Imperial College London

ProfessorSteveMarston

Faculty of MedicineNational Heart & Lung Institute

Emeritus Professor
 
 
 
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Contact

 

+44 (0)20 7594 2732s.marston Website

 
 
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Location

 

433ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

189 results found

Marston SB, Montgiraud C, Munster AB, Copeland O, Choi O, dos Remedios C, Messer AE, Ehler E, Knoell Ret al., 2015, OBSCN Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency, PLOS One, Vol: 10, ISSN: 1932-6203

BackgroundStudies of the functional consequences of DCM-causing mutations have been limited to afew cases where patients with known mutations had heart transplants. To increase the numberof potential tissue samples for direct investigation we performed whole exon sequencingof explanted heart muscle samples from 30 patients that had a diagnosis of familial dilatedcardiomyopathy and screened for potentially disease-causing mutations in 58 HCM orDCM-related genes.ResultsWe identified 5 potentially disease-causing OBSCN mutations in 4 samples; one samplehad two OBSCN mutations and one mutation was judged to be not disease-related. Alsoidentified were 6 truncating mutations in TTN, 3 mutations in MYH7, 2 in DSP and one eachin TNNC1, TNNI3, MYOM1, VCL, GLA, PLB, TCAP, PKP2 and LAMA4. The mean level ofobscurin mRNA was significantly greater and more variable in healthy donor samples thanthe DCM samples but did not correlate with OBSCN mutations. A single obscurin proteinband was observed in human heart myofibrils with apparent mass 960 ± 60 kDa. The threesamples with OBSCN mutations had significantly lower levels of obscurin immunoreactivematerial than DCM samples without OBSCN mutations (45±7, 48±3, and 72±6% of controllevel).Obscurin levels in DCM controls, donor heart and myectomy samples were the same.ConclusionsOBSCN mutations may result in the development of a DCM phenotype via haploinsufficiency.Mutations in the obscurin gene should be considered as a significant causal factorof DCM, alone or in concert with other mutations.

Journal article

Yuen M, Cooper ST, Marston SB, Nowak KJ, McNamara E, Mokbel N, Ilkovski B, Ravenscroft G, Rendu J, de Winter JM, Klinge L, Beggs AH, North KN, Ottenheijm CA, Clarke NFet al., 2015, Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres., Human Molecular Genetics, Vol: 24, Pages: 6278-6292, ISSN: 1460-2083

Dominant mutations in TPM3, encoding α-tropomyosinslow, cause a congenital myopathy characterised by generalised muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in twelve TPM3-myopathy patients.We confirm that slow myofibre hypotrophy is a diagnostic hallmark of TPM3-myopathy, and is commonly accompanied by skewing of fibre-type ratios (either slow or fast fibre predominance). Patient muscle contained normal ratios of the three tropomyosin isoforms and normal fibre-type expression of myosins and troponins. Using 2D-PAGE, we demonstrate that mutant α-tropomyosinslow was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosinslow likely impacts actin-tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosinslow (R168C) to filamentous actin.Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca(2+)] (pCa 4.5), patient slow fibres produced only 63% of the contractile force produced in control slow fibres and had reduced acto-myosin cross-bridge cycling kinetics. Importantly, due to reduced Ca(2+)-sensitivity, at sub-saturating [Ca(2+)] (pCa 6, levels typically released during in vivo contraction) patient slow fibres produced only 26% of the force generated by control slow fibres.Thus, weakness in TPM3-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca(2+)], and impaired acto-myosin cross-bridge cycling kinetics. Fast myofibres are spared; however, they appear to be unable to compensate for slow fibre dysfunction. Abnormal Ca(2+)-sensitivity in TPM3-myopathy patients suggests Ca(2+)-sensitising drugs may represent a useful treatment for this condition.

Journal article

Papadaki M, Vikhorev PG, Marston SB, Messer AEet al., 2015, Uncoupling of myofilament Ca2+-sensitivity from troponin I phosphorylation by mutations can be reversed by Epigallocatechin-3-Gallate., Cardiovascular Research, Vol: 108, Pages: 99-110, ISSN: 1755-3245

