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Muscle contraction results from force-generating interactions between myosin cross-bridges on the thick filament and actin on the thin filament. The force-generating interactions are regulated by Ca(2+) via specialised proteins of the thin filament. It is controversial how the contractile and regulatory systems dynamically interact to determine the...
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... Muscle contraction results from force-generating interactions between myosin cross-bridges on the thick filament and actin on the thin filament. The force- generating interactions are regulated by Ca 2+ via specialised proteins of the thin filament. It is controversial how the contractile and regulatory systems dynamically interact to determine the time course of muscle contraction and relaxation. Whereas kinetics of Ca 2+ -induced thin-filament regulation is often investigated with isolated proteins, force kinetics is usually studied in muscle fibres. The gap between studies on isolated proteins and structured fibres is now bridged by recent techniques that analyse the chemical and mechanical kinetics of small components of a muscle fibre, subcellular myofibrils isolated from skeletal and cardiac muscle. Formed of serially arranged repeating units called sarcomeres, myofibrils have a complete fully structured ensemble of contractile and Ca 2+ regulatory proteins. The small diameter of myofibrils (few micro- metres) facilitates analysis of the kinetics of sarcomere contraction and relaxation induced by rapid changes of [ATP] or [Ca 2+ ]. Among the processes studied on myofibrils are: (1) the Ca 2+ -regulated switch on/off of the troponin complex, (2) the chemical steps in the cross- bridge adenosine triphosphatase cycle, (3) the mechanics of force generation and (4) the length dynamics of individual sarcomeres. These studies give new insights into the kinetics of thin-filament regulation and of cross-bridge turnover, how cross-bridges transform chemical energy into mechanical work, and suggest that the cross-bridge ensembles of each half-sarcomere cooperate with each other across the half-sarcomere borders. Additionally, we now have a better understanding of muscle relaxation and its impairment in certain muscle diseases. Keywords Muscle contraction . Muscle relaxation . Myocardial contraction . Myocardial relaxation . Myofibrils . Sarcomeres . Calcium . Thin-filament regulation . Cross-bridge kinetics . Relaxation . Cross-bridge . Muscle mechanics . Cardiac sarcomere . Cardiac muscle . Cardiac function . Caged calcium . Calcium regulation . Skinned fibre Striated muscles have a hierarchically organized architecture. Skeletal muscles are large bundles of multinucleated cells, called fibres, aligned in parallel. Cardiac muscle consists of networks of branching single nucleated cells called myocytes. The cells contain, in turn, bundles of myofibrils that form the contractile machinery. Myofibrils are aligned in parallel within a skeletal muscle fibre or in branching bundles within a myocyte. On the single myofibril level, skeletal and cardiac muscles have very similar substructures. Both types of myofibrils are constructed of stacks of short cylindrical repeating units called sarcomeres. The sarcomere is the most highly ordered structure of all cellular organelles. It has a bilateral symmetry, i.e. it consists of two antipodal halves, the half- sarcomeres. The sarcomere is constructed by two types of transversally oriented multi-protein scaffolds, the M-line and the Z-disc which anchor an ordered lattice of three types of axial filaments, called the thick, thin and titin filaments. Z-discs form the outer ends of a sarcomere and are shared with neighbouring sarcomeres (Fig. 1). The M- line is at the middle of the sarcomere and is shared by the two half-sarcomeres. The midpoint of the thick filaments are anchored in the M-line; they extend towards the Z-discs but, normally, do not touch it. In contrast, the thin filaments are anchored to the Z-lines but not to the M-line. The elastic titin filament is also attached to the Z-discs and is the only filament that forms a permanent connection between the Z-disc and the M-line; thereby, it determines the elastic properties of the relaxed sarcomere [47, 86]. The thin and thick filaments each contain a precise assembly of several proteins, which together forms the Ca -regulated contractile aggregate. Thin filaments mainly consist of actin and associated regulatory proteins, the troponin complex (Tn) and tropomyosin (Tm). Thick filaments are mainly composed of myosin, myosin light chains and myosin binding protein C. Parts of the myosin, called