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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 -
Circulation Research Jun 2022Heart development relies on tight spatiotemporal control of cardiac gene expression. Genes involved in this intricate process have been identified using animals and...
BACKGROUND
Heart development relies on tight spatiotemporal control of cardiac gene expression. Genes involved in this intricate process have been identified using animals and pluripotent stem cell-based models of cardio(myo)genesis. Recently, the repertoire of cardiomyocyte differentiation models has been expanded with iAM-1, a monoclonal line of conditionally immortalized neonatal rat atrial myocytes (NRAMs), which allows toggling between proliferative and differentiated (ie, excitable and contractile) phenotypes in a synchronized and homogenous manner.
METHODS
In this study, the unique properties of conditionally immortalized NRAMs (iAMs) were exploited to identify and characterize (lowly expressed) genes with an as-of-yet uncharacterized role in cardiomyocyte differentiation.
RESULTS
Transcriptome analysis of iAM-1 cells at different stages during one cycle of differentiation and subsequent dedifferentiation identified ≈13 000 transcripts, of which the dynamic changes in expression upon cardiomyogenic differentiation mostly opposed those during dedifferentiation. Among the genes whose expression increased during differentiation and decreased during dedifferentiation were many with known (lineage-specific) functions in cardiac muscle formation. Filtering for cardiac-enriched low-abundance transcripts, identified multiple genes with an uncharacterized role during cardio(myo)genesis including Sbk2 (SH3 domain binding kinase family member 2). Sbk2 encodes an evolutionarily conserved putative serine/threonine protein kinase, whose expression is strongly up- and downregulated during iAM-1 cell differentiation and dedifferentiation, respectively. In neonatal and adult rats, the protein is muscle-specific, highly atrium-enriched, and localized around the A-band of cardiac sarcomeres. Knockdown of Sbk2 expression caused loss of sarcomeric organization in NRAMs, iAMs and their human counterparts, consistent with a decrease in sarcomeric gene expression as evinced by transcriptome and proteome analyses. Interestingly, co-immunoprecipitation using Sbk2 as bait identified possible interaction partners with diverse cellular functions (translation, intracellular trafficking, cytoskeletal organization, chromatin modification, sarcomere formation).
CONCLUSIONS
iAM-1 cells are a relevant and suitable model to identify (lowly expressed) genes with a hitherto unidentified role in cardiomyocyte differentiation as exemplified by Sbk2: a regulator of atrial sarcomerogenesis.
Topics: Animals; Cell Differentiation; Heart Atria; Myocardium; Myocytes, Cardiac; Rats; Sarcomeres
PubMed: 35587025
DOI: 10.1161/CIRCRESAHA.121.319300 -
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 -
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 -
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... Aug 2021Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 people in the general population. Although characterized by... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 people in the general population. Although characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray, and cardiac fibrosis, HCM is in fact a highly complex disease with heterogenous clinical presentation, onset, and complications. While HCM is generally accepted as a disease of the sarcomere, variable penetrance in families with identical genetic mutations challenges the monogenic origin of HCM and instead implies a multifactorial cause. Furthermore, large-scale genome sequencing studies revealed that many genes previously reported as causative of HCM in fact have little or no evidence of disease association. These findings thus call for a re-evaluation of the sarcomere-centered view of HCM pathogenesis. Here, we summarize our current understanding of sarcomere-independent mechanisms of cardiomyocyte hypertrophy, highlight the role of extracellular signals in cardiac fibrosis, and propose an alternative but integrated model of HCM pathogenesis.
Topics: Cardiomyopathy, Hypertrophic; Genetic Predisposition to Disease; Humans; Phenotype; Sarcomeres
PubMed: 34445638
DOI: 10.3390/ijms22168933 -
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 -
Progress in Biophysics and Molecular... 2012The passive stiffness of cardiac muscle plays a critical role in ventricular filling during diastole and is determined by the extracellular matrix and the sarcomeric... (Review)
Review
The passive stiffness of cardiac muscle plays a critical role in ventricular filling during diastole and is determined by the extracellular matrix and the sarcomeric protein titin. Titin spans from the Z-disk to the M-band of the sarcomere and also contains a large extensible region that acts as a molecular spring and develops passive force during sarcomere stretch. This extensible segment is titin's I-band region, and its force-generating mechanical properties determine titin-based passive tension. The properties of titin's I-band region can be modulated by isoform splicing and post-translational modification and are intimately linked to diastolic function. This review discusses the physical origin of titin-based passive tension, the mechanisms that alter titin stiffness, and titin's role in stress-sensing signaling pathways.
Topics: Adaptation, Physiological; Animals; Connectin; Heart; Humans; Mechanical Phenomena; Sarcomeres; Signal Transduction
PubMed: 22910434
DOI: 10.1016/j.pbiomolbio.2012.08.003 -
Journal of Applied Physiology... Jul 2022Skeletal muscle has the remarkable ability to remodel and adapt, such as the increase in serial sarcomere number (SSN) or fascicle length (FL) observed after... (Review)
Review
Skeletal muscle has the remarkable ability to remodel and adapt, such as the increase in serial sarcomere number (SSN) or fascicle length (FL) observed after overstretching a muscle. This type of remodeling is termed longitudinal muscle fascicle growth, and its impact on biomechanical function has been of interest since the 1960s due to its clinical applications in muscle strain injury, muscle spasticity, and sarcopenia. Despite simplified hypotheses on how longitudinal muscle fascicle growth might influence mechanical function, existing literature presents conflicting results partly due to a breadth of methodologies. The purpose of this review is to outline what is currently known about the influence of longitudinal muscle fascicle growth on mechanical function and suggest future directions to address current knowledge gaps and methodological limitations. Various interventions indicate longitudinal muscle fascicle growth can increase the optimal muscle length for active force, but whether the whole force-length relationship widens has been less investigated. Future research should also explore the ability for longitudinal fascicle growth to broaden the torque-angle relationship's plateau region, and the relation to increased force during shortening. Without a concurrent increase in intramuscular collagen, longitudinal muscle fascicle growth also reduces passive tension at long muscle lengths; further research is required to understand whether this translates to increased joint range of motion. Finally, some evidence suggests longitudinal fascicle growth can increase maximum shortening velocity and peak isotonic power; however, there has yet to be direct assessment of these measures in a neurologically intact model of longitudinal muscle fascicle growth.
Topics: Biomechanical Phenomena; Humans; Muscle Spasticity; Muscle, Skeletal; Range of Motion, Articular; Sarcomeres; Torque
PubMed: 35608202
DOI: 10.1152/japplphysiol.00114.2022 -
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