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Cells & Development Dec 2021Muscles generate forces for animal locomotion. The contractile apparatus of muscles is the sarcomere, a highly regular array of large actin and myosin filaments linked... (Review)
Review
Muscles generate forces for animal locomotion. The contractile apparatus of muscles is the sarcomere, a highly regular array of large actin and myosin filaments linked by gigantic titin springs. During muscle development many sarcomeres assemble in series into long periodic myofibrils that mechanically connect the attached skeleton elements. Thus, ATP-driven myosin forces can power movement of the skeleton. Here we review muscle and myofibril morphogenesis, with a particular focus on their mechanobiology. We describe recent progress on the molecular structure of sarcomeres and their mechanical connections to the skeleton. We discuss current models predicting how tension coordinates the assembly of key sarcomeric components to periodic myofibrils that then further mature during development. This requires transcriptional feedback mechanisms that may help to coordinate myofibril assembly and maturation states with the transcriptional program. To fuel the varying energy demands of muscles we also discuss the close mechanical interactions of myofibrils with mitochondria and nuclei to optimally support powerful or enduring muscle fibers.
Topics: Animals; Biophysics; Morphogenesis; Myofibrils; Myosins; Sarcomeres
PubMed: 34863916
DOI: 10.1016/j.cdev.2021.203760 -
International Journal of Molecular... Dec 2022The cardiac sarcomere is a triumph of biological evolution wherein myriad contractile and regulatory proteins assemble into a quasi-crystalline lattice to serve as the... (Review)
Review
The cardiac sarcomere is a triumph of biological evolution wherein myriad contractile and regulatory proteins assemble into a quasi-crystalline lattice to serve as the central point upon which cardiac muscle contraction occurs. This review focuses on the many signaling components and mechanisms of regulation that impact cardiac sarcomere function. We highlight the roles of the thick and thin filament, both as necessary structural and regulatory building blocks of the sarcomere as well as targets of functionally impactful modifications. Currently, a new focus emerging in the field is inter-myofilament signaling, and we discuss here the important mediators of this mechanism, including myosin-binding protein C and titin. As the understanding of sarcomere signaling advances, so do the methods with which it is studied. This is reviewed here through discussion of recent live muscle systems in which the sarcomere can be studied under intact, physiologically relevant conditions.
Topics: Sarcomeres; Myocardium; Heart; Connectin; Myofibrils; Myocardial Contraction
PubMed: 36555864
DOI: 10.3390/ijms232416223 -
The Journal of Physiology Jun 2017The ubiquitin-proteasome system (UPS) plays a critical role in removing unwanted intracellular proteins and is involved in protein quality control, signalling and cell... (Review)
Review
The ubiquitin-proteasome system (UPS) plays a critical role in removing unwanted intracellular proteins and is involved in protein quality control, signalling and cell death. Because the heart is subject to continuous metabolic and mechanical stress, the proteasome plays a particularly important role in the heart, and proteasome dysfunction has been suggested as a causative factor in cardiac dysfunction. Proteasome impairment has been detected in cardiomyopathies, heart failure, myocardial ischaemia, and hypertrophy. Proteasome inhibition is also sufficient to cause cardiac dysfunction in healthy pigs, and patients using a proteasome inhibitor for cancer therapy have a higher incidence of heart failure. In this Topical Review we discuss the experimental data which suggest UPS dysfunction is a common feature of cardiomyopathies, with an emphasis on hypertrophic cardiomyopathy caused by sarcomeric mutations. We also propose potential mechanisms by which cardiomyopathy-causing mutations may lead to proteasome impairment, such as altered calcium handling and increased oxidative stress due to mitochondrial dysfunction.
Topics: Animals; Cardiomyopathy, Hypertrophic; Heart; Heart Failure; Humans; Proteasome Endopeptidase Complex; Sarcomeres; Ubiquitin
PubMed: 28181243
DOI: 10.1113/JP273607 -
Cells Jul 2021With the advent of super-resolution microscopy, we gained a powerful toolbox to bridge the gap between the cellular- and molecular-level analysis of living organisms.... (Review)
Review
With the advent of super-resolution microscopy, we gained a powerful toolbox to bridge the gap between the cellular- and molecular-level analysis of living organisms. Although nanoscopy is broadly applicable, classical model organisms, such as fruit flies, worms and mice, remained the leading subjects because combining the strength of sophisticated genetics, biochemistry and electrophysiology with the unparalleled resolution provided by super-resolution imaging appears as one of the most efficient approaches to understanding the basic cell biological questions and the molecular complexity of life. Here, we summarize the major nanoscopic techniques and illustrate how these approaches were used in model systems to revisit a series of well-known cell biological phenomena. These investigations clearly demonstrate that instead of simply achieving an improvement in image quality, nanoscopy goes far beyond with its immense potential to discover novel structural and mechanistic aspects. With the examples of synaptic active zones, centrosomes and sarcomeres, we will explain the instrumental role of super-resolution imaging pioneered in in understanding fundamental subcellular constituents.
