Troponin T, High Sensitivity
Total Page：16
File Type：pdf, Size：1020Kb
Load more
Recommended publications
-
Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes
bioRxiv preprint doi: https://doi.org/10.1101/555391; this version posted February 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Disrupted Mechanobiology Links the Molecular and Cellular 2 Phenotypes in Familial Dilated Cardiomyopathy 3 4 Sarah R. Clippinger1,2, Paige E. Cloonan1,2, Lina Greenberg1, Melanie Ernst1, W. Tom 5 Stump1, Michael J. Greenberg1,* 6 7 1 Department of Biochemistry and Molecular Biophysics, Washington University School 8 of Medicine, St. Louis, MO, 63110, USA 9 10 2 These authors contributed equally to this work 11 12 *Corresponding author: 13 Michael J. Greenberg 14 Department of Biochemistry and Molecular Biophysics 15 Washington University School of Medicine 16 660 S. Euclid Ave., Campus Box 8231 17 St. Louis, MO 63110 18 Phone: (314) 362-8670 19 Email: [email protected] 20 21 22 Running title: A DCM mutation disrupts mechanosensing 23 24 25 Keywords: Mechanosensing, stem cell derived cardiomyocytes, muscle regulation, 26 troponin, myosin, traction force microscopy 1 bioRxiv preprint doi: https://doi.org/10.1101/555391; this version posted February 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 27 Abstract 28 Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a 29 major indicator for heart transplant. The disease is frequently caused by mutations of 30 sarcomeric proteins; however, it is not well understood how these molecular mutations 31 lead to alterations in cellular organization and contractility. -
Profiling of the Muscle-Specific Dystroglycan Interactome Reveals the Role of Hippo Signaling in Muscular Dystrophy and Age-Dependent Muscle Atrophy Andriy S
Yatsenko et al. BMC Medicine (2020) 18:8 https://doi.org/10.1186/s12916-019-1478-3 RESEARCH ARTICLE Open Access Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy Andriy S. Yatsenko1†, Mariya M. Kucherenko2,3,4†, Yuanbin Xie2,5†, Dina Aweida6, Henning Urlaub7,8, Renate J. Scheibe1, Shenhav Cohen6 and Halyna R. Shcherbata1,2* Abstract Background: Dystroglycanopathies are a group of inherited disorders characterized by vast clinical and genetic heterogeneity and caused by abnormal functioning of the ECM receptor dystroglycan (Dg). Remarkably, among many cases of diagnosed dystroglycanopathies, only a small fraction can be linked directly to mutations in Dg or its regulatory enzymes, implying the involvement of other, not-yet-characterized, Dg-regulating factors. To advance disease diagnostics and develop new treatment strategies, new approaches to find dystroglycanopathy-related factors should be considered. The Dg complex is highly evolutionarily conserved; therefore, model genetic organisms provide excellent systems to address this challenge. In particular, Drosophila is amenable to experiments not feasible in any other system, allowing original insights about the functional interactors of the Dg complex. Methods: To identify new players contributing to dystroglycanopathies, we used Drosophila as a genetic muscular dystrophy model. Using mass spectrometry, we searched for muscle-specific Dg interactors. Next, in silico analyses allowed us to determine their association with diseases and pathological conditions in humans. Using immunohistochemical, biochemical, and genetic interaction approaches followed by the detailed analysis of the muscle tissue architecture, we verified Dg interaction with some of the discovered factors. -
Illuminating the Divergent Role of Filamin C Mutations in Human Cardiomyopathy
Journal of Clinical Medicine Review Cardiac Filaminopathies: Illuminating the Divergent Role of Filamin C Mutations in Human Cardiomyopathy Matthias Eden 1,2 and Norbert Frey 1,2,* 1 Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany; [email protected] 2 German Centre for Cardiovascular Research, Partner Site Heidelberg, 69120 Heidelberg, Germany * Correspondence: [email protected] Abstract: Over the past decades, there has been tremendous progress in understanding genetic alterations that can result in different phenotypes of human cardiomyopathies. More than a thousand mutations in various genes have been identified, indicating that distinct genetic alterations, or combi- nations of genetic alterations, can cause either hypertrophic (HCM), dilated (DCM), restrictive (RCM), or arrhythmogenic cardiomyopathies (ARVC). Translation of these results from “bench to bedside” can potentially group affected patients according to their molecular etiology and identify subclinical individuals at high risk for developing cardiomyopathy or patients with overt phenotypes at high risk for cardiac deterioration or sudden cardiac death. These advances provide not only mechanistic insights into the earliest manifestations of cardiomyopathy, but such efforts also hold the promise that mutation-specific pathophysiology might result in novel “personalized” therapeutic possibilities. Recently, the FLNC gene encoding the sarcomeric protein filamin C has gained special interest since FLNC mutations were found in several distinct and possibly overlapping cardiomyopathy phenotypes. Specifically, mutations in FLNC were initially only linked to myofibrillar myopathy (MFM), but are now increasingly found in various forms of human cardiomyopathy. FLNC thereby Citation: Eden, M.; Frey, N. Cardiac represents another example for the complex genetic and phenotypic continuum of these diseases. -
Gene Therapy Rescues Cardiac Dysfunction in Duchenne Muscular
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL.4,NO.7,2019 ª 2019 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/). PRECLINICAL RESEARCH Gene Therapy Rescues Cardiac DysfunctioninDuchenneMuscular Dystrophy Mice by Elevating Cardiomyocyte Deoxy-Adenosine Triphosphate a b c d,e Stephen C. Kolwicz, JR,PHD, John K. Hall, PHD, Farid Moussavi-Harami, MD, Xiolan Chen, PHD, d,e b,d,e e,f,g, b,e,g, Stephen D. Hauschka, PHD, Jeffrey S. Chamberlain, PHD, Michael Regnier, PHD, * Guy L. Odom, PHD * VISUAL ABSTRACT Kolwicz, S.C. Jr. et al. J Am Coll Cardiol Basic Trans Science. 2019;4(7):778–91. HIGHLIGHTS rAAV vectors increase cardiac-specific expression of RNR and elevate cardiomyocyte 2-dATP levels. Elevated myocardial RNR and subsequent increase in 2-dATP rescues the performance of failing myocardium, an effect that persists long term. ISSN 2452-302X https://doi.org/10.1016/j.jacbts.2019.06.006 JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 4, NO. 7, 2019 Kolwicz, Jr., et al. 779 NOVEMBER 2019:778– 91 Nucleotide-Based Cardiac Gene Therapy Restores Function in dmd Mice We show the ability to increase both cardiac baseline function and high workload contractile performance in ABBREVIATIONS aged (22- to 24-month old) mdx4cv mice, by high-level muscle-specific expression of either microdystrophin AND ACRONYMS or RNR. mDys = microdystrophin Five months post-treatment, mice systemically injected with rAAV6 vector carrying a striated muscle-specific CK8 regulatory cassette driving expression of microdystrophin in both skeletal and cardiac muscle, exhibited the = miniaturized murine creatine kinase regulatory greatest effect on systolic function. -
Myod Converts Primary Dermal Fibroblasts, Chondroblasts, Smooth
Proc. Natl. Acad. Sci. USA Vol. 87, pp. 7988-7992, October 1990 Developmental Biology MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes (myogenesis/myoflbrils/desmin/master switch genes) J. CHOI*, M. L. COSTAtt, C. S. MERMELSTEINtt, C. CHAGASt, S. HOLTZERt, AND H. HOLTZERt§ Departments of *Biochemistry and tAnatomy, University of Pennsylvania, Philadelphia, PA 19104; and tinstituto de Bioffsica Carlos Chagas Filho, Bloco G, Centro de Ciencias da Sadde, Universidade Federal do Rio de Janeiro, lbha do Funddo, 21941 Rio de Janeiro, Brazil Communicated by Harold Weintraub, June 29, 1990 (received for review June 15, 1990) ABSTRACT Shortly after their birth, postmitotic mono- L6, L8, L6E9, BC3H1, and other types of immortalized nucleated myoblasts in myotomes, limb buds, and conventional and/or mutagenized myogenic lines are induced to differen- muscle cultures elongate and assemble a cohort of myofibrillar tiate (9-13). proteins into definitively striated myofibrils. MyoD induces a MyoD induces a number of immortalized and/or trans- number of immortalized and/or transformed nonmuscle cells formed cell lines to express several myofibrillar genes and to to express desmin and several myofibrillar proteins and to fuse fuse into multinucleated myosacs (14-16). Other transformed into myosacs. We now report that MyoD converts normal lines such as kidney epithelial cells, HeLa cells, and some dermal fibroblasts, chondroblasts, gizzard smooth muscle, and hepatoma lines resist conversion. Judging from the published pigmented retinal epithelial cells into elongated postmitotic micrographs, MyoD-converted nonmuscle cells, like most mononucleated striated myoblasts. The sarcomeric localization myogenic cell lines, do not express the terminal myogenic of antibodies to desmin, a-actinin, titin, troponin-I, a-actin, program fully. -
