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      The M-band: The underestimated part of the sarcomere

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          Abstract

          The sarcomere is the basic unit of the myofibrils, which mediate skeletal and cardiac Muscle contraction. Two transverse structures, the Z-disc and the M-band, anchor the thin (actin and associated proteins) and thick (myosin and associated proteins) filaments to the elastic filament system composed of titin. A plethora of proteins are known to be integral or associated proteins of the Z-disc and its structural and signalling role in muscle is better understood, while the molecular constituents of the M-band and its function are less well defined. Evidence discussed here suggests that the M-band is important for managing force imbalances during active muscle contraction. Its molecular composition is fine-tuned, especially as far as the structural linkers encoded by members of the myomesin family are concerned and depends on the specific mechanical characteristics of each particular muscle fibre type. Muscle activity signals from the M-band to the nucleus and affects transcription of sarcomeric genes, especially via serum response factor (SRF). Due to its important role as shock absorber in contracting muscle, the M-band is also more and more recognised as a contributor to muscle disease.

          Highlights

          • This article reviews the structure, composition and function of the M-band, the central structure of the sarcomere, the basic unit of a myofibril.

          • In addition, signalling pathways emanating from the M-band, which may affect protein turnover from triggering transcription (via SRF) to promoting degradation are discussed.

          • A particular strength of the review is the links that it provides throughout the text to disease.

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          Most cited references127

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          The amphioxus genome and the evolution of the chordate karyotype.

          Lancelets ('amphioxus') are the modern survivors of an ancient chordate lineage, with a fossil record dating back to the Cambrian period. Here we describe the structure and gene content of the highly polymorphic approximately 520-megabase genome of the Florida lancelet Branchiostoma floridae, and analyse it in the context of chordate evolution. Whole-genome comparisons illuminate the murky relationships among the three chordate groups (tunicates, lancelets and vertebrates), and allow not only reconstruction of the gene complement of the last common chordate ancestor but also partial reconstruction of its genomic organization, as well as a description of two genome-wide duplications and subsequent reorganizations in the vertebrate lineage. These genome-scale events shaped the vertebrate genome and provided additional genetic variation for exploitation during vertebrate evolution.
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            RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing.

            Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.
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              Atlas of the clinical genetics of human dilated cardiomyopathy.

              Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
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                Author and article information

                Contributors
                Journal
                Biochim Biophys Acta Mol Cell Res
                Biochim Biophys Acta Mol Cell Res
                Biochimica et Biophysica Acta. Molecular Cell Research
                Elsevier
                0167-4889
                1879-2596
                1 March 2020
                March 2020
                : 1867
                : 3
                : 118440
                Affiliations
                [a ]Biomedical Research Facility 2, School of Medicine, University of California, San Diego, Medical Sciences Research Bldg, 9500 Gilman Drive, La Jolla, CA 92093-0613C, USA
                [b ]University of Gothenburg, Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden
                [c ]Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, Malet Street, London WC1E 7HX, UK
                [d ]InSphero, Wagistrasse 27, CH-8952 Schlieren, Switzerland
                [e ]Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK
                [f ]School of Cardiovascular Medicine and Sciences, British Heart Foundation Research Excellence Centre, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK
                Author notes
                [* ]Corresponding author at: Room 3.26A, New Hunt's House, Guy's Campus, London SE1 1UL, UK. elisabeth.ehler@ 123456kcl.ac.uk
                Article
                S0167-4889(18)30342-2 118440
                10.1016/j.bbamcr.2019.02.003
                7023976
                30738787
                219cbaef-77c3-4ad7-bce6-0228ccca36a2
                © 2019 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 30 November 2018
                : 16 January 2019
                : 5 February 2019
                Categories
                Article

                cytoskeleton,sarcomere,cardiomyopathy,myomesin,obscurin
                cytoskeleton, sarcomere, cardiomyopathy, myomesin, obscurin

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