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Comprehensive Physiology Mar 2017Striated cardiac and skeletal muscles play very different roles in the body, but they are similar at the molecular level. In particular, contraction, regardless of the... (Review)
Review
Striated cardiac and skeletal muscles play very different roles in the body, but they are similar at the molecular level. In particular, contraction, regardless of the type of muscle, is a precise and complex process involving the integral protein myofilaments and their associated regulatory components. The smallest functional unit of muscle contraction is the sarcomere. Within the sarcomere can be found a sophisticated ensemble of proteins associated with the thick filaments (myosin, myosin binding protein-C, titin, and obscurin) and thin myofilaments (actin, troponin, tropomyosin, nebulin, and nebulette). These parallel thick and thin filaments slide across one another, pulling the two ends of the sarcomere together to regulate contraction. More specifically, the regulation of both timing and force of contraction is accomplished through an intricate network of intra- and interfilament interactions belonging to each myofilament. This review introduces the sarcomere proteins involved in striated muscle contraction and places greater emphasis on the more recently identified and less well-characterized myofilaments: cardiac myosin binding protein-C, titin, nebulin, and obscurin. © 2017 American Physiological Society. Compr Physiol 7:675-692, 2017.
Topics: Connectin; Humans; Muscle Contraction; Muscle Proteins; Muscle, Skeletal; Myofibrils; Protein Serine-Threonine Kinases; Rho Guanine Nucleotide Exchange Factors; Sarcomeres; Troponin
PubMed: 28333386
DOI: 10.1002/cphy.c160026 -
Biophysical Journal Dec 2020The smallest contractile unit in striated muscles is the sarcomere. Although some of the classic features of contraction assume a uniform behavior of sarcomeres within... (Review)
Review
The smallest contractile unit in striated muscles is the sarcomere. Although some of the classic features of contraction assume a uniform behavior of sarcomeres within myofibrils, the occurrence of sarcomere length nonuniformities has been well recognized for years, but it is yet not well understood. In the past years, there has been a great advance in experiments using isolated myofibrils and sarcomeres that has allowed scientists to directly evaluate sarcomere length nonuniformity. This review will focus on studies conducted with these preparations to develop the hypotheses that 1) force production in myofibrils is largely altered and regulated by intersarcomere dynamics and that 2) the mechanical work of one sarcomere in a myofibril is transmitted to other sarcomeres in series. We evaluated studies looking into myofibril activation, relaxation, and force changes produced during activation. We conclude that force production in myofibrils is largely regulated by intersarcomere dynamics, which arises from the cooperative work of the contractile and elastic elements within a myofibril.
Topics: Mechanical Phenomena; Muscle Contraction; Muscle, Skeletal; Myofibrils; Sarcomeres
PubMed: 33217382
DOI: 10.1016/j.bpj.2020.11.005 -
Anatomical Record (Hoboken, N.J. : 2007) Sep 2014Mutations in sarcomere genes have been found in many inheritable human diseases, including hypertrophic cardiomyopathy. Elucidating the molecular mechanisms of sarcomere... (Review)
Review
Mutations in sarcomere genes have been found in many inheritable human diseases, including hypertrophic cardiomyopathy. Elucidating the molecular mechanisms of sarcomere assembly shall facilitate understanding of the pathogenesis of sarcomere-based cardiac disease. Recently, biochemical and genomic studies have identified many new genes encoding proteins that localize to the sarcomere. However, their precise functions in sarcomere assembly and sarcomere-based cardiac disease are unknown. Here, we review zebrafish as an emerging vertebrate model for these studies. We summarize the techniques offered by this animal model to manipulate genes of interest, annotate gene expression, and describe the resulting phenotypes. We survey the sarcomere genes that have been investigated in zebrafish and discuss the potential of applying this in vivo model for larger-scale genetic studies.
Topics: Animals; Animals, Genetically Modified; Genetic Predisposition to Disease; Genotype; Heart Diseases; Humans; Mutation; Myocytes, Cardiac; Phenotype; Risk Factors; Sarcomeres; Zebrafish; Zebrafish Proteins
PubMed: 25125181
DOI: 10.1002/ar.22975 -
The Journal of Experimental Biology Jan 2016Highly ordered organisation of striated muscle is the prerequisite for the fast and unidirectional development of force and motion during heart and skeletal muscle... (Review)
Review
Highly ordered organisation of striated muscle is the prerequisite for the fast and unidirectional development of force and motion during heart and skeletal muscle contraction. A group of proteins, summarised as the sarcomeric cytoskeleton, is essential for the ordered assembly of actin and myosin filaments into sarcomeres, by combining architectural, mechanical and signalling functions. This review discusses recent cell biological, biophysical and structural insight into the regulated assembly of sarcomeric cytoskeleton proteins and their roles in dissipating mechanical forces in order to maintain sarcomere integrity during passive extension and active contraction. α-Actinin crosslinks in the Z-disk show a pivot-and-rod structure that anchors both titin and actin filaments. In contrast, the myosin crosslinks formed by myomesin in the M-band are of a ball-and-spring type and may be crucial in providing stable yet elastic connections during active contractions, especially eccentric exercise.
