The serial sarcomere number of skeletal muscle changes in response to chronic length perturbation. The role of the intermediate filament desmin in regulating these changes was investigated by comparing the architectural adaptations of the tibialis anterior, extensor digitorum longus (EDL) and soleus from wild-type mice with those of homozygous desmin knockout mice after hindlimb immobilization. After 28 days, serial sarcomere number increased significantly in the lengthened wild-type tibialis anterior (by approximately 9 %) and EDL (by approximately 17 %). Surprisingly, muscles from desmin knockout mice also experienced significant serial remodeling, with the serial sarcomere number of the tibialis anterior increasing by approximately 10 % and that of the EDL by approximately 27 %. A consistent result was observed in the shortened soleus: a significant decrease in sarcomere number was observed in the muscles from both wild-type (approximately 26 %) and knockout (approximately 12 %) mice. Thus, ...
The purpose of the present study was to describe sarcomere dynamics in thin trabeculae that were dissected from the right ventricle of kittens. The muscles were mounted in an experimental chamber and perfused with a modified Krebs-Henseleit solution (25 degrees C). Sarcomere length (SL) was measured by laser diffraction techniques; force, by a silicon strain gauge; and velocity of sarcomere shortening, by the "isovelocity release" technique. Contractile activation was varied by changing the calcium concentration in the bathing medium ([Ca2+]o). Slack SL was 1.85 +/- 0.04 microns. When length of the muscle was held constant, the sarcomeres in the central region of the muscle shortened during the twitch by up to 21%. Both peak sarcomere isometric twitch force and unloaded velocity of sarcomere shortening (Vo) were a sigmoidal function of [Ca2+]o. Maximum Vo was 9.8 +/- 0.2 microns/sec; maximum sarcomere isometric twitch force was 108 +/- 13.8 mN/mm2. The shape of the force-SL relation was a ...
Cardiac myosin binding protein C phosphorylation affects cross-bridge cycles elementary steps in a site-specific manner.: Based on our recent finding that card
The examination of the expression profiles of other major sarcomere proteins revealed no significant preferential changes in any protein tested, other than titin (Fig. 3 C). When OD was normalized with that of MHC or actin, depending on the molecular weight, only titin was found to be significantly reduced (Fig. 3 C, bar graphs on the right). Therefore, proteins are reduced disproportionately in long-term disuse, with the effect on titin largest among the major sarcomere proteins.. In skeletal muscle, at least half of total protein is thick and thin filament based, and this fraction is lost at a faster rate than other muscle proteins in disuse (Jackman and Kandarian, 2004). The increase in the intensity of some bands in disused muscle (Fig. 3 B, arrows) indicates that the expression of nonsarcomere (or minor/unknown sarcomere) proteins may increase relative to that of the major sarcomere proteins tested in the present study.. It has been reported that gene expression is reduced for nebulin in ...
Mutungi, GM and Ranatunga, KW (2000) Sarcomere length changes during end-held (isometric) contractions in intact mammalian (rat) fast and slow muscle fibres. Journal of Muscle Research and Cell Motility, 21 (6). pp. 565-575. Full text not available from this repository ...
Heritable cardiomyopathy (HCM) is the leading cause of sudden cardiac arrest (SCA) in young people, affecting 1 in 500 individuals. HCM is chiefly caused by mutations in myofibrillar proteins of the cardiac sarcomere, and cardiac myosin binding protein-C (cMyBP-C, encoded by MYBPC3) is one of the most commonly affected. cMyBP-C, an accessory protein that binds tightly to myosin, has an important role in thick filament regulation. Mice with genetic ablation of MYBPC3 exhibit cardiac hypertrophy, reduced ejection fraction, and increased relaxation times in vivo. Experiments with explanted hearts from these mice exhibit greater susceptibility to arrhythmias compared to WT, suggesting derangement of Ca2+ handling. The molecular mechanisms underlying the progression of HCM are poorly understood, and are difficult to tease apart in constitutive knock out models due to potential compensatory changes that can mask important aspects of the disease phenotype. We used a tamoxifen-induced conditional MYBPC3 ...