heads or cross- bridges, protrude at regular intervals from the thick filament backbone towards the thin filaments. This structural hierarchy bundles contractile activity from the molecular level through the filament, the half-sarcomere, the myofibril, the cell and up to the muscle. The smallest complete contractile unit is the half-sarcomere of a single myofibril. The complete functional motor unit is a group of muscle fibres driven by a single motor neuron or a heart. At the molecular and filament level, contraction and relaxation are regulated by the Ca 2+ -binding/dissociation to/from troponin C (TnC). Ca 2+ binding results in a cascade of conformational changes involving TnC and the other thin- filament regulatory proteins, troponin I (TnI), troponin T (TnT), and Tm; this allows the cross-bridges to interact with actin [46, 75, 76]. Driven by their cyclic adenosine triphosphatase (ATPase) activity, cross-bridges exert a force on the thin filament which pulls the latter towards the sarcomere centre, the M-line; the half-sarcomere contracts and shortens [59, 61, 62]. Thereby, cross-bridge cycling kinetics determines the shortening dynamics of a particular half-sarcomere [27]. When the [Ca 2+ ] falls and Ca 2+ dissociates from TnC, the thin filament inactivates; the force-generating interaction of cross-bridges ceases and the half-sarcomere returns to its relaxed length determined by the titin ’ s elasticity. If the ensemble of individual half-sarcomeres acted independently, the mechanism of striated muscle contraction would be defined by the characteristics of a single half- sarcomere. However, the kinetics of the cross-bridge cycle, in particular the transitions of cross-bridges through the force-generating states that determine the apparent rate of cross-bridge detachment from actin, depend themselves on the velocity of filament sliding [41, 59, 129]. This, in turn, depends on the overall force generated by all serially coupled half-sarcomeres. The intersarcomeric coupling of filament sliding and cross-bridge detachment becomes apparent when myofibrils relax after the end of contraction. Rapid relaxation occurs by sequential lengthening of individual half-sarcomeres which spatially propagates along the myofibril until all half-sarcomeres resume their relaxed length [135, 143]. This sequential process enables rapid release of mechanical strain and fast relaxation [117, 135, 147]. The arrangement of myofibrils in fibres and myocytes is optimized for the specific function of the organ. In skeletal muscles, the parallel alignment of myofibrils and fibres transmits their force directly to the tendons. In the heart, branched myocytes form cell bundles with a preferred but not unidirectional orientation that wrap in helices around the cavities [109]. In both muscles, the cells are stabilised by extracellular collagen matrix, which protects them from damage by excessive stretch. In summary, the mechanical performance of a muscle results from interactions occurring at many levels of organisation: intramolecular and intermolecular, between thick and thin filaments, between sarcomeres and between muscle cells and other structures. It is challenging, therefore, to gain insight into the many mechanisms behind the dynamics of a contraction – relaxation cycle. In principle, kinetic parameters can be obtained from preparations at all levels of the structural hierarchy, i.e. from the organ in vivo down to the isolated molecule. While the complete cellular physiology of muscle contraction and relaxation can be only studied in intact muscle preparations that comprise not only the sarcomere but also the intact Ca 2+ -handling structures [5, 67], the gradual rise and fall of [Ca 2+ ] in these preparations prevents exploration of the kinetic mechanisms which underlie the mechanical performance of the muscle. If we focus on the force-generating process and its regulation in the sarcomere, there are mainly two models for investigating their mechanisms. The classical model for studying the Ca 2+ ...
Citations
... However, given their small diameter, myofibrils promptly equilibrate with bathing solutions without significant diffusional constraints. 5 Individual myofibrils were electrostatically tethered between a glass probe connected to a Piezo length controller and a glass cantilever of known stiffness (0.031 N/m). Sarcomere length was set to 2.1 μm from an average of ≈1.7 μm. ...
... Myofibrillar relaxation ki netics following sudden calcium removal are uniquely biphasic, and each phase can inform about deficits linked to regulatory and motor proteins. 5 Data support ing this study are available from the corresponding au thor on reasonable request. ...
