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Journal of Molecular and Cellular... Nov 2020The sarcomere is the basic contractile unit of striated muscle and is a highly ordered protein complex with the actin and myosin filaments at its core. Assembling the... (Review)
Review
The sarcomere is the basic contractile unit of striated muscle and is a highly ordered protein complex with the actin and myosin filaments at its core. Assembling the sarcomere constituents into this organized structure in development, and with muscle growth as new sarcomeres are built, is a complex process coordinated by numerous factors. Once assembled, the sarcomere requires constant maintenance as its continuous contraction is accompanied by elevated mechanical, thermal, and oxidative stress, which predispose proteins to misfolding and toxic aggregation. To prevent protein misfolding and maintain sarcomere integrity, the sarcomere is monitored by an assortment of protein quality control (PQC) mechanisms. The need for effective PQC is heightened in cardiomyocytes which are terminally differentiated and must survive for many years while preserving optimal mechanical output. To prevent toxic protein aggregation, molecular chaperones stabilize denatured sarcomere proteins and promote their refolding. However, when old and misfolded proteins cannot be salvaged by chaperones, they must be recycled via degradation pathways: the calpain and ubiquitin-proteasome systems, which operate under basal conditions, and the stress-responsive autophagy-lysosome pathway. Mutations to and deficiency of the molecular chaperones and associated factors charged with sarcomere maintenance commonly lead to sarcomere structural disarray and the progression of heart disease, highlighting the necessity of effective sarcomere PQC for maintaining cardiac function. This review focuses on the dynamic regulation of assembly and turnover at the sarcomere with an emphasis on the chaperones involved in these processes and describes the alterations to chaperones - through mutations and deficient expression - implicated in disease progression to heart failure.
Topics: Animals; Autophagy; Humans; Lysosomes; Models, Biological; Myocardium; Myofibrils; Sarcomeres
PubMed: 32920010
DOI: 10.1016/j.yjmcc.2020.08.018 -
Chaperones and the Proteasome System: Regulating the Construction and Demolition of Striated Muscle.International Journal of Molecular... Dec 2017Protein folding factors (chaperones) are required for many diverse cellular functions. In striated muscle, chaperones are required for contractile protein function, as... (Review)
Review
Protein folding factors (chaperones) are required for many diverse cellular functions. In striated muscle, chaperones are required for contractile protein function, as well as the larger scale assembly of the basic unit of muscle, the sarcomere. The sarcomere is complex and composed of hundreds of proteins and the number of proteins and processes recognized to be regulated by chaperones has increased dramatically over the past decade. Research in the past ten years has begun to discover and characterize the chaperones involved in the assembly of the sarcomere at a rapid rate. Because of the dynamic nature of muscle, wear and tear damage is inevitable. Several systems, including chaperones and the ubiquitin proteasome system (UPS), have evolved to regulate protein turnover. Much of our knowledge of muscle development focuses on the formation of the sarcomere but recent work has begun to elucidate the requirement and role of chaperones and the UPS in sarcomere maintenance and disease. This review will cover the roles of chaperones in sarcomere assembly, the importance of chaperone homeostasis and the cooperation of chaperones and the UPS in sarcomere integrity and disease.
Topics: Animals; Homeostasis; Humans; Molecular Chaperones; Muscle, Striated; Proteasome Endopeptidase Complex; Protein Folding; Proteolysis; Sarcomeres; Ubiquitin
PubMed: 29271938
DOI: 10.3390/ijms19010032 -
American Journal of Physiology. Cell... Aug 2017Muscle contraction is commonly associated with the cross-bridge and sliding filament theories, which have received strong support from experiments conducted over the... (Review)
Review
Muscle contraction is commonly associated with the cross-bridge and sliding filament theories, which have received strong support from experiments conducted over the years in different laboratories. However, there are studies that cannot be readily explained by the theories, showing ) a plateau of the force-length relation extended beyond optimal filament overlap, and forces produced at long sarcomere lengths that are higher than those predicted by the sliding filament theory; ) passive forces at long sarcomere lengths that can be modulated by activation and Ca, which changes the force-length relation; and ) an unexplained high force produced during and after stretch of activated muscle fibers. Some of these studies even propose "new theories of contraction." While some of these observations deserve evaluation, many of these studies present data that lack a rigorous control and experiments that cannot be repeated in other laboratories. This article reviews these issues, looking into studies that have used intact and permeabilized fibers, myofibrils, isolated sarcomeres, and half-sarcomeres. A common mechanism associated with sarcomere and half-sarcomere length nonuniformities and a Ca-induced increase in the stiffness of titin is proposed to explain observations that derive from these studies.
