Imperial College London

DrPradeepLuther

Faculty of MedicineNational Heart & Lung Institute

Senior Research Fellow
 
 
 
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Contact

 

p.luther Website

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

60 results found

Luther PK, Marston SB, 2024, Complex architecture of cardiac muscle thick filaments revealed, Trends in Pharmacological Sciences, Vol: 45, Pages: 191-192, ISSN: 0165-6147

Muscle contraction is orchestrated by the well-understood thin filaments and the markedly complex thick filaments. Studies by Dutta et al. and Tamborrini et al., discussed here, have unravelled the structure of the mammalian heart thick filament in exquisite near-atomic detail and pave the way for understanding physiological modulation pathways and mutation-induced dysfunction and for designing potential drugs to modify defects.

Journal article

Luther PK, Morris EP, Parry DAD, Taylor KAet al., 2023, John Squire: a leader and seminal contributor to experimental and theoretical muscle research for over 50 years, JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY, Vol: 44, Pages: 123-124, ISSN: 0142-4319

Journal article

Morris EP, Knupp C, Luther PK, 2023, Obituary: Professor John Michael Squire, JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY, Vol: 44, Pages: 125-132, ISSN: 0142-4319

Journal article

Millane RP, Luther PK, 2023, The vertebrate muscle superlattice: discovery, consequences, and link to geometric frustration, JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY, Vol: 44, Pages: 153-163, ISSN: 0142-4319

Journal article

Huang X, Torre I, Chiappi M, Yin Z, Vydyanath A, Cao S, Raschdorf O, Beeby M, Quigley B, de Tombe PP, Liu J, Morris EP, Luther PKet al., 2023, Cryo-electron tomography of intact cardiac muscle reveals myosin binding protein-C linking myosin and actin filaments, JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY, Vol: 44, Pages: 165-178, ISSN: 0142-4319

Journal article

Millane RP, Wojtas DH, Yoon CH, Blakeley ND, Bones PJ, Goyal A, Squire JM, Luther PKet al., 2021, Geometric frustration in the myosin superlattice of vertebrate muscle, Journal of the Royal Society Interface, Vol: 18, ISSN: 1742-5662

Geometric frustration results from an incompatibility between minimum energy arrangements and the geometry of a system, and gives rise to interesting and novel phenomena. Here, we report geometric frustration in a native biological macromolecular system---vertebrate muscle. We analyse the disorder in the myosin filament rotations in the myofibrils of vertebrate striated (skeletal and cardiac) muscle, as seen in thin-section electron micrographs, and show that the distribution of rotations corresponds to an archetypical geometrically frustrated system---the triangular Ising antiferromagnet. Spatial correlations are evident out to at least six lattice spacings. The results demonstrate that geometric frustration can drive the development of structure in complex biological systems, and may have implications for the nature of the actin--myosin interactions involved in muscle contraction. Identification of the distribution of myosin filament rotations with an Ising model allows the extensive results on the latter to be applied to this system. It shows how local interactions (between adjacent myosin filaments) can determine long-range order and, conversely, how observations of long-range order (such as patterns seen in electron micrographs) can be used to estimate the energetics of these local interactions. Furthermore, since diffraction by a disordered system is a function of the second-order statistics, the derived correlations allow more accurate diffraction calculations, which can aid in interpretation of X-ray diffraction data from muscle specimens for structural analysis.

