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Cardiovascular Research Apr 2015The clinical variability in patients with sarcomeric cardiomyopathies is striking: a mutation causes cardiomyopathy in one individual, while the identical mutation is... (Review)
Review
The clinical variability in patients with sarcomeric cardiomyopathies is striking: a mutation causes cardiomyopathy in one individual, while the identical mutation is harmless in a family member. Moreover, the clinical phenotype varies ranging from asymmetric hypertrophy to severe dilatation of the heart. Identification of a single phenotype-associated disease mechanism would facilitate the design of targeted treatments for patient groups with different clinical phenotypes. However, evidence from both the clinic and basic knowledge of functional and structural properties of the sarcomere argues against a 'one size fits all' therapy for treatment of one clinical phenotype. Meticulous clinical and basic studies are needed to unravel the initial and progressive changes initiated by sarcomere mutations to better understand why mutations in the same gene can lead to such opposing phenotypes. Ultimately, we need to design an 'integrative physiology' approach to fully realize patient/gene-tailored therapy. Expertise within different research fields (cardiology, genetics, cellular biology, physiology, and pharmacology) must be joined to link longitudinal clinical studies with mechanistic insights obtained from molecular and functional studies in novel cardiac muscle systems. New animal models, which reflect both initial and more advanced stages of sarcomeric cardiomyopathy, will also aid in achieving these goals. Here, we discuss current priorities in clinical and preclinical investigation aimed at increasing our understanding of pathophysiological mechanisms leading from mutation to disease. Such information will provide the basis to improve risk stratification and to develop therapies to prevent/rescue cardiac dysfunction and remodelling caused by sarcomere mutations.
Topics: Animals; Biomedical Research; Cardiology; Cardiomyopathies; Genetic Markers; Genetic Predisposition to Disease; Humans; Mutation; Phenotype; Research; Sarcomeres
PubMed: 25631582
DOI: 10.1093/cvr/cvv019 -
Biochimica Et Biophysica Acta.... Mar 2020The 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... (Review)
Review
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.
Topics: Actins; Connectin; Humans; Muscle Contraction; Myofibrils; Myosins; Sarcomeres; Serum Response Factor; Transcription, Genetic
PubMed: 30738787
DOI: 10.1016/j.bbamcr.2019.02.003 -
Journal of Biomedicine & Biotechnology 2010The giant protein titin is thought to play major roles in the assembly and function of muscle sarcomeres. Structural details, such as widths of Z- and M-lines and... (Review)
Review
The giant protein titin is thought to play major roles in the assembly and function of muscle sarcomeres. Structural details, such as widths of Z- and M-lines and periodicities in the thick filaments, correlate with the substructure in the respective regions of the titin molecule. Sarcomere rest length, its operating range of lengths, and passive elastic properties are also directly controlled by the properties of titin. Here we review some recent titin data and discuss its implications for sarcomere architecture and elasticity.
Topics: Animals; Connectin; Elasticity; Humans; Muscle Proteins; Myosins; Pliability; Protein Kinases; Sarcomeres
PubMed: 20625501
DOI: 10.1155/2010/612482 -
Pflugers Archiv : European Journal of... Jun 2014Mechanosensation and mechanotransduction are fundamental aspects of biology, but the link between physical stimuli and biological responses remains not well understood.... (Review)
Review
Mechanosensation and mechanotransduction are fundamental aspects of biology, but the link between physical stimuli and biological responses remains not well understood. The perception of mechanical stimuli, their conversion into biochemical signals, and the transmission of these signals are particularly important for dynamic organs such as the heart. Various concepts have been introduced to explain mechanosensation at the molecular level, including effects on signalosomes, tensegrity, or direct activation (or inactivation) of enzymes. Striated muscles, including cardiac myocytes, differ from other cells in that they contain sarcomeres which are essential for the generation of forces and which play additional roles in mechanosensation. The majority of cardiomyopathy causing candidate genes encode structural proteins among which titin probably is the most important one. Due to its elastic elements, titin is a length sensor and also plays a role as a tension sensor (i.e., stress sensation). The recent discovery of titin mutations being a major cause of dilated cardiomyopathy (DCM) also underpins the importance of mechanosensation and mechanotransduction in the pathogenesis of heart failure. Here, we focus on sarcomere-related mechanisms, discuss recent findings, and provide a link to cardiomyopathy and associated heart failure.