Topics: Animals; Biomechanical Phenomena; Calcium; Connectin; Isometric Contraction; Muscle Contraction; Muscle Fibers, Skeletal; Muscle, Striated; Myofibrils; Sarcomeres
PubMed: 28539306
DOI: 10.1152/ajpcell.00050.2017 -
The Journal of Physiology Jun 2017The mechanical role of cardiac microtubules (MTs) has been a topic of some controversy. Early studies, which relied largely on pharmacological interventions that altered... (Review)
Review
The mechanical role of cardiac microtubules (MTs) has been a topic of some controversy. Early studies, which relied largely on pharmacological interventions that altered the MT cytoskeleton as a whole, presented no consistent role. Recent advances in the ability to observe and manipulate specific properties of the cytoskeleton have strengthened our understanding. Direct observation of MTs in working myocytes suggests a spring-like function, one that is surprisingly tunable by post-translational modification (PTM). Specifically, detyrosination of MTs facilitates an interaction with intermediate filaments that complex with the sarcomere, altering myocyte stiffness, contractility, and mechanosignalling. Such results support a paradigm of cytoskeletal regulation based on not only polymerization, but also associations with binding partners and PTMs that divide the MT cytoskeleton into functionally distinct subsets. The evolutionary costs and benefits of tuning cytoskeletal mechanics remain an open question, one that we discuss herein. Nevertheless, mechanically distinct MT subsets provide a rich new source of therapeutic targets for a variety of phenomena in the heart.
Topics: Animals; Cytoskeleton; Humans; Microtubules; Muscle Cells; Protein Processing, Post-Translational; Sarcomeres
PubMed: 28116814
DOI: 10.1113/JP273046 -
FEBS Letters Mar 2022Hypertrophic cardiomyopathy (HCM), a disease characterized by cardiac muscle hypertrophy and hypercontractility, is the most frequently inherited disorder of the heart.... (Review)
Review
Hypertrophic cardiomyopathy (HCM), a disease characterized by cardiac muscle hypertrophy and hypercontractility, is the most frequently inherited disorder of the heart. HCM is mainly caused by variants in genes encoding proteins of the sarcomere, the basic contractile unit of cardiomyocytes. The most frequently mutated among them is MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), a key regulator of sarcomere contraction. In this review, we summarize clinical and genetic aspects of HCM and provide updated information on the function of the healthy and HCM sarcomere, as well as on emerging therapeutic options targeting sarcomere mechanical activity. Building on what is known about cMyBP-C activity, we examine different pathogenicity drivers by which MYBPC3 variants can cause disease, focussing on protein haploinsufficiency as a common pathomechanism also in nontruncating variants. Finally, we discuss recent evidence correlating altered cMyBP-C mechanical properties with HCM development.
Topics: Cardiomyopathy, Hypertrophic; Carrier Proteins; Cytoskeletal Proteins; Humans; Mutation; Myocytes, Cardiac; Sarcomeres
PubMed: 35224729
DOI: 10.1002/1873-3468.14301 -
International Journal of Molecular... Aug 2022The induction of protein synthesis is crucial to counteract the deconditioning of neuromuscular system and its atrophy. In the past, hormones and cytokines acting as... (Review)
Review
The induction of protein synthesis is crucial to counteract the deconditioning of neuromuscular system and its atrophy. In the past, hormones and cytokines acting as growth factors involved in the intracellular events of these processes have been identified, while the implications of signaling pathways associated with the anabolism/catabolism ratio in reference to the molecular mechanism of skeletal muscle hypertrophy have been recently identified. Among them, the mechanotransduction resulting from a mechanical stress applied to the cell appears increasingly interesting as a potential pathway for therapeutic intervention. At present, there is an open question regarding the type of stress to apply in order to induce anabolic events or the type of mechanical strain with respect to the possible mechanosensing and mechanotransduction processes involved in muscle cells protein synthesis. This review is focused on the muscle LIM protein (MLP), a structural and mechanosensing protein with a LIM domain, which is expressed in the sarcomere and costamere of striated muscle cells. It acts as a transcriptional cofactor during cell proliferation after its nuclear translocation during the anabolic process of differentiation and rebuilding. Moreover, we discuss the possible opportunity of stimulating this mechanotransduction process to counteract the muscle atrophy induced by anabolic versus catabolic disorders coming from the environment, aging or myopathies.