Background: Reversible lysine-acetylation of proteins is regulated by histone acetyl transferases and deacetylases (HDACs). Previous studies from this laboratory have shown that a class-II HDAC, HDAC4 is associated with cardiac sarcomeres, and that HDAC-inhibitors enhance the contractile activity of myofilaments. Since, HDAC4 has little or no deacetylase activity of its own, this study was undertaken to examine the presence of other HDACs on cardiac sarcomeres.. Methods and Results: We prepared skinned papillary muscle fibers of the mouse heart and subjected them to western analysis. Results showed that a class-I HDAC, HDAC3 was localized to cardiac sarcomeres. By immuno-histochemical and electron microscopic analyses we found that HDAC3 was localized to the A-band of cardiac sarcomeres. We therefore examined the reversible acetylation of the A-band protein, myosin heavy chains (MHCs). MHC isoforms were prepared from control and PTU-treated mice, and examined for acetylation by western analysis ...
Muscles organise pseudo-crystalline arrays of actin, myosin and titin filaments to build force-producing sarcomeres. To study sarcomerogenesis, we have generated a transcriptomics resource of developing flight muscles and identified 40 distinct expression profile clusters. Strikingly, most sarcomeric components group in two clusters, which are strongly induced after all myofibrils have been assembled, indicating a transcriptional transition during myofibrillogenesis. Following myofibril assembly, many short sarcomeres are added to each myofibril. Subsequently, all sarcomeres mature, reaching 1.5 µm diameter and 3.2 µm length and acquiring stretch-sensitivity. The efficient induction of the transcriptional transition during myofibrillogenesis, including the transcriptional boost of sarcomeric components, requires in part the transcriptional regulator Spalt major. As a consequence of Spalt knock-down, sarcomere maturation is defective and fibers fail to gain stretch-sensitivity. Together, this ...
Myomegalin has been characterized as a protein with the properties of a scaffold or structural protein that is expressed at high levels in skeletal and cardiac tissue, suggesting an important function in muscle, and which interacts with a cAMP-specific phosphodiesterase [13]. However, the precise function and interactions of this protein, and its five isoforms, have been largely unknown. We here describe how the smallest MMGL isoform, isoform 4, binds to known and predicted PKA targets in the cardiac myocyte, including some sarcomeric proteins, viz. cMyBPC, cTNI, ENO1, ENO3, CARP and COMMD4 (Tables 1 and 2). Moreover, we show that MMGL isoform 4 interacts with two regulatory subunits of PKA (Figure 3). Together these results describe MMGL isoform 4 as a novel sarcomeric AKAP, which, like mAKAP [14], is involved in assembling a PKA/PDE cAMP signalling module.. In addition to interacting with both types of regulatory subunits, viz. RI and RII, which qualifies MMGL isoform 4 as a dual-specific AKAP ...
臺大位居世界頂尖大學之列,為永久珍藏及向國際展現本校豐碩的研究成果及學術能量,圖書館整合機構典藏(NTUR)與學術庫(AH)不同功能平台,成為臺大學術典藏NTU scholars。期能整合研究能量、促進交流合作、保存學術產出、推廣研究成果。. To permanently archive and promote researcher profiles and scholarly works, Library integrates the services of "NTU Repository" with "Academic Hub" to form NTU Scholars.. ...
Introduction. The Structure of Skeletal Muscle Skeletal muscles are all muscles that are attached to the skeleton such as the biceps and the hamstring. Within each muscle cell (also known as a muscle fibre) are structures called myofibrils as shown in the picture below: (Ref. The picture above was found at www.google.com) Myofibrils are made up of tiny units called sarcomeres. Sarcomeres are the smallest structures in a muscle that can contract; they are long filament-like structures, arranged in series - end to end - that run lengthways in the myofibril. Within the sarcomeres are two types of protein filaments that are actin and myosin - running lengthways, parallel to each other. The myosin filaments have cross-bridges across to the actin filaments, which during contraction allow them to bond with the actin filaments. The source of energy for this bonding is the molecule adenosine triphosphate (ATP). During the bonding, energy is released by the breaking down of ATP into adenosine ...
