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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 -
Methods in Molecular Biology (Clifton,... 2024Concerted atomic motions are requisite for sarcomere protein function and may become disrupted in HCM pathologies. Computational approaches such as molecular dynamics...
Concerted atomic motions are requisite for sarcomere protein function and may become disrupted in HCM pathologies. Computational approaches such as molecular dynamics simulation can resolve such dynamics with unrivalled spatial and temporal resolution. This chapter describes methods to model structural and dynamical changes in biomolecules with HCM-associated perturbations.
Topics: Sarcomeres; Proteins; Molecular Dynamics Simulation; Motion
PubMed: 38038842
DOI: 10.1007/978-1-0716-3527-8_3 -
The Journal of Clinical Investigation Feb 2020KBTBD13 is a protein expressed in striated muscle whose precise function is unknown. Work by de Winter et al. in this issue of the JCI provides evidence that KBTBD13...
KBTBD13 is a protein expressed in striated muscle whose precise function is unknown. Work by de Winter et al. in this issue of the JCI provides evidence that KBTBD13 localizes to the sarcomere and can directly bind actin. A mutation in KBTBD13 that is associated with nemaline myopathy alters the protein's effects on actin, apparently increasing thin-filament stiffness and ultimately depressing contractile force and relaxation rate. We discuss here the implications of this new sarcomeric protein, some alternate explanations for the effects of KBTBD13R408C, and the advantages of using computational models to interpret functional data from muscle.
Topics: Actins; Humans; Kinetics; Microfilament Proteins; Muscle Proteins; Muscle, Skeletal; Myopathies, Nemaline; Sarcomeres
PubMed: 31904591
DOI: 10.1172/JCI132954 -
American Journal of Physiology. Heart... Mar 2024The molecular mechanisms of sarcomere proteins underlie the contractile function of the heart. Although our understanding of the sarcomere has grown tremendously, the... (Review)
Review
The molecular mechanisms of sarcomere proteins underlie the contractile function of the heart. Although our understanding of the sarcomere has grown tremendously, the focus has been on ventricular sarcomere isoforms due to the critical role of the ventricle in health and disease. However, atrial-specific or -enriched myofilament protein isoforms, as well as isoforms that become expressed in disease, provide insight into ways this complex molecular machine is fine-tuned. Here, we explore how atrial-enriched sarcomere protein composition modulates contractile function to fulfill the physiological requirements of atrial function. We review how atrial dysfunction negatively affects the ventricle and the many cardiovascular diseases that have atrial dysfunction as a comorbidity. We also cover the pathophysiology of mutations in atrial-enriched contractile proteins and how they can cause primary atrial myopathies. Finally, we explore what is known about contractile function in various forms of atrial fibrillation. The differences in atrial function in health and disease underscore the importance of better studying atrial contractility, especially as therapeutics currently in development to modulate cardiac contractility may have different effects on atrial sarcomere function.
Topics: Sarcomeres; Myofibrils; Heart Atria; Atrial Function; Myocardial Contraction; Protein Isoforms
PubMed: 38156887
DOI: 10.1152/ajpheart.00252.2023 -
Journal of the American Heart... Aug 2021Background Sarcomere gene mutations lead to cardiomyocyte hypertrophy and pathological myocardial remodeling. However, there is considerable phenotypic heterogeneity at...
Background Sarcomere gene mutations lead to cardiomyocyte hypertrophy and pathological myocardial remodeling. However, there is considerable phenotypic heterogeneity at both the cellular and the organ level, suggesting modifiers regulate the effects of these mutations. We hypothesized that sarcomere dysfunction leads to cardiomyocyte genotoxic stress, and this modifies pathological ventricular remodeling. Methods and Results Using a murine model deficient in the sarcomere protein, Mybpc3 (cardiac myosin-binding protein 3), we discovered that there was a surge in cardiomyocyte nuclear DNA damage during the earliest stages of cardiomyopathy. This was accompanied by a selective increase in ataxia telangiectasia and rad3-related phosphorylation and increased p53 protein accumulation. The cause of the DNA damage and DNA damage pathway activation was dysregulated cardiomyocyte DNA synthesis, leading to replication stress. We discovered that selective inhibition of ataxia telangiectasia and rad3 related or cardiomyocyte deletion of p53 reduced pathological left ventricular remodeling and cardiomyocyte hypertrophy in Mybpc3 animals. Mice and humans harboring other types of sarcomere gene mutations also had evidence of activation of the replication stress response, and this was associated with cardiomyocyte aneuploidy in all models studied. Conclusions Collectively, our results show that sarcomere mutations lead to activation of the cardiomyocyte replication stress response, which modifies pathological myocardial remodeling in sarcomeric cardiomyopathy.
Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Cardiac Myosins; Cardiomyopathies; Carrier Proteins; DNA Damage; Disease Models, Animal; Mice; Mice, Knockout; Mutation; Myocytes, Cardiac; Sarcomeres; Ventricular Remodeling
PubMed: 34323119
DOI: 10.1161/JAHA.121.021768 -
International Journal of Molecular... Dec 2019Mutations in sarcomere genes can cause both hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). However, the complex genotype-phenotype relationships in... (Review)
Review
Mutations in sarcomere genes can cause both hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). However, the complex genotype-phenotype relationships in pathophysiology of cardiomyopathies by gene or mutation location are not fully understood. In addition, it is still unclear how mutations within same molecule result in different clinical phenotypes such as HCM and DCM. To clarify how the initial functional insult caused by a subtle change in one protein component of the sarcomere with a given mutation is critical for the development of proper effective treatments for cardiomyopathies. Fortunately, recent technological advances and the development of direct sarcomere modulators have provided a more detailed understanding of the molecular mechanisms that govern the effects of specific mutations. The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM. On the other hand, direct activation of sarcomere contractility appears to exert unexpected beneficial effects such as reverse remodeling and lower heart rate without increasing adverse cardiovascular events in patients with systolic heart failure due to DCM. Direct sarcomere modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
Topics: Animals; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Cardiovascular Agents; Humans; Myocardial Contraction; Myosins; Sarcomeres
PubMed: 31905684
DOI: 10.3390/ijms21010226 -
International Journal of Molecular... Feb 2022Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac... (Review)
Review
Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. The clinical course exhibits appreciable variability. However, typically, heart morphology and function are normal at birth, with pathological remodeling developing over years to decades, leading to a phenotype characterized by asymmetric ventricular hypertrophy, scattered fibrosis and myofibrillar/cellular disarray with ultimate mechanical heart failure and/or severe arrhythmias. The identity of the primary mutation-induced changes in sarcomere function and how they trigger debilitating remodeling are poorly understood. Support for the importance of mutation-induced hypercontractility, e.g., increased calcium sensitivity and/or increased power output, has been strengthened in recent years. However, other ideas that mutation-induced hypocontractility or non-uniformities with contractile instabilities, instead, constitute primary triggers cannot yet be discarded. Here, we review evidence for and criticism against the mentioned hypotheses. In this process, we find support for previous ideas that inefficient energy usage and a blunted Frank-Starling mechanism have central roles in pathogenesis, although presumably representing effects secondary to the primary mutation-induced changes. While first trying to reconcile apparently diverging evidence for the different hypotheses in one unified model, we also identify key remaining questions and suggest how experimental systems that are built around isolated primarily expressed proteins could be useful.
Topics: Adolescent; Cardiomyopathy, Hypertrophic; Death, Sudden, Cardiac; Humans; Mutation; Phenotype; Sarcomeres
PubMed: 35216312
DOI: 10.3390/ijms23042195 -
International Journal of Molecular... Sep 2021Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in genes for sarcomeric proteins. Nowadays, the genetic basis of HCM is believed to be rather complex. Thousands of mutations in more than 60 genes have been described in association with HCM. Nevertheless, screening large numbers of genes results in the identification of many genetic variants of uncertain significance and makes the interpretation of the results difficult. Patients lacking a pathogenic variant are now believed to have non-Mendelian HCM and probably have a better prognosis than patients with sarcomeric pathogenic mutations. Identifying the genetic basis of HCM creates remarkable opportunities to understand how the disease develops, and by extension, how to disrupt the disease progression in the future. The aim of this review is to discuss the brief history and recent advances in the genetics of HCM and the application of molecular genetic testing into common clinical practice.
Topics: Cardiomyopathy, Hypertrophic; Genetic Testing; Humans; Muscle Proteins; Mutation; Sarcomeres
PubMed: 34638741
DOI: 10.3390/ijms221910401 -
Physiological Reports Mar 2021The force-length relation of the skeletal muscles is an important factor influencing the joint torque at a given joint angle. We aimed to clarify the relationship...
The force-length relation of the skeletal muscles is an important factor influencing the joint torque at a given joint angle. We aimed to clarify the relationship between the resting sarcomere length and knee joint angle in the vastus intermedius (VI) and to compare it with that of the vastus lateralis (VL). The left and right legs were fixed at knee joint angles of 0° and 90°, respectively, in seven cadavers (age at the time of death: 70-91 years). Muscle tissues were dissected by necropsy of the VL and the VI, and electron microscopy images were obtained to calculate the sarcomere length. At knee joint angles of 0° and 90°, the VL sarcomere length was 2.28 ± 0.49 μm and 2.30 ± 0.48 μm, respectively, and the VI sarcomere length was 2.19 ± 0.35 μm and 2.46 ± 0.53 μm, respectively, with a significant difference between the two (p = 0.028). The magnitude of sarcomere length changes with knee joint angle changes was significantly greater for the VI (0.27 ± 0.20 μm) than for the VL (0.02 ± 0.09 μm) (p = 0.009). Thus, knee joint angle changes may affect the passive and active tension produced by the VI more than those produced by the VL.
Topics: Biomechanical Phenomena; Cadaver; Humans; Knee Joint; Muscle Contraction; Muscle, Skeletal; Quadriceps Muscle; Range of Motion, Articular; Sarcomeres
PubMed: 33650805
DOI: 10.14814/phy2.14771