Journal article

Filomena MC, Yamamoto DL, Caremani M, Kadarla VK, Mastrototaro G, Serio S, Vydyanath A, Mutarelli M, Garofalo A, Pertici I, Knoll R, Nigro V, Luther PK, Lieber RL, Beck MR, Linari M, Bang M-Let al., 2020, Myopalladin promotes muscle growth through modulation of the serum response factor pathway, JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, Vol: 11, Pages: 169-194, ISSN: 2190-5991

Journal article

Squire JM, Luther PK, 2019, Mammalian muscle fibers may be simple as well as slow., Journal of General Physiology, Vol: 151, Pages: 1334-1338, ISSN: 0022-1295

Journal article

Burgoyne T, Heumann J, Morris E, Knupp C, Liu J, Reedy M, Taylor K, Wang K, Luther Pet al., 2019, Three-dimensional structure of the basketweave Z-band in midshipman fish sonic muscle, Proceedings of the National Academy of Sciences, Vol: 116, Pages: 15534-15539, ISSN: 0027-8424

Striated muscle enables movement in all animals by the contraction of myriads of sarcomeres joined end to end by the Z-bands. The contraction is due to tension generated in each sarcomere between overlapping arrays of actin and myosin filaments. At the Z-band, actin filaments from adjoining sarcomeres overlap and are cross-linked in a regular pattern mainly by the protein α-actinin. The Z-band is dynamic, reflected by the 2 regular patterns seen in transverse section electron micrographs; the so-called small-square and basketweave forms. Although these forms are attributed, respectively, to relaxed and actively contracting muscles, the basketweave form occurs in certain relaxed muscles as in the muscle studied here. We used electron tomography and subtomogram averaging to derive the 3D structure of the Z-band in the swimbladder sonic muscle of type I male plainfin midshipman fish (Porichthys notatus), into which we docked the crystallographic structures of actin and α-actinin. The α-actinin links run diagonally between connected pairs of antiparallel actin filaments and are oriented at an angle of about 25° away from the actin filament axes. The slightly curved and flattened structure of the α-actinin rod has a distinct fit into the map. The Z-band model provides a detailed understanding of the role of α-actinin in transmitting tension between actin filaments in adjoining sarcomeres.

Journal article

Barefield DY, McNamara JW, Lynch TL, Kuster DWD, Govindan S, Haar L, Wang Y, Taylor EN, Lorenz JN, Nieman ML, Zhu G, Luther PK, Varro A, Dobrev D, Ai X, Janssen PML, Kass DA, Jones WK, Gilbert RJ, Sadayappan Set al., 2019, Ablation of the calpain-targeted site in cardiac myosin binding protein-C is cardioprotective during ischemia-reperfusion injury, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 129, Pages: 236-246, ISSN: 0022-2828

Journal article

Buyandelger B, Mansfield C, Luther P, Knoell Ret al., 2016, ZBTB17 is a novel cardiomyopathy candidate gene and regulates autophagy in the heart, Cardiovascular Research, Vol: 111, Pages: S36-S36, ISSN: 1755-3245

Journal article

Toepfer CN, Sikkel MB, Caorsi V, Vydyanath A, Torre I, Copeland O, Lyon AR, Marston SB, Luther PK, MacLeod KT, West TG, Ferenczi MAet al., 2016, A post-MI power struggle: adaptations in cardiac power occur at the sarcomere level alongside MyBP-C and RLC phosphorylation., American Journal of Physiology - Heart and Circulatory Physiology, Vol: 311, Pages: H465-H475, ISSN: 0363-6135

Myocardial remodeling in response to chronic myocardial infarction (CMI) progresses through two phases, hypertrophic 'compensation' and congestive 'decompensation'. Nothing is known about the ability of un-infarcted myocardium to produce force, velocity, and power during these clinical phases, even though adaptation in these regions likely drive progression of compensation. We hypothesized that enhanced crossbridge-level contractility underlies mechanical compensation and is controlled in part by changes in the phosphorylation states of myosin regulatory proteins. We induced CMI in rats by left anterior descending coronary artery ligation. We then measured mechanical performance in permeabilized ventricular trabecula taken distant from the infarct zone and assayed myosin regulatory protein phosphorylation in each individual trabecula. During full activation, the compensated myocardium produced twice as much power and 31% greater isometric force compared to non-infarcted controls. Isometric force during submaximal activations was raised >2.4-fold, whilst power was 2-fold greater. EM and confocal microscopy demonstrated that these mechanical changes were not a result of increased density of contractile protein, and therefore not an effect of tissue hypertrophy. Hence, sarcomere-level contractile adaptations are key determinants of enhanced trabecular mechanics and of the overall cardiac compensatory response. Phosphorylation of myosin regulatory light chain (RLC) increased and remained elevated post-MI, while phosphorylation of myosin binding protein-C (MyBP-C) was initially depressed but then increased as the hearts became decompensated. These sensitivities to CMI are in accordance with phosphorylation-dependent regulatory roles for RLC and MyBP-C in crossbridge function and with compensatory adaptation in force and power that we observed in post-CMI trabeculae.

