DOCSLIB.ORG

The Initial Steps of Myofibril Assembly: Integrins Pave The

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Initial Steps of Myofibril Assembly: Integrins Pave The PERSPECTIVES The starting point for assembly OPINION Electron microscopy observations indicate that Z-disks begin as small, membrane- The initial steps of myofibril associated aggregates called Z-bodies, which mature into Z-disks19. Correlating immuno- assembly: integrins pave the way fluorescent and electron microscopy images reveal that Z-bodies are the sites of α-actinin and titin localization (two of the earliest John C. Sparrow and Frieder Schöck Z-disk markers), which further demonstrates 20 Abstract | Myofibril assembly results in a regular array of identical sarcomeres in that Z-bodies are precursors of Z-disks . The first myofibrils are always observed striated muscle. Sarcomere structure is conserved across the animal kingdom, which close to the membrane19,21,22, which indicates implies that the mechanisms of myofibril assembly are also likely to be conserved. that sarcomere assembly begins at the cell Recent advances from model genetic systems and insights from stress fibre cell periphery. Immunofluorescent staining biology have shed light on the mechanisms that set sarcomere spacing and the further located and defined these myofibril 14 initial assembly of sarcomere arrays. We propose a model of integrin-dependent precursors, which are called premyofibrils . Premyofibrils use all of the sarcomeric com- cell–matrix adhesion as the starting point for myofibrillogenesis. ponents except for non-muscle myosin II, which is incorporated first but then replaced Muscle development is a multistep process skele tal muscle thin filaments additionally with muscle myosin II, as they mature that starts with the specification of certain contain nebulin, a long protein that regulates into myofibrils. It was recently shown in cells as muscle precursors, or myoblasts the length of thin filaments1–5. In the middle cardiomyocyte tissue culture and in intact (see Glossary). This is followed by either of the sarcomere, M-line proteins crosslink hearts that myofibril assembly initiates from myoblast fusion, which generates syncitial, and anchor the thick filaments to each other. a premyofibril stage14,23. multi nucleated myotubes, or by direct The thick filaments occupy the sarcomeric Premyofibrils resemble actin stress fibres differ entiation into cardiomyocytes. Muscle A-band, whereas the region in which thin fila- of non-muscle cells because they exhibit the cells then attach to the extracellular matrix ments do not overlap with thick filaments is same irregular α-actinin and non-muscle (ECM) and to other muscle cells before known as the I-band. Actomyosin interactions myosin II periodicity. In addition, premyo - assembling myo fibrils. Muscle cells typically gen er ate contractile force and sarcomeres fibril periodicity is considerably shorter contain dozens of myofibrils, each consisting shorten owing to the sliding of the two fila- than in mature sarcomeres, α-actinin and of many sarcomeres, the smallest functional ment systems. Molecules of the giant protein non-muscle myosin II spots are identical in contractile unit of muscle. These are highly titin span the half-sarcomere with their size, and titin and I-bands are absent. All organized macromolecular complexes that amino termini at the Z-disk and their car- of these features are also observed in actin consist of myosin II-containing thick fila- boxyl termini at the M-line6,7. Each titin exits stress fibres24–27. The precise role of transient ments and actin-containing thin filaments. the Z-disk close to a thin filament, crosses the non-muscle myosin II incorporation is still The initial step of myofibril assembly is the I-band and then binds along a thick filament unclear. Loss of non-muscle myosin IIB (also formation of a regular array of sarcomeres. as far as the M-line. The I-band region of titin known as MYH10) in transgenic mutant These sarco meres later grow in width and in forms an elastic element, which connects the mice causes defects in heart sarcomeres. some cases in length, and eventually align Z-disk to the thick filaments1 (BOX 1). However, initial sarcomere assembly still and attach to each other and the sarcolemma. Myofibril termini