The cellular basis of the length-dependent increases in contractile force in the beating heart has remained unclear. Our aim was to investigate whether length-dependent mediated increases in contractile force are correlated with myosin head proximity to actin filaments, and presumably the number of cross-bridges activated during a contraction. We therefore employed x-ray diffraction analyses of beat-to-beat contractions in spontaneously beating rat hearts under open-chest conditions simultaneous with recordings of left ventricle (LV) pressure-volume. Regional x-ray diffraction patterns were recorded from the anterior LV free wall under steady-state contractions and during acute volume loading (intravenous lactate Ringers infusion at 60 ml/h, |5 min duration) to determine the change in intensity ratio ( I 1,0/ I 1,1) and myosin interfilament spacing ( d 1,0). We found no significant change in end-diastolic (ED) intensity ratio, indicating that the proportion of myosin heads in proximity to actin was
Dilated cardiomyopathy (DCM) is a myocardial disease with a high mortality rate. Approximately 40 genes have been found to be associated with DCM to date. Non-familial DCM can also be caused by gene mutations, suggesting that genetic factors were involved in the pathogenesis of DCM; therefore genetic testing is beneficial for the early diagnosis of DCM, which can facilitate the implementation of preventive measures by and within patients families. Here, we investigated the underlying genetic mutations involved in the cause of patients with DCM.
The structure and function of the sarcomere of striated muscle is well studied but the steps of sarcomere assembly and maintenance remain under-characterized. With the aid of chaperones and factors of the protein quality control system, muscle proteins can be folded and assembled into the contractile apparatus of the sarcomere. When sarcomere assembly is incomplete or the sarcomere becomes damaged, suites of chaperones and maintenance factors respond to repair the sarcomere. Here we show evidence of the importance of the M-line proteins, specifically myomesin, in the monitoring of sarcomere assembly and integrity in previously characterized zebrafish muscle mutants. We show that myomesin is one of the last proteins to be incorporated into the assembling sarcomere, and that in skeletal muscle, its incorporation requires connections with both titin and myosin. In diseased zebrafish sarcomeres, myomesin1a shows an early increase of gene expression, hours before chaperones respond to damaged muscle. ...
A theoretical framework for predicting the macroscopic behavior of a muscle myofibril based on the collective behavior of sarcomeres is presented. The analysis is accomplished by rigorously transforming the nonlinear dynamics of an assemblage of sarcomeres into a partial differential equation for the probability distribution function of sarcomere lengths in the presence of stochastic temporal fluctuations and biological variability. This enables the study of biologically relevant specimens with reasonable computational effort. The model is validated by a comparison to quantitative experimental results. Further, it reproduces experimental observations that cannot be explained by standard single sarcomere models, and provides new insights into muscle function and muscle damage during cyclic loading. We show that the accumulation of overstretched sarcomeres, which is related to muscle damage, depends on a delicate interplay between the dynamics of a large number of sarcomeres and the load ...
Ultrastructural measurements were carried out on the mouse biceps brachii and soleus muscles fixed at different states of contraction and stretch. At a sarcomere length of 2.7-2.9 µm the more peripheral actin filaments ran slightly obliquely from the Z-disk to the A-band. This is due to a mismatch between the rhombic actin lattice at the Z-disk and the hexagonal lattice at the M-line. For a perfect transformation of a rhombic lattice into a hexagonal lattice the ratio of the lattice spacings has to be 1:1.51. However, at this sarcomere length the ratio is about 1:2.0 (Z:M). During contraction the angle of the peripheral actin filaments remains approximately the same because the expansion of the M lattice is compensated for, partly by an increase in the Z-lattice spacing and partly by the bowing of the peripheral myosin filaments. When the sarcomeres are stretched beyond 3.0 µm the myosin filaments straighten out and the Z:M ratio decreases. The ratio of 1:1.51 is almost attained when there is ...