... Shifts from fast α myosin to slower β myosin could partially explain differences in relaxation kinetics. 5 However, mass spectrometry analysis of the purified myofibrils revealed no significant increases in β myosin versus α myosin heavy chain protein content in any of the mod els, implying alternative underlying causes. Our findings demonstrate that myofibril mechanics vary significantly between HFpEF animal models, sug gesting that some may uniquely recapitulate distinct aspects of the disorder and particular subphenotypes observed among patients. ...
... Single myofibrils experiments followed previously described procedures (Poggesi et al., 2005;Stehle et al., 2009;Vitale et al., 2021). Briefly, myofibrils were prepared by high-speed homogenizing skinned surgically cut tissue strips isolated from frozen LV-free wall tissue (18,000 rpm for 9 s). ...
... Dynamic Ca 2+ activation-relaxation dynamics were assessed by using the single myofibril technique (Poggesi et al., 2005;Stehle et al., 2009;Vitale et al., 2021). There were no differences in Ca 2+ activation parameters between the Sham and AOB groups (results presented in Fig. 9). ...
... inset) upon a rapid switch from the activating to the relaxing solution (occurring at time = 0 s; note that force is normalized to the steady state maximum force development). As has been well described, myofilament relaxation upon the rapid withdrawal of activating Ca 2+ is biphasic, where a slow relaxation phase transitions into a rapid phase of relaxation (Poggesi et al., 2005;Stehle et al., 2009;Vitale et al., 2021). The linear phase of relaxation which occurs prior to the onset of the exponential decay of force (as indicated by the arrow in the figure) was significantly prolonged in the AOB group compared with the sham group. ...
Cardiac hypertrophy is associated with diastolic heart failure (DHF), a syndrome in which systolic function is preserved but cardiac filling dynamics are depressed. The molecular mechanisms underlying DHF and the potential role of altered cross-bridge cycling are poorly understood. Accordingly, chronic pressure overload was induced by surgically banding the thoracic ascending aorta (AOB) in ∼400 g female Dunkin Hartley guinea pigs (AOB); Sham-operated age-matched animals served as controls. Guinea pigs were chosen to avoid the confounding impacts of altered myosin heavy chain (MHC) isoform expression seen in other small rodent models. In vivo cardiac function was assessed by echocardiography; cardiac hypertrophy was confirmed by morphometric analysis. AOB resulted in left ventricle (LV) hypertrophy and compromised diastolic function with normal systolic function. Biochemical analysis revealed exclusive expression of β-MHC isoform in both sham control and AOB LVs. Myofilament function was assessed in skinned multicellular preparations, skinned single myocyte fragments, and single myofibrils prepared from frozen (liquid N2) LVs. The rates of force-dependent ATP consumption (tension-cost) and force redevelopment (Ktr), as well as myofibril relaxation time (Timelin) were significantly blunted in AOB, indicating reduced cross-bridge cycling kinetics. Maximum Ca²⁺ activated force development was significantly reduced in AOB myocytes, while no change in myofilament Ca²⁺ sensitivity was observed. Our results indicate blunted cross-bridge cycle in a β-MHC small animal DHF model. Reduced cross-bridge cycling kinetics may contribute, at least in part, to the development of DHF in larger mammals, including humans.
... 26,27 The rate of the slow phase of relaxation (slow k REL ) was markedly faster in the c.772G>A than in the donor myofibrils ( Figure 4C and 4D; Table S4), indicating a faster apparent cross-bridge detachment rate under isometric conditions. 26,[28][29][30] The rate of fast relaxation (fast k REL ) was also greater in the c.772G>A myofibrils ( Figure 4C and 4D; Table S4). The duration of the slow force relaxation phase, D slow , is shorter in the mutant myofibrils (Figure 4D; Table S4). ...
RATIONALE
The pathogenesis of MYBPC3-associated hypertrophic cardiomyopathy is still unresolved. We exploited a large and well-characterized patient population carrying the MYBPC3-c.772G>A variant (p. Glu258Lys, E258K) to provide translational insight based on studies on surgical myectomy samples, human-induced pluripotent stem cell (hiPSC)-cardiomyocytes and engineered heart tissues.
OBJECTIVE
To gain insights into the pathogenic mechanisms driven by the MYBPC3-c.772G>A mutation using a comprehensive investigation of human disease models.