Topics: Animals; Cytoskeleton; Humans; Models, Biological; Motion; Muscle Proteins; Sarcomeres
PubMed: 26792323
DOI: 10.1242/jeb.124941 -
Journal of Cellular Physiology Aug 2018The transmural heterogeneity of the contractility in ventricular muscle has not been well-studied. Here, we investigated the calcium transient and sarcomere...
The transmural heterogeneity of the contractility in ventricular muscle has not been well-studied. Here, we investigated the calcium transient and sarcomere contraction/relaxation in the endocardial (Endo) and epicardial (Epi) myocytes. Endo and Epi myocytes were isolated from C57/BL6 mice by Langendorff perfusion. Ca transient and sarcomere contraction/relaxation were recorded simultaneously at different stimulation frequencies using a dual excitation fluorescence photomultiplier system. We found that the Endo myocytes have higher baseline diastolic calcium, significantly larger calcium transient and stronger sarcomere shortening than Epi myocytes. However, both the rising and decline phases for calcium transient and sarcomere shortening were slower in Endo than in Epi myocytes. When simulation frequency was increased from 1 to 3 Hz, a greater percent increase in the diastole calcium level, Ca transient and sarcomere shortening amplitude has been observed in the Endo myocytes. Accordingly, the frequency-dependent acceleration in the decay rate of calcium transient and sarcomere relaxation was more profound in the Endo than in Epi myocytes. Western blot analysis showed that CaMKII activity was significantly higher in Epi than in Endo myocardium before stimulation. However, this transmural heterogeneity was reversed by rapid pacing. CaMKII inhibition by KN93 diminished the frequency-dependent alterations of Ca transient and sarcomere contraction. Our results suggest that the contractility of ventricular myocytes is heterogeneous. The Endo-myocardium is the major force generating layer in the heart, both at slow and fast heart rate, and the transmural heterogeneity of CaMKII activation plays an important role in the frequency-dependent alterations.
Topics: Animals; Calcium; Calcium Channels, L-Type; Calcium Signaling; Diastole; Heart Ventricles; Male; Mice; Mice, Inbred C57BL; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Sarcomeres
PubMed: 29528120
DOI: 10.1002/jcp.26512 -
International Journal of Molecular... Jul 2021Titin is a giant protein in the sarcomere that plays an essential role in muscle contraction with actin and myosin filaments. However, its utility goes beyond mechanical... (Review)
Review
Titin is a giant protein in the sarcomere that plays an essential role in muscle contraction with actin and myosin filaments. However, its utility goes beyond mechanical functions, extending to versatile and complex roles in sarcomere organization and maintenance, passive force, mechanosensing, and signaling. Titin's multiple functions are in part attributed to its large size and modular structures that interact with a myriad of protein partners. Among titin's domains, the N2A element is one of titin's unique segments that contributes to titin's functions in compliance, contraction, structural stability, and signaling via protein-protein interactions with actin filament, chaperones, stress-sensing proteins, and proteases. Considering the significance of N2A, this review highlights structural conformations of N2A, its predisposition for protein-protein interactions, and its multiple interacting protein partners that allow the modulation of titin's biological effects. Lastly, the nature of N2A for interactions with chaperones and proteases is included, presenting it as an important node that impacts titin's structural and functional integrity.
Topics: Animals; Connectin; Humans; Muscle, Skeletal; Protein Domains; Protein Interaction Domains and Motifs; Sarcomeres
PubMed: 34299183
DOI: 10.3390/ijms22147563 -
Acta Biomaterialia Mar 2019Dilated cardiomyopathy is a progressive irreversible disease associated with contractile dysfunction and heart failure. During dilated cardiomyopathy, elevated diastolic...
Dilated cardiomyopathy is a progressive irreversible disease associated with contractile dysfunction and heart failure. During dilated cardiomyopathy, elevated diastolic wall strains trigger mechanotransduction pathways that initiate the addition of sarcomeres in series and an overall increase in myocyte length. At the whole organ level, this results in a chronic dilation of the ventricles, an increase in end diastolic and end systolic volumes, and a decrease in ejection fraction. However, how exactly changes in sarcomere number translate into changes in myocyte morphology, and how these cellular changes translate into ventricular dilation remains incompletely understood. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. In an eight-week long volume overload study of six pigs, we found that the average sarcomere number increased by +3.8%/week, from 47 to 62, resulting in a myocyte lengthening of +3.3%/week, from 85 to 108 μm, while the sarcomere length and myocyte width remained unchanged. At the same time, the average end diastolic volume increased by +6.0%/week. Using continuum growth modeling and Bayesian inference, we correlated alterations on the subcellular, cellular, and organ scales and found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results demonstrate that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. We anticipate our study to be a starting point for more sophisticated multiscale models of heart failure. Our study suggests that altering sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse the progression of heart failure. STATEMENT OF SIGNIFICANCE: Heart failure is a significant global health problem that affects more than 25 million people worldwide and increases in prevalence as the population ages. Heart failure has been studied excessively at various scales; yet, there is no compelling concept to connect knowledge from the subcellular, cellular, and organ level across the scales. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. We found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results show that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. This suggests that altering the sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse heart failure.
