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Archives of Biochemistry and Biophysics Oct 2021
Topics: Deoxyadenine Nucleotides; Heart; Models, Theoretical; Movement; Muscle Contraction; Myocardium; Myosins; Sarcomeres
PubMed: 34174221
DOI: 10.1016/j.abb.2021.108979 -
Cellular and Molecular Life Sciences :... Oct 2017Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to... (Review)
Review
Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. Current literature clearly shows that hPSC-CMs recapitulate many molecular, cellular, and functional aspects of human heart pathophysiology and their responses to cardioactive drugs. Here, we provide a comprehensive overview of hPSC-CMs models that have been described to date and highlight their most recent and remarkable contributions to research on cardiovascular diseases and disorders with cardiac traits. We conclude discussing immediate challenges, limitations, and emerging solutions.
Topics: Calcium; Cell Differentiation; Heart Diseases; Humans; Metabolome; Mitochondria; Mutation; Myocytes, Cardiac; Pluripotent Stem Cells; Sarcomeres
PubMed: 28573431
DOI: 10.1007/s00018-017-2546-5 -
Journal of Molecular and Cellular... Feb 2016
Topics: Animals; Biomechanical Phenomena; Calcium; Elasticity; Heart Ventricles; Humans; Myocardial Contraction; Myocardium; Sarcomeres; Stress, Mechanical; Stroke Volume
PubMed: 26678623
DOI: 10.1016/j.yjmcc.2015.12.006 -
Nature Communications Oct 2022Sustained muscle contraction occurs through interactions between actin and myosin filaments within sarcomeres and requires a constant supply of adenosine triphosphate...
Sustained muscle contraction occurs through interactions between actin and myosin filaments within sarcomeres and requires a constant supply of adenosine triphosphate (ATP) from nearby mitochondria. However, it remains unclear how different physical configurations between sarcomeres and mitochondria alter the energetic support for contractile function. Here, we show that sarcomere cross-sectional area (CSA) varies along its length in a cell type-dependent manner where the reduction in Z-disk CSA relative to the sarcomere center is closely coordinated with mitochondrial network configuration in flies, mice, and humans. Further, we find myosin filaments near the sarcomere periphery are curved relative to interior filaments with greater curvature for filaments near mitochondria compared to sarcoplasmic reticulum. Finally, we demonstrate variable myosin filament lattice spacing between filament ends and filament centers in a cell type-dependent manner. These data suggest both sarcomere structure and myofilament interactions are influenced by the location and orientation of mitochondria within muscle cells.
Topics: Actins; Adenosine Triphosphate; Animals; Humans; Mice; Mitochondria; Muscle Contraction; Muscle, Striated; Myosins; Sarcomeres
PubMed: 36229433
DOI: 10.1038/s41467-022-33678-y -
Journal of Genetics and Genomics = Yi... Mar 2021Skeletal and cardiac muscles are striated myofibers that contain highly organized sarcomeres for muscle contraction. Recent studies revealed that Smyd1, a lysine...
Skeletal and cardiac muscles are striated myofibers that contain highly organized sarcomeres for muscle contraction. Recent studies revealed that Smyd1, a lysine methyltransferase, plays a key role in sarcomere assembly in heart and trunk skeletal muscles. However, Smyd1 expression and function in craniofacial muscles are not known. Here, we analyze the developmental expression and function of two smyd1 paralogous genes, smyd1a and smyd1b, in craniofacial and cardiac muscles of zebrafish embryos. Our data show that loss of smyd1a (smyd1a) or smyd1b (smyd1b) has no visible effects on myogenic commitment and expression of myod and myosin heavy-chain mRNA transcripts in craniofacial muscles. However, myosin heavy-chain protein accumulation and sarcomere organization are dramatically reduced in smyd1b single mutant, and almost completely diminish in smyd1a; smyd1b double mutant, but not in smyd1a mutant. Similar defects are also observed in cardiac muscles of smyd1b mutant. Defective craniofacial and cardiac muscle formation is associated with an upregulation of hsp90α1 and unc45b mRNA expression in smyd1b and smyd1a; smyd1b mutants. Together, our studies indicate that Smyd1b, but not Smyd1a, plays a key role in myosin heavy-chain protein expression and sarcomere organization in craniofacial and cardiac muscles. Loss of smyd1b results in muscle-specific stress response.
