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The Cytoskeleton of the Cardiac Muscle Cell 1 1 1 Ioannis Sarantitis , Panagiotis Papanastasopoulos , Maria Manousi , 2 2 Nikolaos G

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The Cytoskeleton of the Cardiac Muscle Cell 1 1 1 Ioannis Sarantitis , Panagiotis Papanastasopoulos , Maria Manousi , 2 2 Nikolaos G Hellenic J Cardiol 2012; 53: 367-379 Review Article The Cytoskeleton of the Cardiac Muscle Cell 1 1 1 IOANNIS SARANTITIS , PANAGIOTIS PAPANASTASOPOULOS , MARIA MANOUSI , 2 2 NIKOLAOS G. BAIKOUSSIS , EFSTRATIOS APOSTOLAKIS 1Department of Anatomy, Histology and Embryology, School of Medicine, University of Patras, 2Department of Cardiothoracic Surgery, University Hospital of Patras, Rion, Greece Key words: he cytoskeleton of the cardiomyo- lateral sarcolemma from the intercalat- Cardiac myocyte, cyte has a special place among the ed disc, which is a separate area, as re- intercalated disc, sarcolemma, T subcellular biological structures, gards both structure and function. sarcomere, Z-disc. due to its complexity, its exceptional or- c. The cytoskeleton and, finally, ganisation, and to the multiple roles it d. the cellular organelles. plays. Cytoskeleton proteins and interac- The cardiomyocyte (Figure 1) is cylin- tions among them are constantly being drical, with a diameter of about 10-15 μm discovered. It has been demonstrated that and a length of about 100 μm.8 Usually, it mutations of these proteins, of different branches and is connected to its adjacent type and importance, are involved in the cardiomyocytes along the longitudinal ax- pathogenesis of cardiomyopathies, the is, through the intercalated discs. It is stri- heart’s participation in several muscular ated and has one or two centrally located, Manuscript received: dystrophies, and cardiac arrhythmias.1-5 non-dense, slightly elongated nuclei.6-9 December 3, 2010; The volume of new information added to The cardiomyocytes’ arrangement Accepted: this field is huge and concerns a large vari- leads to the formation of a grid, or syncy- June 19, 2012. ety of cytoskeleton proteins. The purpose tium, which constitutes the cardiac mus- of this review is to present a picture that is cle. However, in the myocardium a vari- Address: analytical, as far as possible, but coherent ety of other cell types are found, such as Ioannis Sarantitis and simplified, of how the parts of the cy- fibroblasts—which represent the majority Department of toskeleton are structured and, finally, how of cells in the normal heart—endothelial 6,10,11 Anatomy, Histology and they are integrated into a unique, effective cells, and smooth muscle cells. The Embryology and functional total. connective tissue that surrounds the car- School of Medicine diomyocytes includes, from the outermost Campus of University of layer to the inner one, the epimysium, the Patras Basic morphology of the cardiac muscle cell 26500 Rion, Greece perimysium and the endomysium. The en- e-mail: In order to describe the sophisticated sub- domysium contains the extracellular ma- [email protected] cellular organisation of the cardiomyo- trix, which plays a key role in the dynamic cyte, is useful to simplify and classify its interaction between cardiomyocytes. The structure. For that purpose, it is necessary normal extracellular matrix in the heart to divide the cardiomyocyte into separate (cardiogel) is produced both by the myo- subcellular areas, as follows (Figure 1): cardial cells themselves and by the myo- a. The intercalated disc, which is an exclu- cardium fibroblasts. It consists of I, III sive feature of the cardiomyocyte.6,7 and IV-type collagen, lamin, fibronectin b. The lateral sarcolemma. This name in- and proteoglycans. It seems that it plays dicates the different topography of the an important role in the generation of the (Hellenic Journal of Cardiology) HJC • 367 I. Sarantitis et al i. The desmosomes, or maculae adherentes, which prevent the detachment of cells under the nor- mal contraction activity.6,7,17 The desmosomes are formed by desmoglein-2 and desmocollin-2 transmembrane proteins, which establish a tran- scellular connection. The following cytoplas- mic proteins also participate: desmin, desmo- Intercalated disk plakin, plakophilin-2, p0071 and plakoglobin, to which the intermediate desmin filaments are at- tached.7,9,14,20 10 μm ii. The adherens junctions or fasciae adherens,18,21 Nucleus FIBRE which serve as attachment points for the terminal Fibrils Sarcolemma Sarcoplasmic reticulum 2 μm sarcomeres’ actin filaments. In this way they rep- T system resent a key-post for the power transmission be- 6,17 Capillary tween neighbouring myocardial cells. The main N Terminal cistero proteins of the adherens junctions include N-cad- herin, which is a transmembrane protein and en- FIBRIL 22 sures the transcellular connection, β1D integrin (also a transmembrane protein), and the following cytoplasmic proteins: α- and β-catenins, to which SARCOMERE