AIMS: Heart muscle contraction is regulated via the β-adrenergic response that leads to phosphorylation of Troponin I (TnI) at Ser22/23, which changes the Ca(2+)-sensitivity of the cardiac myofilament. Mutations in thin filament proteins that cause Dilated Cardiomyopathy (DCM) and some mutations that cause Hypertrophic Cardiomyopathy (HCM) abolish the relationship between TnI phosphorylation and Ca(2+)-sensitivity (uncoupling). Small molecule Ca(2+)-sensitisers and Ca(2+)-desensitisers that act upon troponin alter the Ca(2+)-sensitivity of the thin filament but their relationship with TnI phosphorylation has never been studied before. METHODS AND RESULTS: Quantitative in vitro motility assay showed that 30 µM EMD57033 and 100 µM Bepridil increase Ca(2+)-sensitivity of phosphorylated cardiac thin filaments by 3.1 and 2.8-fold respectively. Additionally they uncoupled Ca(2+)-sensitivity from TnI phosphorylation, mimicking the effect of HCM mutations. EGCG decreased Ca(2+)-sensitivity of phosphorylated and unphosphorylated wild-type thin filaments equally (by 2.15±0.45 and 2.80±0.48-fold respectively), retaining the coupling. Moreover, EGCG also reduced Ca(2+)-sensitivity of phosphorylated but not unphosphorylated thin filaments containing DCM and HCM-causing mutations, thus the dependence of Ca(2+)-sensitivity upon TnI phosphorylation of uncoupled mutant thin filaments was restored in every case. In single mouse heart myofibrils, EGCG reduced Ca(2+)-sensitivity of force and kACT and also preserved coupling. Myofibrils from the ACTC E361G (DCM) mouse were uncoupled; EGCG reduced Ca(2+)-sensitivity more for phosphorylated than unphosphorylated myofibrils, thus restoring coupling. CONCLUSION: We conclude that it is possible to both mimic and reverse the pathological defects in troponin caused by cardiomyopathy mutations pharmacologically. Re-coupling by EGCG may be of potential therapeutic significance for treating cardiomyopathies.

Journal article

Vikhorev PG, Song W, Wilkinson R, Copeland O, Messer AE, Ferenczi MA, Marston SBet al., 2014, The Dilated Cardiomyopathy-Causing Mutation ACTC E361G in Cardiac Muscle Myofibrils Specifically Abolishes Modulation of Ca2+ Regulation by Phosphorylation of Troponin I, Biophysical Journal, Vol: 107, Pages: 2369-2380, ISSN: 1542-0086

Phosphorylation of troponin I by protein kinase A (PKA) reduces Ca2þ sensitivity and increases the rate of Ca2þrelease from troponin C and the rate of relaxation in cardiac muscle. In vitro experiments indicate that mutations that causedilated cardiomyopathy (DCM) uncouple this modulation, but this has not been demonstrated in an intact contractile system.Using a Ca2þ-jump protocol, we measured the effect of the DCM-causing mutation ACTC E361G on the equilibrium and kineticparameters of Ca2þ regulation of contractility in single transgenic mouse heart myofibrils. We used propranolol treatment of miceto reduce the level of troponin I and myosin binding protein C (MyBP-C) phosphorylation in their hearts before isolating the myo-fibrils. In nontransgenic mouse myofibrils, the Ca2þ sensitivity of force was increased, the fast relaxation phase rate constant,kREL, was reduced, and the length of the slow linear phase, tLIN, was increased when the troponin I phosphorylation level wasreduced from 1.02 to 0.3 molPi/TnI (EC50 P/unp ¼ 1.8 5 0.2, p < 0.001). Native myofibrils from ACTC E361G transgenic micehad a 2.4-fold higher Ca2þ sensitivity than nontransgenic mouse myofibrils. Strikingly, the Ca2þ sensitivity and relaxation parametersof ACTC E361G myofibrils did not depend on the troponin I phosphorylation level (EC50 P/unp ¼ 0.88 5 0.17, p ¼ 0.39).Nevertheless, modulation of the Ca2þ sensitivity of ACTC E361G myofibrils by sarcomere length or EMD57033 was indistinguishablefrom that of nontransgenic myofibrils. Overall, EC50 measured in different conditions varied over a 7-fold range.The time course of relaxation, as defined by tLIN and kREL, was correlated with EC50 but varied by just 2.7- and 3.3-fold, respectively.Our results confirm that troponin I phosphorylation specifically alters the Ca2þ sensitivity of isometric tension and the timecourse of relaxation in cardiac muscle myofibrils. Moreove

Journal article

Marttila M, Lehtokari V-L, Marston S, Nyman TA, Barnerias C, Beggs AH, Bertini E, Ceyhan-Birsoy O, Cintas P, Gerard M, Gilbert-Dussardier B, Hogue JS, Longman C, Eymard B, Frydman M, Kang PB, Klinge L, Kolski H, Lochmueller H, Magy L, Manel V, Mayer M, Mercuri E, North KN, Peudenier-Robert S, Pihko H, Probst FJ, Reisin R, Stewart W, Taratuto AL, de Visser M, Wilichowski E, Winer J, Nowak K, Laing NG, Winder TL, Monnier N, Clarke NF, Pelin K, Groenholm M, Wallgren-Pettersson Cet al., 2014, Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies, HUMAN MUTATION, Vol: 35, Pages: 779-790, ISSN: 1059-7794

Journal article

Memo M, Marston S, 2013, Skeletal muscle myopathy mutations at the actin tropomyosin interface that cause gain- or loss-of-function, JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY, Vol: 34, Pages: 165-169, ISSN: 0142-4319