Topics: LIM Domain Proteins; Mechanotransduction, Cellular; Muscle Proteins; Muscle, Skeletal; Sarcomeres
PubMed: 36077180
DOI: 10.3390/ijms23179785 -
Journal of Muscle Research and Cell... Jun 2019The technique of electron microscopy (EM) has been fundamental to muscle research since the days of Huxley and Hanson. Direct observation of how proteins in the... (Review)
Review
The technique of electron microscopy (EM) has been fundamental to muscle research since the days of Huxley and Hanson. Direct observation of how proteins in the sarcomere are arranged and visualising the changes that occur upon activation have greatly increased our understanding of function. In the 1980s specimen preparation techniques for biological EM moved away from traditional fixing and staining. The technique known as cryo-electron microscopy (Cryo-EM) was developed, which involves rapidly freezing proteins in liquid ethane which maintains them in a near native state. Within the last 5 years there has been a step change in the achievable resolution using Cryo-EM. This 'resolution revolution' can be attributed to advances in detector technology, microscope automation and maximum likelihood image processing. In this article we look at how Cryo-EM has contributed to the field of muscle research in this post revolution era, focussing on recently published high resolution structures of sarcomeric proteins.
Topics: Animals; Biomedical Research; Cryoelectron Microscopy; History, 20th Century; History, 21st Century; Humans; Sarcomeres
PubMed: 31302812
DOI: 10.1007/s10974-019-09537-7 -
The Journal of Clinical Investigation Jul 2022
Topics: Intracellular Signaling Peptides and Proteins; Nerve Tissue Proteins; Sarcomeres
PubMed: 35838052
DOI: 10.1172/JCI162883 -
The FEBS Journal Jun 2020Skeletal muscles constitute roughly 40% of human body mass. Muscles are specialized tissues that generate force to drive movements through ATP-driven cyclic interactions... (Review)
Review
Skeletal muscles constitute roughly 40% of human body mass. Muscles are specialized tissues that generate force to drive movements through ATP-driven cyclic interactions between the protein filaments, namely actin and myosin filaments. The filaments are organized in an intricate structure called the 'sarcomere', which is a fundamental contractile unit of striated skeletal and cardiac muscle, hosting a fine assembly of macromolecular protein complexes. The micrometer-sized sarcomere units are arranged in a reiterated array within myofibrils of muscle cells. The precise spatial organization of sarcomere is tightly controlled by several molecular mechanisms, indispensable for its force-generating function. Disorganized sarcomeres, either due to erroneous molecular signaling or due to mutations in the sarcomeric proteins, lead to human diseases such as cardiomyopathies and muscle atrophic conditions prevalent in cachexia. Protein post-translational modifications (PTMs) of the sarcomeric proteins serve a critical role in sarcomere formation (sarcomerogenesis), as well as in the steady-state maintenance of sarcomeres. PTMs such as phosphorylation, acetylation, ubiquitination, and SUMOylation provide cells with a swift and reversible means to adapt to an altered molecular and therefore cellular environment. Over the past years, SUMOylation has emerged as a crucial modification with implications for different aspects of cell function, including organizing higher-order protein assemblies. In this review, we highlight the fundamentals of the small ubiquitin-like modifiers (SUMO) pathway and its link specifically to the mechanisms of sarcomere assembly. Furthermore, we discuss recent studies connecting the SUMO pathway-modulated protein homeostasis with sarcomere organization and muscle-related pathologies.
Topics: Actin Cytoskeleton; Animals; Cell Differentiation; Cytoskeleton; Humans; Morphogenesis; Muscle Contraction; Muscle, Skeletal; Myofibrils; Sarcomeres; Sumoylation; Ubiquitin
PubMed: 32096922
DOI: 10.1111/febs.15263 -
Cardiovascular Research Apr 2015To date, no compounds or interventions exist that treat or prevent sarcomeric cardiomyopathies. Established therapies currently improve the outcome, but novel therapies... (Review)
Review
To date, no compounds or interventions exist that treat or prevent sarcomeric cardiomyopathies. Established therapies currently improve the outcome, but novel therapies may be able to more fundamentally affect the disease process and course. Investigations of the pathomechanisms are generating molecular insights that can be useful for the design of novel specific drugs suitable for clinical use. As perturbations in the heart are stage-specific, proper timing of drug treatment is essential to prevent initiation and progression of cardiac disease in mutation carrier individuals. In this review, we emphasize potential novel therapies which may prevent, delay, or even reverse hypertrophic cardiomyopathy caused by sarcomeric gene mutations. These include corrections of genetic defects, altered sarcomere function, perturbations in intracellular ion homeostasis, and impaired myocardial energetics.
Topics: Animals; Cardiomyopathies; Cardiovascular Agents; Energy Metabolism; Genetic Markers; Genetic Predisposition to Disease; Genetic Therapy; Humans; Molecular Targeted Therapy; Mutation; Phenotype; Sarcomeres; Signal Transduction
PubMed: 25634554
DOI: 10.1093/cvr/cvv023