Journal article

Jacob F, Yonis AY, Cuello F, Luther P, Schulze T, Eder A, Streichert T, Mannhardt I, Hirt MN, Schaaf S, Stenzig J, Force T, Eschenhagen T, Hansen Aet al., 2016, Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue, PLOS One, Vol: 11, ISSN: 1932-6203

IntroductionLeft ventricular dysfunction is a frequent and potentially severe side effect of many tyrosine kinase inhibitors (TKI). The mode of toxicity is not identified, but may include impairment of mitochondrial or sarcomeric function, autophagy or angiogenesis, either as an on-target or off-target mechanism.Methods and ResultsWe studied concentration-response curves and time courses for nine TKIs in three-dimensional, force generating engineered heart tissue (EHT) from neonatal rat heart cells. We detected a concentration- and time-dependent decline in contractile force for gefitinib, lapatinib, sunitinib, imatinib, sorafenib, vandetanib and lestaurtinib and no decline in contractile force for erlotinib and dasatinib after 96 hours of incubation. The decline in contractile force was associated with an impairment of autophagy (LC3 Western blot) and appearance of autophagolysosomes (transmission electron microscopy).ConclusionThis study demonstrates the feasibility to study TKI-mediated force effects in EHTs and identifies an association between a decline in contractility and inhibition of autophagic flux.

Journal article

Luther PK, Burgoyne T, Morris E, 2015, Three-Dimensional Structure of Vertebrate Muscle Z-Band: The Small-Square Lattice Z-Band in Rat Cardiac Muscle, Journal of Molecular Biology, Vol: 427, Pages: 3527-3537, ISSN: 1089-8638

The Z-band in vertebrate striated muscle crosslinks actin filaments of opposite polarity from adjoiningsarcomeres and transmits tension along myofibrils during muscular contraction. It is also the location of anumber of proteins involved in signalling and myofibrillogenesis; mutations in these proteins lead to myopathies.Understanding the high-resolution structure of the Z-band will help us understand its role in muscle contractionand the role of these proteins in the function of muscle. The appearance of the Z-band in transverse-sectionelectron micrographs typically resembles a small-square lattice or a basketweave appearance. In longitudinalsections, the Z-band width varies more with muscle type than species: slow skeletal and cardiac muscles havewider Z-bands than fast skeletal muscles. As the Z-band is periodic, Fourier methods have previously beenused for three-dimensional structural analysis. To cope with variations in the periodic structure of the Z-band, wehave used subtomogram averaging of tomograms of rat cardiac muscle in which subtomograms are extractedand compared and similar ones are averaged. We show that the Z-band comprises four to six layers of links,presumably α-actinin, linking antiparallel overlapping ends of the actin filaments from the adjoining sarcomeres.The reconstruction shows that the terminal 5–7 nm of the actin filaments within the Z-band is devoid of anyα-actinin links and is likely to be the location of capping protein CapZ.