Journal article

Marston SB, Copeland O, Messer AE, MacNamara E, Nowak K, Zampronio CG, Ward DGet al., 2013, Tropomyosin isoform expression and phosphorylation in the human heart in health and disease, JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY, Vol: 34, Pages: 189-197, ISSN: 0142-4319

Journal article

Marston SB, Memo M, Messer A, Papadaki M, Nowak K, McNamara E, Ong R, EL-Mezgueldi M, Li X, Lehman Wet al., 2013, Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients, Human Molecular Genetics

Journal article

Memo M, Leung M-C, Ward DG, dos Remedios C, Morimoto S, Zhang L, Ravenscroft G, McNamara E, Nowak KJ, Marston SB, Messer AEet al., 2013, Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca-2 sensitivity, CARDIOVASCULAR RESEARCH, Vol: 99, Pages: 65-73, ISSN: 0008-6363

Journal article

Song W, Vikhorev PG, Kashyap MN, Rowlands C, Ferenczi MA, Woledge RC, MacLeod K, Marston S, Curtin NAet al., 2013, Mechanical and energetic properties of papillary muscle from ACTC E99K transgenic mouse models of hypertrophic cardiomyopathy, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol: 304, Pages: H1513-H1524, ISSN: 0363-6135

Journal article

Toepfer C, Caorsi V, Kampourakis T, Sikkel MB, West TG, Leung M-C, Al-Saud SA, MacLeod KT, Lyon AR, Marston SB, Sellers JR, Ferenczi MAet al., 2013, Myosin Regulatory Light Chain (RLC) Phosphorylation Change as a Modulator of Cardiac Muscle Contraction in Disease, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 288, Pages: 13446-13454

Journal article

Toepfer C, caorsi V, Kampourakis T, Sikkel MB, West TG, Leung MC, Al-Saud SA, Macleod KT, Lyon AR, Marston SB, Sellers JR, Ferenczi MAet al., 2013, Myosin regulatory light chain (RLC) phosphorylation change as a modulator of cardiac muscle contraction in disease., The Journal of Biological Chemistry

Journal article

Bayliss CR, Jacques AM, Leung M-C, Ward DG, Redwood CS, Gallon CE, Copeland O, McKenna WJ, dos Remedios C, Marston SB, Messer AEet al., 2013, Myofibrillar Ca2+ sensitivity is uncoupled from troponin I phosphorylation in hypertrophic obstructive cardiomyopathy due to abnormal troponin T, CARDIOVASCULAR RESEARCH, Vol: 97, Pages: 500-508, ISSN: 0008-6363

Journal article

Kuster DWD, Sequeira V, Najafi A, Boontje NM, Wijnker PJM, Witjas-Paalberends ER, Marston SB, dos Remedios CG, Carrier L, Demmers JAA, Redwood C, Sadayappan S, van der Velden Jet al., 2013, GSK3 beta Phosphorylates Newly Identified Site in the Proline-Alanine-Rich Region of Cardiac Myosin-Binding Protein C and Alters Cross-Bridge Cycling Kinetics in Human, CIRCULATION RESEARCH, Vol: 112, Pages: 633-+, ISSN: 0009-7330

Journal article

Leung M-C, Hitchen PG, Ward DG, Messer AE, Marston SBet al., 2013, Z-band Alternatively Spliced PDZ Motif Protein (ZASP) Is the Major O-Linked beta-N-Acetylglucosamine-substituted Protein in Human Heart Myofibrils, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 288, Pages: 4891-4898

Journal article

Mokbel N, Ilkovski B, Kreissl M, Memo M, Jeffries CM, Marttila M, Lehtokari V-L, Lemola E, Gronholm M, Yang N, Menard D, Marcorelles P, Echaniz-Laguna A, Reimann J, Vainzof M, Monnier N, Ravenscroft G, McNamara E, Nowak KJ, Laing NG, Wallgren-Pettersson C, Trewhella J, Marston S, Ottenheijm C, North KN, Clarke NFet al., 2013, K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity, BRAIN, Vol: 136, Pages: 494-507, ISSN: 0006-8950

Journal article

AL-Khayat HA, Kensler RW, Squire JM, Marston SB, Morris EPet al., 2013, Atomic model of the human cardiac muscle myosin filament, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 318-323, ISSN: 0027-8424

Journal article

Toepfer C, Caorsi V, Kampourakis T, Sikkel MB, West T, Leung JC, Al-Saud SA, Macleod K, Lyon AR, Marston SB, Sellers J, Ferenczi MAet al., 2013, Myosin Regulatory Light Chain (RLC) Phosphorylation Change as a Modulator of Cardiac Muscle Contraction in Disease, Biophysical Journal, Vol: 104, Pages: 309a-310a, ISSN: 0006-3495