Topics: Animals; Centrosome; Drosophila; Microscopy, Fluorescence; Models, Biological; Sarcomeres; Single Molecule Imaging
PubMed: 34440693
DOI: 10.3390/cells10081924 -
International Journal of Molecular... Jan 2020Sarcomere assembly and maintenance are essential physiological processes required for cardiac and skeletal muscle function and organism mobility. Over decades of... (Review)
Review
Sarcomere assembly and maintenance are essential physiological processes required for cardiac and skeletal muscle function and organism mobility. Over decades of research, components of the sarcomere and factors involved in the formation and maintenance of this contractile unit have been identified. Although we have a general understanding of sarcomere assembly and maintenance, much less is known about the development of the thin filaments and associated factors within the sarcomere. In the last decade, advancements in medical intervention and genome sequencing have uncovered patients with novel mutations in sarcomere thin filaments. Pairing this sequencing with reverse genetics and the ability to generate patient avatars in model organisms has begun to deepen our understanding of sarcomere thin filament development. In this review, we provide a summary of recent findings regarding sarcomere assembly, maintenance, and disease with respect to thin filaments, building on the previous knowledge in the field. We highlight debated and unknown areas within these processes to clearly define open research questions.
Topics: Actin Cytoskeleton; Animals; Humans; Muscle Contraction; Muscle Proteins; Muscle, Skeletal; Muscular Diseases; Mutation; Sarcomeres; Whole Genome Sequencing
PubMed: 31952119
DOI: 10.3390/ijms21020542 -
International Journal of Molecular... Oct 2021Inherited cardiomyopathies form a heterogenous group of disorders that affect the structure and function of the heart. Defects in the genes encoding sarcomeric proteins... (Review)
Review
Inherited cardiomyopathies form a heterogenous group of disorders that affect the structure and function of the heart. Defects in the genes encoding sarcomeric proteins are associated with various perturbations that induce contractile dysfunction and promote disease development. In this review we aimed to outline the functional consequences of the major inherited cardiomyopathies in terms of myocardial contraction and kinetics, and to highlight the structural and functional alterations in some sarcomeric variants that have been demonstrated to be involved in the pathogenesis of the inherited cardiomyopathies. A particular focus was made on mutation-induced alterations in cardiomyocyte mechanics. Since no disease-specific treatments for familial cardiomyopathies exist, several novel agents have been developed to modulate sarcomere contractility. Understanding the molecular basis of the disease opens new avenues for the development of new therapies. Furthermore, the earlier the awareness of the genetic defect, the better the clinical prognostication would be for patients and the better the prevention of development of the disease.
Topics: Animals; Cardiomyopathies; Humans; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Sarcomeres
PubMed: 34681814
DOI: 10.3390/ijms222011154 -
Progress in Molecular Biology and... 2019The role and utility of intrinsically disordered regions (IDRs) is reviewed for two groups of sarcomeric proteins, such as members of tropomodulin/leiomodin (Tmod/Lmod)... (Review)
Review
The role and utility of intrinsically disordered regions (IDRs) is reviewed for two groups of sarcomeric proteins, such as members of tropomodulin/leiomodin (Tmod/Lmod) protein homology group and myosin binding protein C (MyBP-C). These two types of sarcomeric proteins represent very different but strongly interdependent functions, being responsible for maintaining structure and operation of the muscle sarcomere. The role of IDRs in the formation of complexes between thin filaments and Tmods/Lmods is discussed within the framework of current understanding of the thin filament length regulation. For MyBP-C, the function of IDRs is discussed in the context of MYBP-C-dependent sarcomere contraction and actomyosin activation.
Topics: Amino Acid Sequence; Animals; Binding Sites; Carrier Proteins; Humans; Intrinsically Disordered Proteins; Muscles; Sarcomeres; Tropomodulin
PubMed: 31521234
DOI: 10.1016/bs.pmbts.2019.03.014 -
Philosophical Transactions of the Royal... Nov 2022During postnatal cardiac development, cardiomyocytes mature and turn into adult ones. Hence, all cellular properties, including morphology, structure, physiology and... (Review)
Review
During postnatal cardiac development, cardiomyocytes mature and turn into adult ones. Hence, all cellular properties, including morphology, structure, physiology and metabolism, are changed. One of the most important aspects is the contractile apparatus, of which the minimum unit is known as a sarcomere. Sarcomere maturation is evident by enhanced sarcomere alignment, ultrastructural organization and myofibrillar isoform switching. Any maturation process failure may result in cardiomyopathy. Sarcomere function is intricately related to other organelles, and the growing evidence suggests reciprocal regulation of sarcomere and mitochondria on their maturation. Herein, we summarize the molecular mechanism that regulates sarcomere maturation and the interplay between sarcomere and other organelles in cardiomyocyte maturation. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.
Topics: Mitochondria; Myocytes, Cardiac; Sarcomeres
PubMed: 36189811
DOI: 10.1098/rstb.2021.0325 -
Pflugers Archiv : European Journal of... May 2019
Topics: Animals; Cardiac Myosins; Heart Diseases; Humans; Sarcomeres
PubMed: 30976925
DOI: 10.1007/s00424-019-02275-2 -
Biophysical Journal Sep 2023
Topics: Sarcomeres; Actins; Muscle Contraction; Muscle Fibers, Skeletal
PubMed: 37582376
DOI: 10.1016/j.bpj.2023.08.002