The effect of MgADP on the sarcomere length (SL) dependence of tension generation was investigated using skinned rat ventricular trabeculae. Increasing SL from 1.9 to 2.3 microm decreased the muscle width by approximately 11% and shifted the midpoint of the pCa-tension relationship (pCa(50)) leftward by about 0.2 pCa units. MgADP (0.1, 1, and 5 mmol/L) augmented maximal and submaximal Ca(2+)-activated tension and concomitantly diminished the SL-dependent shift of pCa(50) in a concentration-dependent manner. In contrast, pimobendan, a Ca(2+) sensitizer, which promotes Ca(2+) binding to troponin C (TnC), exhibited no effect on the SL-dependent shift of pCa(50), suggesting that TnC does not participate in the modulation of SL-dependent tension generation by MgADP. At a SL of 1. 9 microm, osmotic compression, produced by 5% wt/vol dextran (molecular weight approximately 464 000), reduced the muscle width by approximately 13% and shifted pCa(50) leftward to a similar degree as that observed when increasing
The |i|Journal of Biomedical Optics|/i| (JBO) publishes peer-reviewed papers on the use of novel optical systems and techniques for improved health care and biomedical research.
TY - JOUR. T1 - Differential contribution of cardiac sarcomeric proteins in the myofibrillar force response to stretch. AU - Ait Mou, Younss. AU - Le Guennec, Jean Yves. AU - Mosca, Emilio. AU - De Tombe, Pieter P.. AU - Cazorla, Olivier. PY - 2008/10. Y1 - 2008/10. N2 - The present study examined the contribution of myofilament contractile proteins to regional function in guinea pig myocardium. We investigated the effect of stretch on myofilament contractile proteins, Ca2+ sensitivity, and cross-bridge cycling kinetics (K tr) of force in single skinned cardiomyocytes isolated from the sub-endocardial (ENDO) or sub-epicardial (EPI) layer. As observed in other species, ENDO cells were stiffer, and Ca2+ sensitivity of force at long sarcomere length was higher compared with EPI cells. Maximal K tr was unchanged by stretch, but was higher in EPI cells possibly due to a higher α-MHC content. Submaximal Ca2+-activated K tr increased only in ENDO cells with stretch. Stretch of skinned ENDO muscle ...
A skeletal muscle that is stretched while contracting will produce more force at steady state than if it is stretched passively and then stimulated to contract. This phenomenon is known as residual fo
Each muscle fiber is made up of a collection of smaller fibers called Myofibrils. Muscle hypertrophy is due to an increase in the number of myofibrils within each fiber. Each myofibril extends the full length of the fiber, and is made up of a longitudinal arrangement of units called sarcomeres. The sarcomere is the structure responsible for the actual contraction. Each sarcomere consists of thick (myosin) and thin (actin) protein filaments that lie adjacent to one another horizontally, but are slightly separated longitudinally. Contraction occurs when the thick filaments attach to the thin filaments (crossbridge) and pull the thin filaments toward the center of the thick filament. The number of sarcomeres in series along a myofibril depends on the length and architecture of the specific muscle. The sartorius, which is the longest muscle in the body, has more than 100,000 sarcomeres in series, while a shorter muscle, such as the soleus, has closer to 10,000 sarcomeres in series. ...
contractile fiber, myofibril, protein-containing complex, striated muscle thin filament, Z disc, actin filament binding, cardiac muscle thin filament assembly, muscle fiber development, regulation of actin filament length, sarcomere organization
In this study, we aimed to further dissect the molecular components required for the coordinated organization of Z-line components into regular, hexagonal lattices. We took the approach of searching for protein interactions that anchor the COOH-terminal region of nebulin within the sarcomere. This allowed us to identify the specific binding of the nebulin modules M160-M183, from the peripheral (I-band side) region of the Z-line (Millevoi et al. 1998), with the intermediate filament protein, desmin. Studies are currently under investigation to determine whether desmin and nebulin indeed participate in a coordinated cytoskeletal network that could provide lateral linkages in the Z-line perimyofibrillar space, allowing for efficient force transmission and mechanochemical signaling.. This study has also led to the identification of a novel nebulin-binding protein, myopalladin, which we named based on its striking homology with the recently described ubiquitously expressed protein, palladin (Parast ...