Journal article

Luther PK, Squire JM, 2014, The intriguing dual lattices of the Myosin filaments in vertebrate striated muscles: evolution and advantage., Biology (Basel), Vol: 3, Pages: 846-865, ISSN: 2079-7737

Myosin filaments in vertebrate striated muscle have a long roughly cylindrical backbone with cross-bridge projections on the surfaces of both halves except for a short central bare zone. In the middle of this central region the filaments are cross-linked by the M-band which holds them in a well-defined hexagonal lattice in the muscle A-band. During muscular contraction the M-band-defined rotation of the myosin filaments around their long axes influences the interactions that the cross-bridges can make with the neighbouring actin filaments. We can visualise this filament rotation by electron microscopy of thin cross-sections in the bare-region immediately adjacent to the M-band where the filament profiles are distinctly triangular. In the muscles of teleost fishes, the thick filament triangular profiles have a single orientation giving what we call the simple lattice. In other vertebrates, for example all the tetrapods, the thick filaments have one of two orientations where the triangles point in opposite directions (they are rotated by 60° or 180°) according to set rules. Such a distribution cannot be developed in an ordered fashion across a large 2D lattice, but there are small domains of superlattice such that the next-nearest neighbouring thick filaments often have the same orientation. We believe that this difference in the lattice forms can lead to different contractile behaviours. Here we provide a historical review, and when appropriate cite recent work related to the emergence of the simple and superlattice forms by examining the muscles of several species ranging back to primitive vertebrates and we discuss the functional differences that the two lattice forms may have.

Journal article

Hirt MN, Boeddinghaus J, Mitchell A, Schaaf S, Boernchen C, Mueller C, Schulz H, Hubner N, Stenzig J, Stoehr A, Neuber C, Eder A, Luther PK, Hansen A, Eschenhagen Tet al., 2014, Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 74, Pages: 151-161, ISSN: 0022-2828

Journal article

Smyth E, Solomon A, Vydyanath A, Luther PK, Pitchford S, Tetley TD, Emerson Met al., 2014, Induction and enhancement of platelet aggregation in vitro and in vivo by model polystyrene nanoparticles, Nanotoxicology, Vol: 9, Pages: 356-364, ISSN: 1743-5404

Abstract Nanoparticles (NPs) may come into contact with circulating blood elements including platelets following inhalation and translocation from the airways to the bloodstream or during proposed medical applications. Studies with model polystyrene latex nanoparticles (PLNPs) have shown that NPs are able to induce platelet aggregation in vitro suggesting a poorly defined potential mechanism of increased cardiovascular risk upon NP exposure. We aimed to provide insight into the mechanisms by which NPs may increase cardiovascular risk by determining the impact of a range of concentrations of PLNPs on platelet activation in vitro and in vivo and identifying the signaling events driving NP-induced aggregation. Model PLNPs of varying nano-size (50 and 100 nm) and surface chemistry [unmodified (uPLNP), amine-modified (aPLNP) and carboxyl-modified (cPLNP)] were therefore examined using in vitro platelet aggregometry and an established mouse model of platelet thromboembolism. Most PLNPs tested induced GPIIb/IIIa-mediated platelet aggregation with potencies that varied with both surface chemistry and nano-size. Aggregation was associated with signaling events, such as granule secretion and release of secondary agonists, indicative of conventional agonist-mediated aggregation. Platelet aggregation was associated with the physical interaction of PLNPs with the platelet membrane or internalization. 50 nm aPLNPs acted through a distinct mechanism involving the physical bridging of adjacent non-activated platelets leading to enhanced agonist-induced aggregation in vitro and in vivo. Our study suggests that should they translocate the pulmonary epithelium, or be introduced into the blood, NPs may increase the risk of platelet-driven events by inducing or enhancing platelet aggregation via mechanisms that are determined by their distinct combination of nano-size and surface chemistry.