Topics: Animals; Computer Simulation; Diastole; Female; Heart Failure; Heart Ventricles; Male; Muscle Cells; Sarcomeres; Swine; Systole
PubMed: 30630123
DOI: 10.1016/j.actbio.2018.12.053 -
Pathologie (Heidelberg, Germany) Mar 2023Muscle diseases include hereditary and acquired diseases with clinical manifestation in both childhood and adulthood. The different muscle diseases may have... (Review)
Review
Muscle diseases include hereditary and acquired diseases with clinical manifestation in both childhood and adulthood. The different muscle diseases may have ultrastructural alterations that help us further understand the pathology of the disease. Specific changes in sarcomere structure help to classify a congenital myopathy. The detection of cellular aggregates supports the classification of myositis. Pathologically altered mitochondria, on the other hand, can occur both in genetic mitochondriopathies but also secondarily in acquired muscle diseases like myositis. Ultrastructural analysis of the myocardium is also helpful in the diagnosis of hereditary cardiomyopathies in childhood. This review article highlights the ultrastructural features of different muscle diseases and pathognomonic findings in specific disease groups.
Topics: Humans; Muscular Diseases; Myositis; Myocardium; Sarcomeres
PubMed: 36459202
DOI: 10.1007/s00292-022-01163-4 -
Nature Nov 2023The thick filament is a key component of sarcomeres, the basic units of striated muscle. Alterations in thick filament proteins are associated with familial hypertrophic...
The thick filament is a key component of sarcomeres, the basic units of striated muscle. Alterations in thick filament proteins are associated with familial hypertrophic cardiomyopathy and other heart and muscle diseases. Despite the central importance of the thick filament, its molecular organization remains unclear. Here we present the molecular architecture of native cardiac sarcomeres in the relaxed state, determined by cryo-electron tomography. Our reconstruction of the thick filament reveals the three-dimensional organization of myosin, titin and myosin-binding protein C (MyBP-C). The arrangement of myosin molecules is dependent on their position along the filament, suggesting specialized capacities in terms of strain susceptibility and force generation. Three pairs of titin-α and titin-β chains run axially along the filament, intertwining with myosin tails and probably orchestrating the length-dependent activation of the sarcomere. Notably, whereas the three titin-α chains run along the entire length of the thick filament, titin-β chains do not. The structure also demonstrates that MyBP-C bridges thin and thick filaments, with its carboxy-terminal region binding to the myosin tails and directly stabilizing the OFF state of the myosin heads in an unforeseen manner. These results provide a foundation for future research investigating muscle disorders involving sarcomeric components.
Topics: Connectin; Cryoelectron Microscopy; Electron Microscope Tomography; Myocardium; Sarcomeres; Cardiac Myosins
PubMed: 37914933
DOI: 10.1038/s41586-023-06690-5 -
Journal of Applied Physiology... Jun 2019Passive force enhancement is defined as the increase in passive, steady-state, isometric force of an actively stretched muscle compared with the same muscle stretched... (Review)
Review
Passive force enhancement is defined as the increase in passive, steady-state, isometric force of an actively stretched muscle compared with the same muscle stretched passively to that same length. Passive force enhancement is long lasting, increases with increasing muscle length and increasing stretch magnitudes, contributes to the residual force enhancement in skeletal and cardiac muscle, and is typically only observed at muscle lengths at which passive forces occur naturally. Passive force enhancement is typically equal to or smaller than the total residual force enhancement, it persists when a muscle is deactivated and reactivated, but can be abolished instantaneously when a muscle is shortened quickly from its stretched length. There is strong evidence that the passive force enhancement is caused by the filamentous sarcomeric protein titin, although the detailed molecular mechanisms underlying passive force enhancement remain unknown. Here I propose a tentative mechanism based on experimental evidence that associates passive force enhancement with the shortening of titin's free spring length in the I-band region of sarcomeres. I suggest that this shortening is accomplished by titin binding to actin and that the trigger for titin-actin interactions is associated with the formation of strongly bound cross bridges between actin and myosin that exposes actin attachment sites for titin through movement of the regulatory proteins troponin and tropomyosin.
Topics: Animals; Humans; Muscle Proteins; Muscle, Skeletal; Muscle, Striated; Myocardium; Sarcomeres
PubMed: 31070958
DOI: 10.1152/japplphysiol.00676.2018