The Frank-Starling law of the heart (also known as Starling's law and the Frank-Starling mechanism) represents the relationship between stroke volume and end diastolic volume . The law states that the stroke volume of the heart increases in response to an increase in the volume of blood in the ventricles , before contraction (the end diastolic volume), when all other factors remain constant. As a larger volume of blood flows into the ventricle, the blood stretches the cardiac muscle fibers, leading to an increase in the force of contraction. The Frank-Starling mechanism allows the cardiac output to be synchronized with the venous return, arterial blood supply and humoral length, without depending upon external regulation to make alterations. The physiological importance of the mechanism lies mainly in maintaining left and right ventricular output equality. Physiology The Frank-Starling mechanism occurs as the result of the length-tension relationship observed in skeletal muscles . As a muscle
Munich, Germany - Skeletal muscles are built from small contractile units, the sarcomeres. Many of these sarcomeres are connected in a well-ordered series to form myofibrils that span from one muscle end to the other. Contractions of these sarcomeres result in contraction of the entire muscle. Scientists at the Max Planck Institute (MPI) of Biochemistry…
We discovered a unique pattern of optical reflectance from fresh prerigor skeletal muscles, which can not be described using existing theories. A numerical fitting function was developed to quantify the equi-intensity contours of acquired reflectance images. Using this model, we studied the changes of reflectance profile during stretching and rigor process. We found that the prominent anisotropic features diminished after rigor completion. These results suggested that muscle sarcomere structures played important roles in modulating light propagation in whole muscle. When incorporating the sarcomere diffraction in a Monte Carlo model, we showed that the resulting reflectance profiles quantitatively resembled the experimental observation.. ©2007 Optical Society of America. Full Article , PDF Article ...
Sarcomeres are extremely highly ordered macromolecular assemblies where structural organization is intimately linked to their functionality as contractile units. Although the structural basis of actin and Myosin interaction is revealed at a quasiatomic resolution, much less is known about the molecular organization of the I-band and H-zone. We report the development of a powerful nanoscopic approach, combined with a structure-averaging algorithm, that allowed us to determine the position of 27 sarcomeric proteins in Drosophila melanogaster flight muscles with a quasimolecular, ∼5- to 10-nm localization precision. With this protein localization atlas and template-based protein structure modeling, we have assembled refined I-band and H-zone models with unparalleled scope and resolution. In addition, we found that actin regulatory proteins of the H-zone are organized into two distinct layers, suggesting that the major place of thin filament assembly is an M-line-centered narrow domain where short ...
Marked sarcomere disorganization is a well-documented characteristic of cardiomyocytes in the failing human myocardium. in cardiogenesis. Introduction Despite recent advances in pharmacologic and surgical therapies, chronic heart failure (CHF) is still a leading cause of death worldwide (1). Currently, heart transplant is thought to be the most effective therapy for end-stage CHF. However, this approach obviously cannot be used for all of the numerous affected patients and is not suitable for patients with a mild disease state. Therefore, there is increasing demand for new therapeutic targets for CHF. Cardiomyocytes, the most basic cellular unit of the myocardium, express several sarcomeric proteins, including myosin and actin; abnormalities in these sarcomeric proteins are major causes of idiopathic cardiomyopathies and lead to CHF (2C4). Type II myosin is the major constituent of sarcomeres. In the neck region of this protein, there are binding sites for a pair of myosin light chains, which ...
The smallest contractile unit of muscle fiber is the sarcomere. Sarcomeres are stacked throughout muscle tissue. These units are so small that some muscle cells contain thousands of...