Topics: Animals; Heart Failure; Humans; Mechanotransduction, Cellular; Muscle Proteins; Sarcomeres
PubMed: 24531746
DOI: 10.1007/s00424-014-1468-4 -
Heart Failure Clinics Apr 2018Sarcomere cardiomyopathies are genetic diseases that perturb contractile function and lead to hypertrophic or dilated myocardial remodeling. Identification of... (Review)
Review
Sarcomere cardiomyopathies are genetic diseases that perturb contractile function and lead to hypertrophic or dilated myocardial remodeling. Identification of preclinical mutation carriers has yielded insights into the earliest biomechanical defects that link pathogenic variants to cardiac dysfunction. Understanding this early molecular pathophysiology can illuminate modifiable pathways to reduce the emergence of overt cardiomyopathy and curb adverse outcomes. Here, the authors review current understandings of how human hypertrophic cardiomyopathy- and hypertrophic dilated cardiomyopathy-linked mutations disrupt the normal structure and function of the sarcomere.
Topics: Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Humans; Sarcomeres
PubMed: 29525643
DOI: 10.1016/j.hfc.2017.12.004 -
Physiological Reviews Jan 2019The sarcomeric proteins represent the structural building blocks of heart muscle, which are essential for contraction and relaxation. During recent years, it has become... (Review)
Review
The sarcomeric proteins represent the structural building blocks of heart muscle, which are essential for contraction and relaxation. During recent years, it has become evident that posttranslational modifications of sarcomeric proteins, in particular phosphorylation, tune cardiac pump function at rest and during exercise. This delicate, orchestrated interaction is also influenced by mutations, predominantly in sarcomeric proteins, which cause hypertrophic or dilated cardiomyopathy. In this review, we follow a bottom-up approach starting from a description of the basic components of cardiac muscle at the molecular level up to the various forms of cardiac disorders at the organ level. An overview is given of sarcomere changes in acquired and inherited forms of cardiac disease and the underlying disease mechanisms with particular reference to human tissue. A distinction will be made between the primary defect and maladaptive/adaptive secondary changes. Techniques used to unravel functional consequences of disease-induced protein changes are described, and an overview of current and future treatments targeted at sarcomeric proteins is given. The current evidence presented suggests that sarcomeres not only form the basis of cardiac muscle function but also represent a therapeutic target to combat cardiac disease.
Topics: Animals; Carrier Proteins; Heart Diseases; Humans; Mutation; Myocardium; Phosphorylation; Sarcomeres
PubMed: 30379622
DOI: 10.1152/physrev.00040.2017 -
Circulation Research Jan 2013Oxidative stress accompanies a wide spectrum of clinically important cardiac disorders, including ischemia/reperfusion, diabetes mellitus, and hypertensive heart... (Review)
Review
Oxidative stress accompanies a wide spectrum of clinically important cardiac disorders, including ischemia/reperfusion, diabetes mellitus, and hypertensive heart disease. Although reactive oxygen species (ROS) can activate signaling pathways that contribute to ischemic preconditioning and cardioprotection, high levels of ROS induce structural modifications of the sarcomere that impact on pump function and the pathogenesis of heart failure. However, the precise nature of the redox-dependent change in contractility is determined by the source/identity of the oxidant species, the level of oxidative stress, and the chemistry/position of oxidant-induced posttranslational modifications on individual proteins within the sarcomere. This review focuses on various ROS-induced posttranslational modifications of myofilament proteins (including direct oxidative modifications of myofilament proteins, myofilament protein phosphorylation by ROS-activated signaling enzymes, and myofilament protein cleavage by ROS-activated proteases) that have been implicated in the control of cardiac contractility.
Topics: Animals; Humans; Oxidative Stress; Protein Kinases; Reactive Oxygen Species; Sarcomeres; Troponin C
PubMed: 23329794
DOI: 10.1161/CIRCRESAHA.111.300496 -
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 -
Advances in Experimental Medicine and... 2010The single muscle fiber preparation provides an excellent tool for studying the mechanical behaviour of the contractile system at sarcomere level. The present article... (Review)
Review
The single muscle fiber preparation provides an excellent tool for studying the mechanical behaviour of the contractile system at sarcomere level. The present article gives an overview of studies based on intact single fibers from frog and mouse skeletal muscle. The following aspects of muscle function are treated: (1) The length-tension relationship. (2) The biphasic force-velocity relationship. (3) The maximum speed of shortening, its independence of sarcomere length and degree of activation. (4) Force enhancement during stretch, its relation to sarcomere length and myofilament lattice width. (5) Residual force enhancement after stretch. (6) Force reduction after loaded shortening. (7) Deactivation by active shortening. (8) Differences in kinetic properties along individual muscle fibers.
Topics: Animals; Kinetics; Mice; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Striated; Myosins; Phosphorylation; Sarcomeres; Stress, Mechanical
PubMed: 20824518
DOI: 10.1007/978-1-4419-6366-6_2