Mini-Thin Filaments Regulated by Troponin–Tropomyosin
Mini-thin filaments regulated by troponin–tropomyosin Huiyu Gong*, Victoria Hatch†, Laith Ali‡, William Lehman†, Roger Craig§, and Larry S. Tobacman‡¶ *Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; †Department of Physiology and Biophysics, Boston University, Boston, MA 02118; §Department of Cell Biology, University of Massachusetts, Worcester, MA 01655; and ‡Departments of Medicine and Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612 Edited by Edward D. Korn, National Institutes of Health, Bethesda, MD, and approved December 9, 2004 (received for review September 29, 2004) Striated muscle thin filaments contain hundreds of actin monomers normal-length thin filaments. They also would make possible and scores of troponins and tropomyosins. To study the coopera- approaches to thin-filament structural analysis. We report here tive mechanism of thin filaments, ‘‘mini-thin filaments’’ were the design and purification of mini-thin filaments with the generated by isolating particles nearly matching the minimal intended composition and compare their function to the function structural repeat of thin filaments: a double helix of actin subunits of conventional-length thin filaments. with each strand approximately seven actins long and spanned by Ca2ϩ regulates muscle contraction in the heart and in skeletal a troponin–tropomyosin complex. One end of the particles was muscle by binding to specific site(s) in the NH2 domain of the capped by a gelsolin (segment 1–3)–TnT fusion protein (substitut- troponin subunit, TnC. Significantly, Ca2ϩ activates tension very ing for normal TnT), and the other end was capped by tropomodu- cooperatively (3, 4) even in cardiac muscle, in which each TnC lin. -
Postmortem Changes in the Myofibrillar and Other Cytoskeletal Proteins in Muscle
BIOCHEMISTRY - IMPACT ON MEAT TENDERNESS Postmortem Changes in the Myofibrillar and Other C'oskeletal Proteins in Muscle RICHARD M. ROBSON*, ELISABETH HUFF-LONERGAN', FREDERICK C. PARRISH, JR., CHIUNG-YING HO, MARVIN H. STROMER, TED W. HUIATT, ROBERT M. BELLIN and SUZANNE W. SERNETT introduction filaments (titin), and integral Z-line region (a-actinin, Cap Z), as well as proteins of the intermediate filaments (desmin, The cytoskeleton of "typical" vertebrate cells contains paranemin, and synemin), Z-line periphery (filamin) and three protein filament systems, namely the -7-nm diameter costameres underlying the cell membrane (filamin, actin-containing microfilaments, the -1 0-nm diameter in- dystrophin, talin, and vinculin) are listed along with an esti- termediate filaments (IFs), and the -23-nm diameter tubu- mate of their abundance, approximate molecular weights, lin-containing microtubules (Robson, 1989, 1995; Robson and number of subunits per molecule. Because the myofibrils et al., 1991 ).The contractile myofibrils, which are by far the are the overwhelming components of the skeletal muscle cell major components of developed skeletal muscle cells and cytoskeleton, the approximate percentages of the cytoskel- are responsible for most of the desirable qualities of muscle eton listed for the myofibrillar proteins (e.g., myosin, actin, foods (Robson et al., 1981,1984, 1991 1, can be considered tropomyosin, a-actinin, etc.) also would represent their ap- the highly expanded corollary of the microfilament system proximate percentages of total myofibrillar protein. of non-muscle cells. The myofibrils, IFs, cell membrane skel- eton (complex protein-lattice subjacent to the sarcolemma), Some Important Characteristics, Possible and attachment sites connecting these elements will be con- Roles, and Postmortem Changes of Key sidered as comprising the muscle cell cytoskeleton in this Cytoskeletal Proteins review. -
Tyrosine Phosphorylation Regulates Dystroglycan 1719