Journal article

Amat-Roldan I, Torre I, Luther PK, 2014, Molecular model confirms experimental differences on polarization second harmonic signal from cardiac myosin isoforms, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363

Journal article

Torre I, Jeddi M, Amat-Roldan I, Hunter S, Sadayappan S, Robbins J, Moss RL, Luther PKet al., 2014, Ultrastructural and electron tomography analyses of cardiac muscle: normal muscle compared to presence and absence of myosin binding protein C-phosphorylation, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363

Journal article

Burgoyne T, Lewis A, Dewar A, Luther P, Hogg C, Shoemark A, Dixon Met al., 2014, Characterizing the ultrastructure of primary ciliary dyskinesia transposition defect using electron tomography, CYTOSKELETON, Vol: 71, Pages: 294-301, ISSN: 1949-3584

Journal article

Craig R, Lee KH, Mun JY, Torre I, Luther PKet al., 2014, Structure, sarcomeric organization, and thin filament binding of cardiac myosin-binding protein-C, PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, Vol: 466, Pages: 425-431, ISSN: 0031-6768

Journal article

Hirt MN, Boeddinghaus J, Schaaf S, Mitchell A, Eder A, Luther PK, Boernchen C, Stenzig J, Hansen A, Eschenhagen Tet al., 2014, Maturation of Engineered Heart Tissue (EHT) by Permanent Electrical Stimulation, 80th Annual Meeting of the Deutsche-Gesellschaft-fur-Experimentelle-und-Klinische-Pharmakologie-und-Toxikologie-e-V, Publisher: SPRINGER, Pages: S50-S50, ISSN: 0028-1298

Conference paper

Toepfer C, Sikkel M, Caorsi V, Copeland O, Martinez IT, West T, Marston S, Luther P, Lyon A, Macleod K, Ferenczi Met al., 2014, Effects of Chronic Myocardial Infarction on Cardiac Muscle Performance and Structure In-Vivo and In-Vitro, 58th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 343A-344A, ISSN: 0006-3495

Conference paper

Ha K, Buchan JG, Alvarado DM, Mccall K, Vydyanath A, Luther PK, Goldsmith MI, Dobbs MB, Gurnett CAet al., 2013, MYBPC1 mutations impair skeletal muscle function in zebrafish models of arthrogryposis, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 4967-4977, ISSN: 0964-6906

Journal article

Squire JM, Guerreiro MJ, Sidebotham RL, Reis CA, Wiseman J, Luther PKet al., 2013, Quantitative MUC5AC and MUC6 mucin estimations in gastric mucus by a least-squares minimization method, ANALYTICAL BIOCHEMISTRY, Vol: 439, Pages: 204-211, ISSN: 0003-2697

Journal article

Emerson M, Solomon A, Smyth E, Vydyanath A, Luther P, Tetley TDet al., 2013, Role of platelets in driving the thrombotic risk and protective processes associated with exposure to diesel exhaust particles, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 11, Pages: 643-644, ISSN: 1538-7933

Journal article

Smyth E, Solomon A, Vydyanath A, Luther P, Pitchford S, Tetley TD, Emerson Met al., 2013, The potencies and mechanisms by which engineered nanoparticles induce platelet aggregation are dependent upon their precise physicochemistry, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 11, Pages: 895-896, ISSN: 1538-7933

Journal article

Solomon A, Smyth E, Mitha N, Pitchford S, Vydyanath A, Luther PK, Thorley AJ, Tetley TD, Emerson Met al., 2013, Induction of platelet aggregation after a direct physical interaction with diesel exhaust particles, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 11, Pages: 325-334, ISSN: 1538-7933

Journal article

Burgoyne T, Dixon M, Luther P, Hogg C, Shoemark Aet al., 2012, Generation of a Three-Dimensional Ultrastructural Model of Human Respiratory Cilia, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 47, Pages: 800-806, ISSN: 1044-1549

Journal article

Barefield D, Ji X, Zhu G, Takimoto E, Luther PK, Dobrev D, Kass DA, Sadayappan Set al., 2012, Ablation of the Calpain-Targeted Site in Cardiac Myosin Binding Protein-C is Cardioprotective, CIRCULATION, Vol: 126, ISSN: 0009-7322

Journal article

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