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Nature Reviews. Cardiology Jun 2022Variants in >12 genes encoding sarcomeric proteins can cause various cardiomyopathies. The two most common are hypertrophic cardiomyopathy (HCM) and dilated... (Review)
Review
Variants in >12 genes encoding sarcomeric proteins can cause various cardiomyopathies. The two most common are hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Current therapeutics do not target the root causes of these diseases, but attempt to prevent disease progression and/or to manage symptoms. Accordingly, novel approaches are being developed to treat the cardiac muscle dysfunction directly. Challenges to developing therapeutics for these diseases include the diverse mechanisms of pathogenesis, some of which are still being debated and defined. Four small molecules that modulate the myosin motor protein in the cardiac sarcomere have shown great promise in the settings of HCM and DCM, regardless of the underlying genetic pathogenesis, and similar approaches are being developed to target other components of the sarcomere. In the setting of HCM, mavacamten and aficamten bind to the myosin motor and decrease the ATPase activity of myosin. In the setting of DCM, omecamtiv mecarbil and danicamtiv increase myosin activity in cardiac muscle (but omecamtiv mecarbil decreases myosin activity in vitro). In this Review, we discuss the therapeutic strategies to alter sarcomere contractile activity and summarize the data indicating that targeting one protein in the sarcomere can be effective in treating patients with genetic variants in other sarcomeric proteins, as well as in patients with non-sarcomere-based disease.
Topics: Cardiomyopathies; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Humans; Mutation; Myocardium; Myosins; Sarcomeres
PubMed: 35304599
DOI: 10.1038/s41569-022-00682-0 -
Current Cardiology Reports Jun 2022The lack of adult human cardiomyocyte proliferative capacity impairs cardiac regeneration such as after myocardial injury. The sarcomere, a specialized actin... (Review)
Review
PURPOSE OF REVIEW
The lack of adult human cardiomyocyte proliferative capacity impairs cardiac regeneration such as after myocardial injury. The sarcomere, a specialized actin cytoskeletal structure that is essential for twitch contraction in cardiomyocytes, has been considered a critical factor limiting adult human cardiomyocyte proliferation through incompletely understood mechanisms.
RECENT FINDINGS
This review summarizes known and emerging regulatory mechanisms connecting the human cardiomyocyte sarcomere to cell cycle regulation including structural and signaling mechanisms. Cardiac regeneration could be augmented through targeting the inhibitory effects of the sarcomere on cardiomyocyte proliferation.
Topics: Cell Cycle; Cell Proliferation; Heart; Humans; Myocytes, Cardiac; Regeneration; Sarcomeres; Signal Transduction
PubMed: 35380383
DOI: 10.1007/s11886-022-01682-9 -
Cell Apr 2021Sarcomeres are force-generating and load-bearing devices of muscles. A precise molecular picture of how sarcomeres are built underpins understanding their role in health...
Sarcomeres are force-generating and load-bearing devices of muscles. A precise molecular picture of how sarcomeres are built underpins understanding their role in health and disease. Here, we determine the molecular architecture of native vertebrate skeletal sarcomeres by electron cryo-tomography. Our reconstruction reveals molecular details of the three-dimensional organization and interaction of actin and myosin in the A-band, I-band, and Z-disc and demonstrates that α-actinin cross-links antiparallel actin filaments by forming doublets with 6-nm spacing. Structures of myosin, tropomyosin, and actin at ~10 Å further reveal two conformations of the "double-head" myosin, where the flexible orientation of the lever arm and light chains enable myosin not only to interact with the same actin filament, but also to split between two actin filaments. Our results provide unexpected insights into the fundamental organization of vertebrate skeletal muscle and serve as a strong foundation for future investigations of muscle diseases.
Topics: Actin Cytoskeleton; Actinin; Actomyosin; Animals; Cryoelectron Microscopy; Female; Mice; Mice, Inbred BALB C; Models, Molecular; Muscle, Skeletal; Protein Binding; Sarcomeres; Tropomyosin
PubMed: 33765442
DOI: 10.1016/j.cell.2021.02.047 -
Current Cardiology Reports Jun 2023The pace of identifying cardiomyopathy-associated mutations and advances in our understanding of sarcomere function that underlies many cardiomyopathies has been... (Review)
Review
PURPOSE OF REVIEW
The pace of identifying cardiomyopathy-associated mutations and advances in our understanding of sarcomere function that underlies many cardiomyopathies has been remarkable. Here, we aim to synthesize how these advances have led to the promising new treatments that are being developed to treat cardiomyopathies.