Journal article

Li XE, Suphamungmee W, Janco M, Geeves MA, Marston SB, Fischer S, Lehman Wet al., 2012, The flexibility of two tropomyosin mutants, D175N and E180G, that cause hypertrophic cardiomyopathy, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 424, Pages: 493-496, ISSN: 0006-291X

Journal article

Marston SB, Gautel M, 2012, Introducing a series of topical special issues of the Journal of Muscle Research and Cell Motility, JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY, Vol: 33, Pages: 1-3, ISSN: 0142-4319

Journal article

Vydyanath A, Gurnett CA, Marston S, Luther PKet al., 2012, Axial distribution of myosin binding protein-C is unaffected by mutations in human cardiac and skeletal muscle, Journal of Muscle Research and Cell Motility, Vol: 33, Pages: 61-74, ISSN: 1573-2657

Myosin binding protein-C (MyBP-C), a majorthick filament associated sarcomeric protein, plays animportant functional and structural role in regulating sarcomereassembly and crossbridge formation. Missing oraberrant MyBP-C proteins (both cardiac and skeletal) havebeen shown to cause both cardiac and skeletal myopathies,thereby emphasising its importance for the normal functioningof the sarcomere. Mutations in cardiac MyBP-C area major cause of hypertrophic cardiomyopathy (HCM),while mutations in skeletal MyBP-C have been implicatedin a disease of skeletal muscle—distal arthrogryposis type1 (DA-1). Here we report the first detailed electronmicroscopy studies on human cardiac and skeletal tissuescarrying MyBP-C gene mutations, using samples obtainedfrom HCM and DA-1 patients. We have used establishedimage averaging methods to identify and study the axialdistribution of MyBP-C on the thick filament by averagingprofile plots of the A-band of the sarcomere from electronmicrographs of human cardiac and skeletal myopathyspecimens. Due to the difficulty of obtaining normal humantissue, we compared the distribution to the A-band structurein normal frog skeletal, rat cardiac muscle and incardiac muscle of MyBP-C-deficient mice. Very similaroverall profile averages were obtained from the C-zones incardiac HCM samples and skeletal DA-1 samples withMyBP-C gene mutations, suggesting that mutations inMyBP-C do not

Journal article

Marston S, Copeland O, Gehmlich K, Schlossarek S, Carrrier Let al., 2012, How do MYBPC3 mutations cause hypertrophic cardiomyopathy?, JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY, Vol: 33, Pages: 75-80, ISSN: 0142-4319

Journal article

Marston S, Copeland O, Gehmlich K, Schlossarek S, Carrier Let al., 2012, Erratum to: How do MYBPC3 mutations cause hypertrophic cardiomyopathy?, J Muscle Res Cell Motil, Vol: 33

Journal article

Jain RK, Jayawant S, Squier W, Muntoni F, Sewry CA, Manzur A, Quinlivan R, Lillis S, Jungbluth H, Sparrow JC, Ravenscroft G, Nowak KJ, Memo M, Marston SB, Laing NGet al., 2012, NEMALINE MYOPATHY WITH STIFFNESS AND HYPERTONIA ASSOCIATED WITH AN ACTA1 MUTATION, NEUROLOGY, Vol: 78, Pages: 1100-1103, ISSN: 0028-3878

Journal article

Marttila M, Lemola E, Wallefeld W, Memo M, Donner K, Laing NG, Marston S, Gronholm M, Wallgren-Pettersson Cet al., 2012, Abnormal actin binding of aberrant beta-tropomyosins is a molecular cause of muscle weakness in TPM2-related nemaline and cap myopathy, BIOCHEMICAL JOURNAL, Vol: 442, Pages: 231-239, ISSN: 0264-6021

Journal article

Knoell R, Marston S, 2012, On Mechanosensation, Acto/Myosin Interaction, and Hypertrophy, TRENDS IN CARDIOVASCULAR MEDICINE, Vol: 22, Pages: 17-22, ISSN: 1050-1738

Journal article

Song W, Dyer E, Stuckey DJ, Copeland O, Leung M-C, Bayliss C, Messer A, Wilkinson R, Tremoleda JL, Schneider MD, Harding SE, Redwood CS, Clarke K, Nowak K, Monserrat L, Wells D, Marston SBet al., 2011, Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 27582-27593

Journal article

Marston SB, 2011, How Do Mutations in Contractile Proteins Cause the Primary Familial Cardiomyopathies?, JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, Vol: 4, Pages: 245-255, ISSN: 1937-5387

Journal article

Copeland O, Sadayappan S, Messer AE, Steinen GJM, van der Velden J, Marston SBet al., 2010, Analysis of cardiac myosin binding protein-C phosphorylation in human heart muscle, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 49, Pages: 1003-1011, ISSN: 0022-2828

Journal article

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