attach to the skeleton occurs. It is interesting to note that one-half An important question in muscle different- at myotendinous junctions or are connected of non-muscle myosin IIB-knockout iation is how the striated muscle cell pro- end-to-end at intercalated discs in cardiac mice showed upregulation of non-muscle duces these myofibrils with such regular muscle. Heterodimeric integrins, which myosin IIA (also known as MYH9) in the arrays of sarcomeres. connect thin filaments to ECM ligands, are heart, which might partly compensate for Neighbouring sarcomeres share a Z-disk, the main structural and functional compo- the absence of non-muscle myosin IIB28. in which thin filaments are anchored and nents of myotendinous junctions. Peripheral crosslinked by dimeric actin-binding myofibrils are also laterally anchored to the Integrin adhesion sites initiate assembly. All α-actinin molecules1,2. Thin filaments ECM at the level of the Z-disk in both verte- immunofluorescent observations support consist of filamentous (F)-actin and the brates and invertebrates8–11 (FIG. 1). These the view that the accumulation of muscle tropomyosin–troponin complex. The heads adhesion sites are termed costameres, and, as myosin II in myofibrils is one of the final steps of myosin II proteins in thick filaments bind with myotendinous junctions, they consist of after premyofibril formation and titin recruit- to the F-actin of thin filaments to produce many components that are typically found in ment14,20,29. By contrast, integrins, α-actinin contraction, a process that is regulated by the integrin adhesion sites11–13. and the integrin adhesion site components tropomyosin–troponin complex. Thin fila- Here, we review the initial steps of myo- vinculin and talin are the first proteins that ments are polar owing to the inherent polarity fibril assembly before presenting an exten- can be observed in periodic patterning at the of the actin monomers in the F-actin core. sion of the premyofibril model for myofibril plasma membrane22,30. We propose that these The thin filament ends, which are known as assembly14,15. This model is supported by early integrin adhesion sites, which we term plus and minus ends because of the relative pioneering genetic studies in Drosophila protocostameres, serve as nucleation sites for rates of monomer addition during F-actin melanogaster and Caenorhabditis elegans and α-actinin accumulation, which then causes polymeriza tion, are capped by CAPZ and highlights an important role for integrins in the independent assembly of premyofibril- tropomodulin, respectively. Vertebrate myofibril assembly9,16–18. associated Z-bodies. Finally, the maturation NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 10 | APRIL 2009 | 293 © 2009 Macmillan Publishers Limited. All rights reserved PERSPECTIVES Box 1 | Sarcomere structure Assembly of thin filaments. The initial step in the formation of an actin filament is actin Actin Tropomyosin–troponin complex M-line nucleation, in which a few actin monomers Nebulin Z-disk combine to form a nucleus or ‘seed’ on a Tropomodulin Tropomyosin Thin filament template protein. It is on this seed that a new F-actin filament can then polymerize. ZASP The elongation of thin filaments has Titin been studied in cultured muscle cells and D. melano gaster flight muscle, and, in con- CAPZ Myosin Thick filament trast to actin filament elongation in vitro, occurs at the minus end through regulation α-Actinin by tropomodulin (REFS 36–39). However, little is known about the nucleation and I-band A-band I-band initial assembly of thin filaments. Recently, Sarcomere leiomodin, a protein that is similar in struc- ture to tropomodulin, has been shown to Thin filaments of opposite polarity are crosslinked by -actinin and anchored on either side of the α Nature Reviews | Molecular Cell Biology Z-disk, which forms the boundary of the sarcomere (see the figure). Thin filaments consist of accelerate actin filament nucleation in vitro filamentous (F)-actin and the tropomyosin–troponin complex, which are required for the proper and is also crucial for myofibril assembly in 40 interaction of thin filaments with myosin. Thin filaments also contain nebulin, a vertebrate thin muscle cell culture . Leiomodin localizes to filament length regulator. Thin filaments are capped at the