Intercalated disk Intercalated disk thin actin filaments are attached, vinculin, meta- vinculin, plakoglobin, spectrin, and ARVCF (Ar- Figure 1. The basic morphology of the cardiac muscle cell. Top: madillo repeat gene deleted in Velo-cardio-facial The cardiac muscle as seen in the electron microscope. Middle: syndrome), SPAL (Spa-1-like protein), a GTPase- An illustration of the cardiac muscle grid. Bottom: An illustration activating protein (GAP family protein), ALP (ac- of part of a cardiac muscle cell in higher magnification. tinin-associated LIM Protein), and N-RAP (a LIM domain-containing protein), which possibly func- tion as tension sensors.9,14,17,20,23 myofibrils and the intercalated disc, during the differ- iii. The gap junctions or nexuses or maculae commu- 18 entiation and maturation of the cardiac stem cells to nicantes, which are key structures for ion trans- myocardial cells.11-16 portation between adjacent cardiomyocytes. Gap junctions are formed by connexins. In this type of intercellular communication, the non-muscular Intercalated disc cells of myocardium may also participate.6,10 As The intercalated disc (Figure 1) represents the area regards connexins, in the ventricular myocardium where the adjacent myocardial cells are connected connexin-43 predominates, while connexin-40 and along the longitudinal axis, and it appears as a spe- connexin-45 are present in different quantities. Six cialised part of the cell membrane.7,9,17 It is present connexin molecules per cell membrane are neces- as an intercalated structure, and consists of two parts: sary for the formation of a gap junction between the transverse part, which extends across the longitu- two myocardial cells. It is not yet been confirmed dinal axis of the muscle fibres, and the lateral part, whether there is a fourth type of connection in the which goes along the axis of the muscle fibres. In the intercalated disc, called tight junction.9,23,24 area of the intercalated disc, the membrane forms leafing protrusions. The intercalated disc presents Lateral sarcolemma certain differences in morphology among the several types of myocardial cells (atrial, ventricular, conduc- The lateral sarcolemmatic area is the total remaining tion system cells).6,18 In fact, the intercalated disc is sarcolemma (the myocardial cell’s membrane) apart a synaptic complex with a specific functional mission: from the intercalated disc. In this part of the mem- to provide proper connection and communication be- brane, specialised areas of the cardiomyocyte are rec- tween myocardial cells. According to its functional ognised that are very important for its homeostasis. mission, the intercalated disc consists of:6,7,9,19 These sites are called costameres (Figure 2). Costa- 368 • HJC (Hellenic Journal of Cardiology) The Cytoskeleton of the Cardiac Muscle Cell Cytoskeleton The cytoskeleton is the structure that provides me- Collagen chanical support to the cell, also contributing to the spatial arrangement of the other subcellular el- Extracellular matrix Basel Lamina Laminin ements. The cytoskeleton preserves the structur- α-DG α7β1 integrin al and functional integrity of the myocardial cell. Sarcolemma Moreover, parts of the cytoskeleton participate in Cell membrane SP SG β-DG α β various cell procedures, such as cell increase and di- Na, K-ATPase Dystrophin V Costamere Spectrin vision, cell migration, intracellular transfer of ves- ANK α-Actinin icles, proper arrangement and function of the cell Actin organelles, allocation of membrane receptors, and Actin Myosin intercellular communication. It is also believed to Cytokeratin Desmin play an important role in the cell’s mechanical signal α-Actinin transduction.14,29 Z-Line The cytoskeleton, as regards morphology and to- pography, is divided into sarcomeric, extra-sarcomer- Figure 2. Schematic illustration of the lateral sarcolemma con- ic, membrane-submembrane and nuclear cytoskeleton 9 taining a costamere. Costameres consist of the dystrophin-gly- (Figure 3). This division constitutes a simplifica- coprotein complex, the focal adhesion complex and the spectrin tion, since the cytoskeleton is literally a complicated, complex (not shown here), and play an important role in con- but united and inextricable entity, so the purpose of necting the extracellular matrix with the rest of the cytoskeleton. DG – dystroglycan; SP – sarcospan; SG – sarcoglycan complex; α, the simplification is to facilitate the study and under- β – syntrophins; V – vinculin; ANK – ankyrin 3. (From reference standing of this entity. On the other hand, there is the 26. Reproduced with permission from Wolters Kluwer Health.) functional division of the cytoskeleton, according to which it consists of the contractile part, exclusively re- garding the thin and thick filaments of the sarcomere, and the non-contractile part, which serves the trans- meres are sub-sarcolemmatic structures that are con- mission
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