Figure 2. Facing page. Differentiation of neonatal cardiomyocyte grafts. Host myocardium is shown only in day-3 panels (B, F, J, and N). Each time point shows serial sections from same heart. Bar=35 μm. Hematoxylin and eosin staining: A, At day 1, graft cardiomyocytes appeared small, round, and undifferentiated. Graft area was mostly surrounded by necrotic host myocardium and interstitial hemorrhage. B, At day 3, progressive wound healing was observed and graft cardiomyocytes began to elongate. C, At day 6, all necrotic host myocardium was removed. Graft cardiomyocytes began to enlarge and had early sarcomere formation (see also Figure 3⇓). Inset in C, Potential proliferation of graft neonatal cardiomyocytes was studied by double-staining for PCNA (blue) and α-cardiac myosin heavy chain (brown). PCNA-positive graft neonatal cardiomyocytes were observed from 3 days to 2 weeks, with peak frequency of 2% double-positive cells occurring at 6 days (as shown). Bar=10 μm. D, By 8 weeks, graft ...
A higher magnification of a field that suggests a non-satellite (resident) progenitor cell. No satellite cells are seen. The sarcomeres are formed. Z: Z lines;
Myosin Binding Protein-C (MyBP-C) comprises a family of accessory proteins that includes the cardiac, slow skeletal, and fast skeletal isoforms. The three isoforms share structural and sequence homology, and localize at the C-zone of the sarcomeric A-band where they interact with thick and thin filaments to regulate the cycling of actomyosin crossbridges. The cardiac isoform, encoded by MYBPC3, has been extensively studied over the last several decades due to its high mutational rate in congenital hypertrophic and dilated cardiomyopathy. It is only recently, however, that the MYBPC1 gene encoding the slow skeletal isoform (sMyBP-C) has gained attention. Accordingly, during the last five years it has been shown that MYBPC1 undergoes extensive exon shuffling resulting in the generation of multiple slow variants, which are co-expressed in different combinations and amounts in both slow and fast skeletal muscles. The sMyBP-C variants are subjected to PKA- and PKC-mediated phosphorylation in constitutive and
Relaxed sarcomeres contain myosin heads that have released their pull on the thin filaments. This allows them to return back to their relaxed state and causes the I bands and H zones to appear. The...
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Bundles of filaments and motors are central to contractility in cells. The classic example is striated muscle, where actomyosin contractility is mediated by highly organized sarcomeres which act as fundamental contractile units. However, many contractile bundles in vivo and in vitro lack sarcomeric organization. Here we propose a model for how contractility can arise in bundles without sarcomeric organization and validate its predictions with experiments on a reconstituted system. In the model, internal stresses in frustrated arrangements of motors with diverse velocities cause filaments to buckle, leading to overall shortening. We describe the onset of buckling in the presence of stochastic motor head detachment and predict that buckling-induced contraction occurs in an intermediate range of motor densities. We then calculate the size of the contractile units associated with this process. Consistent with these results, our reconstituted actomyosin bundles show contraction at relatively high ...
Although mutations in cMyBP‐C are one of the most frequent causes of hypertrophic cardiomyopathy on a per gene basis with ,150 individual mutations being documented, the majority of these mutations (≈60%) result not in a full‐length, mutated protein, but in a truncated peptide and these mutated alleles exhibit autosomal dominance.29, 30 We have shown that a truncated form of cMyBP‐C is produced from endogenous, normal cMyBP‐C as a result of ischemia-reperfusion injury and/or general cardiovascular stress and is generated from Ca2+ activated μ‐calpain activity.2 This fragment is stable, can be expressed inducibly in cardiomyocytes and causes cardiac disease, fibrosis, and eventually heart failure and death.4 This model displays pathology that is often seen in human cardiac fibrosis and myocardial disease: the hearts develop hypertrophy and show extensive interstitial fibrosis and perivascular fibrosis while maintaining systolic function. Thus, in terms of a fibrotic response, the ...
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Glycerol-extracted rabbit psoas muscle fibers were examined by electron microscopy both before and after ATP-induced isotonic shortening. Ultrastructural changes were correlated with the initial sarcomere length and the degree of shortening. The ultrastructural appearance of the resting fiber at rest length was identical with that described by H. E. Huxley and Hanson. At sarcomere lengths greater than 3.7 to 3.8 µ, the A and I filaments were detached and separated by a gap. The presence of "gap" filaments was confirmed, and evidence is presented which indicates that these filaments form connections between the ends of the A and I filaments. Shortening from initial sarcomere lengths at which the filaments overlapped took place through sliding of the filaments. If shortening was initiated from sarcomere lengths at which there was a gap, a narrowing of the I band was brought about by a curling of the I filaments at the boundary between the A and I bands. No evidence could be found that the I ...