Journal of Cell Science 113, 1717-1726 (2000) 1717 Printed in Great Britain © The Company of Biologists Limited 2000 JCS0874 Adhesion-dependent tyrosine phosphorylation of β-dystroglycan regulates its interaction with utrophin M. James1,*, A. Nuttall1, J. L. Ilsley1, K. Ottersbach1,‡, J. M. Tinsley2, M. Sudol3 and S. J. Winder1,4,§ 1Institute of Cell and Molecular Biology, University of Edinburgh, King’s Buildings, Mayfield Road, Edinburgh, EH9 3JR, UK 2Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK 3Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, One Gustav Levy Place, New York, NY 10029, USA 4IBLS, Division of Biochemistry and Molecular Biology, Davidson Building, University of Glasgow, Glasgow, G12 8QQ, Scotland, UK *Present address: Department of Medicine, University of Leicester, Leicester, UK ‡Beatson Institute for Cancer Research, Garscube Estate, Switchback Rd, Bearsden, Glasgow, UK §Author for correspondence at address 4 (e-mail: [email protected]) Accepted 9 March; published on WWW 18 April 2000 SUMMARY Many cell adhesion-dependent processes are regulated by treated with peroxyvanadate, where endogenous β- tyrosine phosphorylation. In order to investigate the role of dystroglycan was tyrosine phosphorylated, β-dystroglycan tyrosine phosphorylation of the utrophin-dystroglycan was no longer co-immunoprecipitated with utrophin fusion complex we treated suspended or adherent cultures of constructs. Peptide ‘SPOTs’ assays confirmed that tyrosine HeLa cells with peroxyvanadate and immunoprecipitated phosphorylation of β-dystroglycan regulated the binding of β-dystroglycan and utrophin from cell extracts. Western utrophin. The phosphorylated tyrosine was identified as blotting of β-dystroglycan and utrophin revealed adhesion- Y892 in the β-dystroglycan WW domain binding motif and peroxyvanadate-dependent mobility shifts which were PPxY thus demonstrating the physiological regulation of recognised by anti-phospho-tyrosine antibodies. -
Elevation of Fast but Not Slow Troponin I in the Circulation of Patients With
Russell Alan (Orcid ID: 0000-0001-7545-5008) Elevation of fast but not slow troponin I in the circulation of patients with Becker and Duchenne muscular dystrophy Benjamin L Barthel PhD1, Dan Cox BSc2, Marissa Barbieri BA3, Michael Ziemba3, Volker Straub MD, PhD2, Eric P. Hoffman PhD3, Alan J Russell PhD1 1Edgewise Therapeutics, BioFrontiers Institute, University of Colorado, Boulder, CO 80303, USA. 2The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 3BZ, UK 3Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University – State University of New York, Binghamton, NY 13902 USA Acknowledgements: Source of funding, private industry Number of words in abstract: 220 Number of words in manuscript: 2490 Corresponding author: Alan J Russell, 1Edgewise Therapeutics, BioFrontiers Institute, University of Colorado, Boulder, CO 80303, USA. [email protected]. ORCID ID https://orcid.org/0000-0001-7545-5008 Ethical publication statement: We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/mus.27222 This article is protected by copyright. All rights reserved. with those guidelines. Key words: Muscular dystrophy, biomarker, muscle injury, creatine kinase, troponin Conflicts of interest: Benjamin Barthel and Alan Russell are paid employees of Edgewise Therapeutics, Inc. -
Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach
International Journal of Molecular Sciences Review Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach Diana Cimiotti 1,* , Heidi Budde 2, Roua Hassoun 2 and Kornelia Jaquet 2,* 1 Department of Clinical Pharmacology, Ruhr-University Bochum, 44801 Bochum, Germany 2 Experimental and Molecular Cardiology, St. Josef Hospital and BG Bergmannsheil, Clinics of the Ruhr-University Bochum, 44791 Bochum, Germany; [email protected] (H.B.); [email protected] (R.H.) * Correspondence: [email protected] (D.C.); [email protected] (K.J.); Tel.: +49-234-32-27639 (D.C.) Abstract: The sarcomere as the smallest contractile unit is prone to alterations in its functional, structural and associated proteins. Sarcomeric dysfunction leads to heart failure or cardiomyopathies like hypertrophic (HCM) or restrictive cardiomyopathy (RCM) etc. Genetic based RCM, a very rare but severe disease with a high mortality rate, might be induced by mutations in genes of non- sarcomeric, sarcomeric and sarcomere associated proteins. In this review, we discuss the functional effects in correlation to the phenotype and present an integrated model for the development of genetic RCM. Keywords: cardiomyopathy; restrictive cardiomyopathy; pediatric; sarcomere; contractile dysfunc- tion; calcium; aggregation; gene expression 1. The Sarcomere The sarcomere as the substructure of myofibrils is the contractile unit of striated muscles i.e. skeletal and cardiac muscle (Figure1). It forms a symmetric unit with the Citation: Cimiotti, D.; Budde, H.; M-disc in the center and is bordered by the Z-discs. M-disc and Z-disc provide the anchors Hassoun, R.; Jaquet, K. Genetic for thin, thick and elastic filaments. The elastic filament is composed of the giant protein Restrictive Cardiomyopathy: Causes and Consequences—An Integrative titin spanning half the sarcomere. -
Muscle Diseases: the Muscular Dystrophies
ANRV295-PM02-04 ARI 13 December 2006 2:57 Muscle Diseases: The Muscular Dystrophies Elizabeth M. McNally and Peter Pytel Department of Medicine, Section of Cardiology, University of Chicago, Chicago, Illinois 60637; email: [email protected] Department of Pathology, University of Chicago, Chicago, Illinois 60637; email: [email protected] Annu. Rev. Pathol. Mech. Dis. 2007. Key Words 2:87–109 myotonia, sarcopenia, muscle regeneration, dystrophin, lamin A/C, The Annual Review of Pathology: Mechanisms of Disease is online at nucleotide repeat expansion pathmechdis.annualreviews.org Abstract by Drexel University on 01/13/13. For personal use only. This article’s doi: 10.1146/annurev.pathol.2.010506.091936 Dystrophic muscle disease can occur at any age. Early- or childhood- onset muscular dystrophies may be associated with profound loss Copyright c 2007 by Annual Reviews. All rights reserved of muscle function, affecting ambulation, posture, and cardiac and respiratory function. Late-onset muscular dystrophies or myopathies 1553-4006/07/0228-0087$20.00 Annu. Rev. Pathol. Mech. Dis. 2007.2:87-109. Downloaded from www.annualreviews.org may be mild and associated with slight weakness and an inability to increase muscle mass. The phenotype of muscular dystrophy is an endpoint that arises from a diverse set of genetic pathways. Genes associated with muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, and the sarcomere and Z band, as well as nuclear membrane components. Because muscle has such distinctive structural and regenerative properties, many of the genes implicated in these disorders target pathways unique to muscle or more highly expressed in muscle. -
Slow Skeletal Troponin I Gene Transfer, Expression, and Myofilament Incorporation Enhances Adult Cardiac Myocyte Contractile Function
Proc. Natl. Acad. Sci. USA Vol. 94, pp. 5444–5449, May 1997 Physiology Slow skeletal troponin I gene transfer, expression, and myofilament incorporation enhances adult cardiac myocyte contractile function MARGARET V. WESTFALL*, ELIZABETH M. RUST, AND JOSEPH M. METZGER Department of Physiology, School of Medicine, University of Michigan, Ann Arbor, MI, 48109-0622 Communicated by James A. Spudich, Stanford University, Stanford, CA, March 7, 1997 (received for review November 5, 1996) ABSTRACT The functional significance of the develop- changes remains unclear, because developmental transitions in mental transition from slow skeletal troponin I (ssTnI) to other contractile protein isoforms occur over the same time cardiac TnI (cTnI) isoform expression in cardiac myocytes interval as the TnI isoform transition. remains unclear. We show here the effects of adenovirus- TnI isoforms are also postulated to influence cardiac myo- mediated ssTnI gene transfer on myofilament structure and filament pH sensitivity (4, 5). Contractile function decreases function in adult cardiac myocytes in primary culture. Gene markedly during acute myocardial ischemia (4), and acidosis transfer resulted in the rapid, uniform, and nearly complete plays a significant role in this decreased function by reducing replacement of endogenous cTnI with the ssTnI isoform with myofilament Ca21 sensitivity (4–7). Solution studies indicate no detected changes in sarcomeric ultrastructure, or in the that TnI may play a role in this phenomenon because acidic isoforms and stoichiometry of other myofilament proteins pH-induced decreases in Ca21 binding to andyor subsequent compared with control myocytes over 7 days in primary conformational changes within troponin C (TnC) are in- culture. In functional studies on permeabilized single cardiac creased in magnitude in the presence of TnI (8).