plus end by CAPZ and at the minus end by the minus end of thin filaments, close to the tropomodulin. The PDZ–LIM domain protein ZASP organizes the Z-disk. Thick filaments (bipolar M-line in mature myofibrils40. Small inter- myosin) are anchored at the M-line. The area that is spanned by thick filaments is known as the fering RNA knockdown of leiomodin A-band. The area on both sides of the Z-disk that is spanned by thin filaments that do not overlap with severely disrupts sarcomere assembly, but a thick filaments is known as the I-band. Titin molecules in vertebrates extend from the M-line to the periodic α-actinin arrangement along actin Z-disk and provide elastic support and anchoring of thick filaments in the middle of the sarcomere. filaments is preserved. Therefore, it is poss- Striated muscle cytoarchitecture and many of its components are highly conserved from jellyfish to ible that another actin nucleator is involved humans68. Mutations in many costamere and sarcomere components cause myopathies, in particular in this process. Formins, which are proces- actin, myosin II, titin, α-actinin, nebulin family members, PDZ–LIM domain family members, troponin, tropomyosin, integrins, desmin and focal adhesion kinase2,69,70. Figure is modified, with permission, sive nucleators that remain associated with from REF. 71 (2004) Birkhauser. the plus end, might be good candidates for the initial actin filament polymerization in muscle cells. of the Z-bodies forms the Z-disks. As differ- ZASP is required for Z-disk assembly and Intriguingly, in vitro, integrin adhesion entiation proceeds, many myofibrils are the maintenance of muscle attachments.
Load more

Recommended publications
  • Microanatomy of Muscles
    Microanatomy of Muscles Anatomy & Physiology Class Three Main Muscle Types Objectives: By the end of this presentation you will have the information to: 1. Describe the 3 main types of muscles. 2. Detail the functions of the muscle system. 3. Correctly label the parts of a myocyte (muscle cell) 4. Identify the levels of organization in a skeletal muscle from organ to myosin. 5. Explain how a muscle contracts utilizing the correct terminology of the sliding filament theory. 6. Contrast and compare cardiac and smooth muscle with skeletal muscle. Major Functions: Muscle System 1. Moving the skeletal system and posture. 2. Passing food through the digestive system & constriction of other internal organs. 3. Production of body heat. 4. Pumping the blood throughout the body. 5. Communication - writing and verbal Specialized Cells (Myocytes) ~ Contractile Cells Can shorten along one or more planes because of specialized cell membrane (sarcolemma) and specialized cytoskeleton. Specialized Structures found in Myocytes Sarcolemma: The cell membrane of a muscle cell Transverse tubule: a tubular invagination of the sarcolemma of skeletal or cardiac muscle fibers that surrounds myofibrils; involved in transmitting the action potential from the sarcolemma to the interior of the myofibril. Sarcoplasmic Reticulum: The special type of smooth endoplasmic Myofibrils: reticulum found in smooth and a contractile fibril of skeletal muscle, composed striated muscle fibers whose function mainly of actin and myosin is to store and release calcium ions. Multiple Nuclei (skeletal) & many mitochondria Skeletal Muscle - Microscopic Anatomy A whole skeletal muscle (such as the biceps brachii) is considered an organ of the muscular system. Each organ consists of skeletal muscle tissue, connective tissue, nerve tissue, and blood or vascular tissue.
    [Show full text]
  • Genetic Mutations and Mechanisms in Dilated Cardiomyopathy
    Genetic mutations and mechanisms in dilated cardiomyopathy Elizabeth M. McNally, … , Jessica R. Golbus, Megan J. Puckelwartz J Clin Invest. 2013;123(1):19-26. https://doi.org/10.1172/JCI62862. Review Series Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are “private” or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia. Find the latest version: https://jci.me/62862/pdf Review series Genetic mutations and mechanisms in dilated cardiomyopathy Elizabeth M. McNally, Jessica R. Golbus, and Megan J. Puckelwartz Department of Human Genetics, University of Chicago, Chicago, Illinois, USA. Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of conges- tive heart failure.