RECENT FINDINGS
The genomics era has identified and validated many genetic causes of hypertrophic and dilated cardiomyopathies. Recent advances in our mechanistic understanding of sarcomere pathophysiology include high-resolution molecular models of sarcomere components and the identification of the myosin super-relaxed state. The advances in our understanding of sarcomere function have yielded several therapeutic agents that are now in development and clinical use to correct contractile dysfunction-mediated cardiomyopathy. New genes linked to cardiomyopathy include targets with limited clinical evidence and require additional investigation. Large portions of cardiomyopathy with family history remain genetically undiagnosed and may be due to polygenic disease.
Topics: Humans; Cardiomyopathy, Hypertrophic; Sarcomeres; Cardiomyopathies; Cardiomyopathy, Dilated; Mutation
PubMed: 37060436
DOI: 10.1007/s11886-023-01876-9 -
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 -
Journal of Neuromuscular Diseases 2017Nemaline myopathy (NM) is among the most common non-dystrophic congenital myopathies (incidence 1:50.000). Hallmark features of NM are skeletal muscle weakness and the... (Review)
Review
Nemaline myopathy (NM) is among the most common non-dystrophic congenital myopathies (incidence 1:50.000). Hallmark features of NM are skeletal muscle weakness and the presence of nemaline bodies in the muscle fiber. The clinical phenotype of NM patients is quite diverse, ranging from neonatal death to normal lifespan with almost normal motor function. As the respiratory muscles are involved as well, severely affected patients are ventilator-dependent. The mechanisms underlying muscle weakness in NM are currently poorly understood. Therefore, no therapeutic treatment is available yet.Eleven implicated genes have been identified: ten genes encode proteins that are either components of thin filament, or are thought to contribute to stability or turnover of thin filament proteins. The thin filament is a major constituent of the sarcomere, the smallest contractile unit in muscle. It is at this level of contraction - thin-thick filament interaction - where muscle weakness originates in NM patients.This review focusses on how sarcomeric gene mutations directly compromise sarcomere function in NM. Insight into the contribution of sarcomeric dysfunction to muscle weakness in NM, across the genes involved, will direct towards the development of targeted therapeutic strategies.
Topics: Animals; Humans; Myopathies, Nemaline; Sarcomeres
PubMed: 28436394
DOI: 10.3233/JND-160200 -
Circulation Jun 2021
Review
Topics: Cardiomyopathy, Hypertrophic; Genetic Testing; Humans; Sarcomeres
PubMed: 34152793
DOI: 10.1161/CIRCULATIONAHA.121.053527 -
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 -
Comprehensive Physiology Jun 2017Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere,... (Review)
Review
Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease. © 2017 American Physiological Society. Compr Physiol 7:891-944, 2017.
Topics: Actins; Animals; Cytoskeleton; Humans; Muscle Contraction; Myosins; Sarcomeres
PubMed: 28640448
DOI: 10.1002/cphy.c160033 -
Philosophical Transactions of the Royal... May 2011Skeletal muscles are length- and velocity-sensitive force producers, constructed of a vast array of sarcomeres. Muscles come in a variety of sizes and shapes to... (Review)
Review
Skeletal muscles are length- and velocity-sensitive force producers, constructed of a vast array of sarcomeres. Muscles come in a variety of sizes and shapes to accomplish a wide variety of tasks. How does muscle design match task performance? In this review, we outline muscle's basic properties and strategies that are used to produce movement. Several examples are provided, primarily for human muscles, in which skeletal muscle architecture and moment arms are tailored to a particular performance requirement. In addition, the concept that muscles may have a preferred sarcomere length operating range is also introduced. Taken together, the case is made that muscles can be fine-tuned to perform specific tasks that require actuators with a wide range of properties.
Topics: Biomechanical Phenomena; Humans; Magnetic Resonance Imaging; Muscle Contraction; Muscle, Skeletal; Sarcomeres
PubMed: 21502118
DOI: 10.1098/rstb.2010.0316