DS, Zollman J, Reuben JP, Brandt PW (1975) Human skeletal muscle: properties of the “chemically skinned” fiber. Science 187:1075–1076. doi:10.1126/science.187.4181.1075
Woodhead JL, Zhao F-Q, Craig R, Egelman EH, Alamo L, Padron R (2005) Atomic model of a myosin filament in the relaxed state. Nature 436:1195–1199 http://www.nature.com/nature/journal/v436/n7054/suppinfo/nature03920_S1.html
Woodward SK, Eccleston JF, Geeves MA (1991) Kinetics of the interaction of 2′(3′)-O-(N-methylanthraniloyl)-ATP with myosin subfragment 1 and actomyosin subfragment 1: characterization of two acto-S1-ADP complexes. Biochemistry 30:422–430
Zoghbi ME, Woodhead JL, Moss RL, Craig R (2008) Three-dimensional structure of vertebrate cardiac muscle myosin filaments. Proc Natl Acad Sci U S A 105:2386–2390. doi:10.1073/pnas.0708912105
Conflict of interest
This article does not contain any studies performed by the any of the authors involving animal or human experimentation. J.M., A.L., C.d.R., R.C. each declare that they have no conflict of interest. Figure 3 (B)-(D) was reprinted from Biophysical Journal, 100(8), Hooijman P, Stewart MA, Cooke R, A new state of cardiac myosin with very slow ATP turnover: a potential cardioprotective mechanism in the heart. pp. 1969–1976, 2011, with permission from Elsevier. Figure 1 (B) was reprinted from Current Opinion in Structural Biology, 16(2), Craig R, Woodhead JL, Structure and function of myosin filaments. pp. 204–2012, 2006, with permission from Elsevier.
Author information
Authors and Affiliations
Corresponding author
Additional information
Special Issue: Biophysics of Human Heart Failure
Rights and permissions
About this article
Cite this article
McNamara, J.W., Li, A., dos Remedios, C. et al. The role of super-relaxed myosin in skeletal and cardiac muscle. Biophys Rev 7, 5–14 (2015). https://doi.org/10.1007/s12551-014-0151-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12551-014-0151-5
Keywords
Profiles
- Amy Li View author profile