    [Show full text]
  • Vocabulario De Morfoloxía, Anatomía E Citoloxía Veterinaria
    Vocabulario de Morfoloxía, anatomía e citoloxía veterinaria (galego-español-inglés) Servizo de Normalización Lingüística Universidade de Santiago de Compostela COLECCIÓN VOCABULARIOS TEMÁTICOS N.º 4 SERVIZO DE NORMALIZACIÓN LINGÜÍSTICA Vocabulario de Morfoloxía, anatomía e citoloxía veterinaria (galego-español-inglés) 2008 UNIVERSIDADE DE SANTIAGO DE COMPOSTELA VOCABULARIO de morfoloxía, anatomía e citoloxía veterinaria : (galego-español- inglés) / coordinador Xusto A. Rodríguez Río, Servizo de Normalización Lingüística ; autores Matilde Lombardero Fernández ... [et al.]. – Santiago de Compostela : Universidade de Santiago de Compostela, Servizo de Publicacións e Intercambio Científico, 2008. – 369 p. ; 21 cm. – (Vocabularios temáticos ; 4). - D.L. C 2458-2008. – ISBN 978-84-9887-018-3 1.Medicina �������������������������������������������������������������������������veterinaria-Diccionarios�������������������������������������������������. 2.Galego (Lingua)-Glosarios, vocabularios, etc. políglotas. I.Lombardero Fernández, Matilde. II.Rodríguez Rio, Xusto A. coord. III. Universidade de Santiago de Compostela. Servizo de Normalización Lingüística, coord. IV.Universidade de Santiago de Compostela. Servizo de Publicacións e Intercambio Científico, ed. V.Serie. 591.4(038)=699=60=20 Coordinador Xusto A. Rodríguez Río (Área de Terminoloxía. Servizo de Normalización Lingüística. Universidade de Santiago de Compostela) Autoras/res Matilde Lombardero Fernández (doutora en Veterinaria e profesora do Departamento de Anatomía e Produción Animal.
    [Show full text]
  • (7E) Powerpoint Lecture Outline Chapter 8: Control of Movement
    Carlson (7e) PowerPoint Lecture Outline Chapter 8: Control of Movement This multimedia product and its contents are protected under copyright law. The following are prohibited by law: •any public performance or display, including transmission of any image over a network; •preparation of any derivative work, including extraction, in whole or in part, of any images; •any rental, lease, or lending of the program. Copyright 2001 by Allyn & Bacon Skeletal Muscle n Movements of our body are accomplished by contraction of the skeletal muscles l Flexion: contraction of a flexor muscle draws in a limb l Extension: contraction of extensor muscle n Skeletal muscle fibers have a striated appearance n Skeletal muscle is composed of two fiber types: l Extrafusal: innervated by alpha-motoneurons from the spinal cord: exert force l Intrafusal: sensory fibers that detect stretch of the muscle u Afferent fibers: report length of intrafusal: when stretched, the fibers stimulate the alpha-neuron that innervates the muscle fiber: maintains muscle tone u Efferent fibers: contraction adjusts sensitivity of afferent fibers. 8.2 Copyright 2001 by Allyn & Bacon Skeletal Muscle Anatomy n Each muscle fiber consists of a bundle of myofibrils l Each myofibril is made up of overlapping strands of actin and myosin l During a muscle twitch, the myosin filaments move relative to the actin filaments, thereby shortening the muscle fiber 8.3 Copyright 2001 by Allyn & Bacon Neuromuscular Junction n The neuromuscular junction is the synapse formed between an alpha motor neuron
    [Show full text]
  • CAP2 Deficiency Delays Myofibril Actin Cytoskeleton Differentiation and Disturbs Skeletal Muscle Architecture and Function
    CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function Lara-Jane Kepsera, Fidan Damara, Teresa De Ciccob, Christine Chaponnierc, Tomasz J. Prószynski b, Axel Pagenstecherd, and Marco B. Rusta,e,f,1 aMolecular Neurobiology Group, Institute of Physiological Chemistry, University of Marburg, 35032 Marburg, Germany; bLaboratory of Synaptogenesis, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland; cDepartment of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; dInstitute of Neuropathology, University of Marburg, 35032 Marburg, Germany; eCenter for Mind, Brain and Behavior, Research Campus of Central Hessen, 35032 Marburg, Germany; and fDFG Research Training Group “Membrane Plasticity in Tissue Development and Remodeling,” GRK 2213, University of Marburg, 35032 Marburg, Germany Edited by Yale E. Goldman, University of Pennsylvania/PMI, Philadelphia, PA, and approved March 14, 2019 (received for review August 7, 2018) Actin filaments (F-actin) are key components of sarcomeres, the have acquired specific functions. While previous analyses of mu- basic contractile units of skeletal muscle myofibrils. A crucial step tant mice demonstrated a role of CAP2 in neuron morphology and during myofibril differentiation is the sequential exchange of heart physiology (13–15), its function in skeletal muscles has not α-actin isoforms from smooth muscle (α-SMA) and cardiac (α-CAA) been investigated, yet. to skeletal muscle α-actin (α-SKA) that, in mice, occurs during early We here report a function for CAP2 in skeletal muscle de- postnatal life. This “α-actin switch” requires the coordinated activ- velopment. We found that CAP2 controls the exchange of ity of actin regulators because it is vital that sarcomere structure α-actin isoforms during myofibril differentiation.