The thin and thick filaments of muscle sarcomeres are interconnected by the giant protein titin, which is a scaffolding filament, signaling platform, and provider of passive tension and elasticity in myocytes. This review summarizes recent insight into the mechanisms behind how titin gene mutations cause hereditary cardiomyopathy and how titin protein is mechanically active in skeletal and cardiac myocytes. A main theme is the evolving role of titin as a modulator of contraction. Topics include strain-sensing via titin in the sarcomeric A-band as the basis for length-dependent activation, titin elastic recoil and refolding of titin domains as an energy source, and Ca2+-dependent stiffening of titin stretched during eccentric muscle contractions ...
Background: Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease. Methods: A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The ...
Hypertrophic cardiomyopathy (HCM), an inherited disease of the heart muscle, is among the most common Mendelian cardiac diseases, occurring in 1 in 500 people (1). Advances in genetics have facilitated identification of a subpopulation of patients with pathogenic variants in cardiac sarcomere genes. The earliest family mapped by positional cloning had a disease-causing mutation at position 403 of the β-myosin heavy chain (MHC) protein (2). A knock-in mouse model of this variant recapitulated aspects of human disease (3); many other sarcomere genes have been implicated subsequently (4). In clinics today, coding regions of numerous cardiac sarcomere genes are routinely sequenced, and, excluding those patients with discrete upper septal thickening, clearly pathogenic variants are identified in 30% to 50% of patients (5), thus marking a subset of "sarcomeric" HCM.. Current therapy for HCM is primarily palliative. Beta-blockers, nondihydropyridine calcium channel blockers, and the class Ia ...
Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM ...
The Frank-Starling mechanism occurs as the result of the length-tension relationship observed in striated muscle, including for example skeletal muscles, arthropod muscle[4] and cardiac (heart) muscle.[5][6][7] As a muscle fiber is stretched, active tension is created by altering the overlap of thick and thin filaments. The greatest isometric active tension is developed when a muscle is at its optimal length. In most relaxed skeletal muscle fibers, passive elastic properties maintain the muscle fibers length near optimal, as determined usually by the fixed distance between the attachment points of tendons to the bones (or the exoskeleton of arthropods) at either end of the muscle. In contrast, the relaxed sarcomere length of cardiac muscle cells, in a resting ventricle, is lower than the optimal length for contraction.[1] There is no bone to fix sarcomere length in the heart (of any animal) so sarcomere length is very variable and depends directly upon blood filling and thereby expanding the ...
The M-band is the transverse structure that cross-links the thick filaments in the center and provides a perfect alignment of the A-band in the activated sarcomere. The molecular composition of the M-bands in adult mouse skeletal muscle is fiber-type dependent. All M-bands in fast fibers contain M-protein while M-bands in slow fibers contain a significant proportion of the EH-myomesin isoform, previously detected only in embryonic heart muscle. This fiber-type specificity develops during the first postnatal weeks. However, the ratio between the amounts of myosin and of myomesin, taken as sum of both isoforms, remains nearly constant in all studied muscles. Ultrastructural analysis demonstrates that some of the soleus fibers show a diffuse appearance of the M-band, resembling the situation in the embryonic heart. A model is proposed to explain the functional consequence of differential M-band composition for the physiological and morphological properties of sarcomeres in different muscle ...
The efficient functioning of striated muscle is dependent upon the precise interactions and alignment of complex cytoskeletal networks. For example, sarcomeres, the basic contractile units of myofibrils, are comprised of uniformly arranged filament systems and regulatory proteins. The actin-containing thin filaments are anchored in the Z-lines and extend toward the middle of the sarcomere, the M-line, where they interact with the myosin-containing thick filaments to drive contraction. A third filament system is composed of single molecules of titin, the largest known vertebrate protein (∼3.7 MDa). Titin filaments span half sarcomeres, with their N-termini overlapping in the Z-lines and their C-termini overlapping in the M-lines, thus forming a continuous filament system among adjacent myofibrils (Obermann et al., 1996; Gregorio et al., 1998; Mues et al., 1998). Based on the assembly properties, molecular layout and modular structure of titin, it is proposed to act as a template for ...