Topics: Animals; Myocardium; Myosins; Sarcomeres; Zebrafish
PubMed: 33958316
DOI: 10.1016/j.jgg.2021.03.004 -
Journal of Muscle Research and Cell... Jun 2021Appropriate organization of cytoskeletal components are required for normal distribution and intracellular localization of different ion channels and proteins involved... (Review)
Review
Appropriate organization of cytoskeletal components are required for normal distribution and intracellular localization of different ion channels and proteins involved in calcium homeostasis, signal transduction, and contractile function of striated muscle. Proteins of the contractile system are in direct or indirect connection with the extrasarcomeric cytoskeleton. A number of other molecules which have essential role in regulating stretch-, voltage-, and chemical signal transduction from the surface into the cytoplasm or other intracellular compartments are already well characterized. Sarcomere, the basic contractile unit, is comprised of a precisely organized system of thin (actin), and thick (myosin) filaments. Intermediate filaments connect the sarcomeres and other organelles (mitochondria and nucleus), and are responsible for the cellular integrity. Interacting proteins have a very diverse function in coupling of the intracellular assembly components and regulating the normal physiological function. Despite the more and more intense investigations of a new cytoskeletal protein family, the septins, only limited information is available regarding their expression and role in striated, especially in skeletal muscles. In this review we collected basic and specified knowledge regarding this protein group and emphasize the importance of this emerging field in skeletal muscle biology.
Topics: Cytoskeleton; Muscle, Skeletal; Muscle, Striated; Sarcomeres; Septins
PubMed: 31955380
DOI: 10.1007/s10974-020-09573-8 -
Journal of Neuroengineering and... Sep 2017Skeletal muscle mechanics have been studied ever since people have shown an interest in human movement. However, our understanding of muscle contraction and muscle... (Review)
Review
Skeletal muscle mechanics have been studied ever since people have shown an interest in human movement. However, our understanding of muscle contraction and muscle mechanical properties has changed fundamentally with the discovery of the sliding filament theory in 1954 and associated cross-bridge theory in 1957. Nevertheless, experimental evidence suggests that our knowledge of the mechanisms of contraction is far from complete, and muscle properties and muscle function in human movement remain largely unknown.In this manuscript, I am trying to identify some of the crucial challenges we are faced with in muscle mechanics, offer possible solutions to questions, and identify problems that might be worthwhile exploring in the future. Since it is impossible to tackle all (worthwhile) problems in a single manuscript, I identified three problems that are controversial, important, and close to my heart. They may be identified as follows: (i) mechanisms of muscle contraction, (ii) in vivo whole muscle mechanics and properties, and (iii) force-sharing among synergistic muscles. These topics are fundamental to our understanding of human movement and movement control, and they contain a series of unknowns and challenges to be explored in the future.It is my hope that this paper may serve as an inspiration for some, may challenge current beliefs in selected areas, tackle important problems in the area of muscle mechanics, physiology and movement control, and may guide and focus some of the thinking of future muscle mechanics research.
Topics: Animals; Biomechanical Phenomena; Cytoskeleton; Humans; Models, Biological; Muscle Contraction; Muscle, Skeletal; Sarcomeres
PubMed: 28915834
DOI: 10.1186/s12984-017-0310-6 -
Cell Reports Aug 2021Decreased ability to maintain tissue integrity is critically involved in aging and degenerative diseases. Fatty acid (FA) metabolism has a profound impact on animal...