    [Show full text]
  • Physiologist Physiologist
    Published by The American Physiological Society Integrating the Life Sciences from Molecule to Organism The PhysiologistPhysiologist Generating Support for Science INSIDE in the 111th Congress Rebecca Osthus APS Science Policy Analyst APS The 2008 election cycle brings a new is somewhat more promising. There is a administration to Washington, DC this plan to double the agency’s budget over Bylaw Changes January and also ushers in the 111th the next several years as part of the p. 240 Congress. With many new Members of America COMPETES Act, but so far Congress in both the House of yearly increases have not lived up to Representatives and the Senate, now is the goals laid out by Congress. Annual Meeting of the time for APS members to reach out Lawmakers are also making deci- the Nebraska and communicate the importance of sions about what regulations govern Physiological supporting biomedical research the use of animals in research, whether through strong federal funding and federally funded scientists should con- Society sound policy making. While scientists tinue to consult for and own stock in p. 243 carry out research in labs across the pharmaceutical and biotechnology com- country, many decisions are being made in APS Membership Washington, DC that Statistics will affect how they do p. 244 their jobs. The current fiscal cri- sis means that it is Starting a Lab: more important than How to Develop a ever before to make a strong case for federal Budget and Buy investment in research. Equipment Since the completion of p. 252 the doubling of the NIH budget, yearly increas- es have failed to keep Congress Extends pace with inflation, Current Levels of causing success rates for extramural grants Research Funding to fall into the teens.
    [Show full text]
  • Nomina Histologica Veterinaria, First Edition
    NOMINA HISTOLOGICA VETERINARIA Submitted by the International Committee on Veterinary Histological Nomenclature (ICVHN) to the World Association of Veterinary Anatomists Published on the website of the World Association of Veterinary Anatomists www.wava-amav.org 2017 CONTENTS Introduction i Principles of term construction in N.H.V. iii Cytologia – Cytology 1 Textus epithelialis – Epithelial tissue 10 Textus connectivus – Connective tissue 13 Sanguis et Lympha – Blood and Lymph 17 Textus muscularis – Muscle tissue 19 Textus nervosus – Nerve tissue 20 Splanchnologia – Viscera 23 Systema digestorium – Digestive system 24 Systema respiratorium – Respiratory system 32 Systema urinarium – Urinary system 35 Organa genitalia masculina – Male genital system 38 Organa genitalia feminina – Female genital system 42 Systema endocrinum – Endocrine system 45 Systema cardiovasculare et lymphaticum [Angiologia] – Cardiovascular and lymphatic system 47 Systema nervosum – Nervous system 52 Receptores sensorii et Organa sensuum – Sensory receptors and Sense organs 58 Integumentum – Integument 64 INTRODUCTION The preparations leading to the publication of the present first edition of the Nomina Histologica Veterinaria has a long history spanning more than 50 years. Under the auspices of the World Association of Veterinary Anatomists (W.A.V.A.), the International Committee on Veterinary Anatomical Nomenclature (I.C.V.A.N.) appointed in Giessen, 1965, a Subcommittee on Histology and Embryology which started a working relation with the Subcommittee on Histology of the former International Anatomical Nomenclature Committee. In Mexico City, 1971, this Subcommittee presented a document entitled Nomina Histologica Veterinaria: A Working Draft as a basis for the continued work of the newly-appointed Subcommittee on Histological Nomenclature. This resulted in the editing of the Nomina Histologica Veterinaria: A Working Draft II (Toulouse, 1974), followed by preparations for publication of a Nomina Histologica Veterinaria.