Wang et al (Nat Med. 2014 May 11. doi: 10.1038/nm.3545.) just published a fascinating set of experiences in which they created a model of a Barth Syndrome cardiac dysfunction by using "heart on chip" technology. This technology involves using Barth patient derived induced pluripotent stem cell derived cardiomyocytes seeded on micropatterned fibronectin rectangles in order to recapitulate cardiac tissue structure. From these experiments, the authors were able to derive information about sarcomere organization, contractile dysfunction among other relevant parameters. This model, and the success of these experiments, holds great promise in the development of therapies for cardiomyopathy, as well as creating a system in which phenotype/genotype correlations of specific gene mutations can be better understood.. Hilary Vernon, MD PhD. ...
We found that the lengths of all sarcomeres spontaneously oscillated in an isolated skeletal myofibril, when both ends were fixed, submillimolar to millimolar concentrations of ATP, ADP and inorganic...
Human induced pluripotent stem cells (iPSCs) represent a powerful human model to study cardiac disease in vitro, notably channelopathies and sarcomeric cardiomyopathies. Different protocols for cardiac differentiation of iPSCs have been proposed either based on embroid body formation (3D) or, more recently, on monolayer culture (2D). We performed a direct comparison of the characteristics of the derived cardiomyocytes (iPSC-CMs) on day 27 ± 2 of differentiation between 3D and 2D differentiation protocols with two different Wnt-inhibitors were compared: IWR1 (inhibitor of Wnt response) or IWP2 (inhibitor of Wnt production). We firstly found that the level of Troponin T (TNNT2) expression measured by FACS was significantly higher for both 2D protocols as compared to the 3D protocol. In the three methods, iPSC-CM show sarcomeric structures. However, iPSC-CM generated in 2D protocols constantly displayed larger sarcomere lengths as compared to the 3D protocol. In addition, mRNA and protein analyses reveal
Titin also known as connectin is a large filamentous protein that greatly contributes to passive myocardial stiffness. to passive myocardial stiffness in all tissue types but most in MLV least in BLA and an intermediate level in BLV. We also studied whether titin-actin interaction is regulated by S100A1/calcium and found that calcium alone or S100A1 alone did not alter passive stiffness but that combined they significantly lowered stiffness. We propose that titin-actin interaction is a "viscous break" that is on during diastole and off during systole. RAF265 Rabbit polyclonal to AIM1L. 1 Introduction Passive tension development in the sarcomere plays a critical role in diastolic function. The giant protein titin/connectin spans the half-sarcomere from Z-disk to M-line [1] and is responsible for the development of passive tension within the sarcomere [2]. Titin-based passive tension constitutes a large fraction of the myocardial passive tension; the other main contributor is the extracellular ...
Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are two common cardiomyopathies with an estimated prevalence of 1:250 and 1:200 in adults (McKenna et al., 2017; Prondzynski et al., 2018). The prognoses of cardiomyopathies are poor, and the annual mortalities for DCM and HCM are 1.55% and 2.5%, respectively (Pelliccia et al., 2017; Vischer et al., 2009). During the past few decades, genetic screening has identified a list of autosomal inherited mutations as potential drivers or susceptible factors for cardiomyopathy, and approximately 40-50% of all cases can be attributed to genetic mutations (Zou et al., 2013; Paldino et al., 2018). Among these, genes coding sarcomere proteins are frequently found to be dysfunctional in both DCM and HCM, and it is estimated that around 30-40% DCM-associated mutations and 60% HCM-associated mutations occur in sarcomere genes (McNally et al., 2013; Hershberger et al., 2013; Veselka et al., 2017). Besides, mutations in a single sarcomere gene ...