Decreased ability to maintain tissue integrity is critically involved in aging and degenerative diseases. Fatty acid (FA) metabolism has a profound impact on animal development and tissue maintenance, but our understanding of the underlying mechanisms is limited. We investigated whether and how FA abundance affects muscle integrity using Caenorhabditis elegans. We show that reducing the overall FA level by blocking FA biosynthesis or inhibiting protein myristoylation leads to disorganization of sarcomere structure and adult-onset paralysis. Further analysis indicates that myristoylation of two ARF guanosine triphosphatases (GTPases) critically mediates the effect of FA deficiency on sarcomere integrity through inducing endoplasmic reticulum (ER) stress and ER unfolded protein response (UPR), which in turn leads to reduction of the level of sarcomere component PINCH and myosin disorganization. We thus present a mechanism that links FA signal, protein myristoylation, and ER homeostasis with muscle integrity, which provides valuable insights into the regulatory role of nutrients and ER homeostasis in muscle maintenance.
Topics: Animals; Biosynthetic Pathways; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Fatty Acids; Homeostasis; Movement; Muscles; Myosins; Myristic Acid; Phosphorylation; Sarcomeres
PubMed: 34407398
DOI: 10.1016/j.celrep.2021.109539 -
Pflugers Archiv : European Journal of... May 2019Mutations in genes encoding sarcomeric proteins are the most important causes of inherited cardiomyopathies, which are a major cause of mortality and morbidity... (Review)
Review
Mutations in genes encoding sarcomeric proteins are the most important causes of inherited cardiomyopathies, which are a major cause of mortality and morbidity worldwide. Although genetic screening procedures for early disease detection have been improved significantly, treatment to prevent or delay mutation-induced cardiac disease onset is lacking. Recent findings indicate that loss of protein quality control (PQC) is a central factor in the disease pathology leading to derailment of cellular protein homeostasis. Loss of PQC includes impairment of heat shock proteins, the ubiquitin-proteasome system, and autophagy. This may result in accumulation of misfolded and aggregation-prone mutant proteins, loss of sarcomeric and cytoskeletal proteins, and, ultimately, loss of cardiac function. PQC derailment can be a direct effect of the mutation-induced activation, a compensatory mechanism due to mutation-induced cellular dysfunction or a consequence of the simultaneous occurrence of the mutation and a secondary hit. In this review, we discuss recent mechanistic findings on the role of proteostasis derailment in inherited cardiomyopathies, with special focus on sarcomeric gene mutations and possible therapeutic applications.
Topics: Animals; Cardiomyopathies; Humans; Mutation; Proteolysis; Proteostasis; Sarcomeres; Ubiquitination
PubMed: 30109411
DOI: 10.1007/s00424-018-2194-0 -
The American Journal of Cardiology Feb 2024Genetic testing is an important tool in the diagnosis and management of patients and families with hypertrophic cardiomyopathy (HCM). Modern testing can identify...
Genetic testing is an important tool in the diagnosis and management of patients and families with hypertrophic cardiomyopathy (HCM). Modern testing can identify causative variants in 30 to >60% of patients, with probability of a positive test varying with baseline characteristics such as known family history of HCM. Patients diagnosed with HCM should be offered genetic counseling and genetic testing as appropriate. Standard multigene panels evaluate sarcomeric genes known to cause HCM as well as genetic conditions that can mimic HCM but require different management. Positive genetic testing (finding a pathogenic or likely pathogenic variant) helps to clarify diagnosis and assists in family screening. If there is high confidence that an identified variant is the cause of HCM, at-risk family members can pursue predictive testing to determine if they are truly at risk or if they can be dismissed from serial screening based on whether they inherited the family's causative variant. Interpreting test results can be complex, and providers should make use of multidisciplinary teams as well as evidence-based resources to obtain the best possible understanding of pathogenicity.
Topics: Humans; Genetic Testing; Cardiomyopathy, Hypertrophic; Genetic Counseling; Family; Sarcomeres; Mutation
PubMed: 38368035
DOI: 10.1016/j.amjcard.2023.10.032