    [Show full text]
  • Loss of Mouse Cardiomyocyte Talin-1 and Talin-2 Leads to Β-1 Integrin
    Loss of mouse cardiomyocyte talin-1 and talin-2 leads PNAS PLUS to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy Ana Maria Mansoa,b,1, Hideshi Okadaa,b, Francesca M. Sakamotoa, Emily Morenoa, Susan J. Monkleyc, Ruixia Lia, David R. Critchleyc, and Robert S. Rossa,b,1 aDivision of Cardiology, Department of Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093; bCardiology Section, Department of Medicine, Veterans Administration Healthcare, San Diego, CA 92161; and cDepartment of Molecular Cell Biology, University of Leicester, Leicester LE1 9HN, United Kingdom Edited by Kevin P. Campbell, Howard Hughes Medical Institute, University of Iowa, Iowa City, IA, and approved May 30, 2017 (received for review January 26, 2017) Continuous contraction–relaxation cycles of the heart require ognized as key mechanotransducers, converting mechanical per- strong and stable connections of cardiac myocytes (CMs) with turbations to biochemical signals (5, 6). the extracellular matrix (ECM) to preserve sarcolemmal integrity. The complex of proteins organized by integrins has been most CM attachment to the ECM is mediated by integrin complexes commonly termed focal adhesions (FA) by studies performed in localized at the muscle adhesion sites termed costameres. The cells such as fibroblasts in a 2D environment. It is recognized that ubiquitously expressed cytoskeletal protein talin (Tln) is a compo- this structure is important for organizing and regulating the me- nent of muscle costameres that links integrins ultimately to the chanical and signaling events that occur upon cellular adhesion to sarcomere. There are two talin genes, Tln1 and Tln2. Here, we ECM (7, 8).
    [Show full text]
  • 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.
    [Show full text]
  • Disease-Proportional Proteasomal Degradation of Missense Dystrophins
    Disease-proportional proteasomal degradation of missense dystrophins Dana M. Talsness, Joseph J. Belanto, and James M. Ervasti1 Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota–Twin Cities, Minneapolis, MN 55455 Edited by Louis M. Kunkel, Children’s Hospital Boston, Harvard Medical School, Boston, MA, and approved September 1, 2015 (received for review May 5, 2015) The 427-kDa protein dystrophin is expressed in striated muscle insertions or deletions (indels) represent ∼7% of the total DMD/ where it physically links the interior of muscle fibers to the BMD population (13). When indel mutations cause a frameshift, they extracellular matrix. A range of mutations in the DMD gene encod- can specifically be targeted by current exon-skipping strategies (15). ing dystrophin lead to a severe muscular dystrophy known as Du- Patients with missense mutations account for only a small percentage chenne (DMD) or a typically milder form known as Becker (BMD). of dystrophinopathies (<1%) (13), yet they represent an orphaned Patients with nonsense mutations in dystrophin are specifically tar- subpopulation with an undetermined pathomechanism and no cur- geted by stop codon read-through drugs, whereas out-of-frame de- rent personalized therapies. letions and insertions are targeted by exon-skipping therapies. Both The first missense mutation reported to cause DMD was L54R treatment strategies are currently in clinical trials. Dystrophin mis- in ABD1 of an 8-y-old patient (16). Another group later reported sense mutations, however, cause a wide range of phenotypic se- L172H, a missense mutation in a structurally analogous location of verity in patients. The molecular and cellular consequences of such ABD1 (17), yet this patient presented with mild symptoms at 42 mutations are not well understood, and there are no therapies spe- years of age.
    [Show full text]
  • Costamere Protein Expression and Tissue Composition of Rotator Cuff Muscle After Tendon Release in Sheep
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Costamere protein expression and tissue composition of rotator cuff muscle after tendon release in sheep Ruoss, Severin ; Möhl, Christoph B ; Benn, Mario C ; von Rechenberg, Brigitte ; Wieser, Karl ; Meyer, Dominik C ; Gerber, Christian ; Flück, Martin Abstract: Previous studies suggested that degradation of contractile tissue requires cleavage of the costamere, a structural protein complex that holds sarcomeres in place. This study examined if costamere turnover is affected by a rotator cuff tear in a previously established ovine model. We found theactivity of focal adhesion kinase (FAK), a main regulator of costamere turnover, was unchanged at 2 weeks but decreased by 27% 16 weeks after surgical release of the infraspinatus tendon. This was accompanied by cleavage of the costamere protein talin into a 190 kDa fragment while full length talin remained un- changed. At 2 weeks after tendon release, muscle volume decreased by 17 cm from an initial 185 cm(3) , the fatty tissue volume was halved, and the contractile tissue volume remained unchanged. After 16 weeks, the muscle volume decreased by 36 cm(3) , contractile tissue was quantitatively lost, and the fat content increased by 184%. Nandrolone administration mitigated the loss of contractile tissue by 26% and prevented fat accumulation, alterations in FAK activity, and talin cleavage. Taken together, these findings imply that muscle remodeling after tendon release occurs in two stages. The early decreaseof muscle volume is associated with reduction of fat; while, the second stage is characterized by substantial loss of contractile tissue accompanied by massive fat accumulation.
    [Show full text]
  • Breakdown of Filamentous Myofibrils by the UPS–Step by Step
    biomolecules Review Breakdown of Filamentous Myofibrils by the UPS–Step by Step Dina Aweida and Shenhav Cohen * Faculty of Biology, Technion Institute of Technology, Haifa 32000, Israel; [email protected] * Correspondence: [email protected]; Tel.: +972-4-8294214 Abstract: Protein degradation maintains cellular integrity by regulating virtually all biological pro- cesses, whereas impaired proteolysis perturbs protein quality control, and often leads to human disease. Two major proteolytic systems are responsible for protein breakdown in all cells: autophagy, which facilitates the loss of organelles, protein aggregates, and cell surface proteins; and the ubiquitin- proteasome system (UPS), which promotes degradation of mainly soluble proteins. Recent findings indicate that more complex protein structures, such as filamentous assemblies, which are not acces- sible to the catalytic core of the proteasome in vitro, can be efficiently degraded by this proteolytic machinery in systemic catabolic states in vivo. Mechanisms that loosen the filamentous structure seem to be activated first, hence increasing the accessibility of protein constituents to the UPS. In this review, we will discuss the mechanisms underlying the disassembly and loss of the intricate insoluble filamentous myofibrils, which are responsible for muscle contraction, and whose degradation by the UPS causes weakness and disability in aging and disease. Several lines of evidence indicate that myofibril breakdown occurs in a strictly ordered and controlled manner, and the function of AAA-ATPases is crucial for their disassembly and loss. Keywords: ubiquitin; proteasome; autophagy; muscle atrophy; intermediate filaments; myofibrils; AAA-ATPases 1. Introduction Citation: Aweida, D.; Cohen, S. Proteolysis promotes tissue homeostasis by controlling protein abundance in response Breakdown of Filamentous Myofibrils to extracellular and intracellular cues, and by preventing accumulation of misfolded or by the UPS–Step by Step.
    [Show full text]