METHODS AND RESULTS
Haplotype analysis revealed MYBPC3-c.772G>A as a founder mutation in Tuscany. The mutation leads to reduced cMyBP-C (cardiac myosin binding protein-C) expression, supporting haploinsufficiency as the main primary disease mechanism. Functional perturbations were studied in left ventricular samples from 4 patients who underwent myectomy, as well as in human hiPSC-cardiomyocytes and engineered heart tissues harboring c.772G>A, compared with samples from nonfailing nonhypertrophic surgical patients and hiPSC lines from healthy controls. Mechanical studies in single myofibrils and permeabilized muscle strips highlighted faster cross-bridge cycling, and higher energy cost of tension generation. A novel approach based on tissue clearing and advanced optical microscopy supported the idea that the sarcomere energetics dysfunction is intrinsically related with the reduction in cMyBP-C. Studies in single cardiomyocytes (native and hiPSC-derived), intact trabeculae and hiPSC-engineered heart tissues revealed prolonged action potentials, slowerCa ²⁺ transients and preserved twitch duration, suggesting that the slower excitation-contraction coupling counterbalanced the faster sarcomere kinetics. This conclusion was strengthened by in silico simulations. Of note, the results from patient tissues and hiPSC-derived models obtained from the same patients were essentially the same, supporting the use of hiPSC-models for hypertrophic cardiomyopathy studies.
CONCLUSIONS
Hypertrophic cardiomyopathy–related MYBPC3 -c.772G>A mutation invariably impairs sarcomere energetics and cross-bridge cycling. Compensatory electrophysiological changes (eg, reduced potassium channel expression) appear to preserve twitch contraction parameters, but may expose patients to greater arrhythmic propensity and disease progression. Therapeutic approaches correcting the primary sarcomeric defects may prevent secondary cardiomyocyte remodeling.
... Instrumentation 1 H (500 MHz) and 19 F (471 MHz) spectroscopic data were collected using a Bruker Ascend TM500 spectrometer with a Prodigy cryoprobe. 13 C (100.6 MHz) was collected using a Bruker Avance NEO 400 MHz spectrometer with a 5 mm double resonance broad banded iProbe. PAG2 was dissolved to 5 μg mL -1 in methanol and measured in positive ion ESI mode (resolving power 60,000 at 202 m/z) using an Orbitrap Fusion mass spectrometer. ...
Filamentous bundles are ubiquitous in Nature, achieving highly adaptive functions and structural integrity from assembly of diverse mesoscale supramolecular elements. Engineering routes to synthetic, topologically integrated analogs demands precisely coordinated control of multiple filaments’ shapes and positions, a major challenge when performed without complex machinery or labor-intensive processing. Here, we demonstrate a photocreasing design that encodes local curvature and twist into mesoscale polymer filaments, enabling their programmed transformation into target 3-dimensional geometries. Importantly, patterned photocreasing of filament arrays drives autonomous spinning to form linked filament bundles that are highly entangled and structurally robust. In individual filaments, photocreases unlock paths to arbitrary, 3-dimensional curves in space. Collectively, photocrease-mediated bundling establishes a transformative paradigm enabling smart, self-assembled mesostructures that mimic performance-differentiating structures in Nature (e.g., tendon and muscle fiber) and the macro-engineered world (e.g., rope).
... Key natural examples include collagen in load-bearing tendon and bone. 5-10 actuating muscle, [11][12][13][14][15][16][17] and plant structures that simultaneously provide strength, flexibility, and nutrient transport. [18][19][20][21][22] In these systems, unique, anisotropic properties are derived from organization and collective behavior of aligned mesoscale filaments. ...
Filamentous bundles are ubiquitous in Nature, achieving highly adaptive functions and structural integrity from assembly of diverse mesoscale supramolecular elements. Engineering routes to synthetic, topologically integrated analogs demands precisely coordinated control of multiple filaments’ shapes and positions, a major challenge when performed without complex machinery or labor-intensive processing. Here, we demonstrate a photocreasing design that encodes local curvature and twist into mesoscale polymer filaments, enabling their programmed transformation into target 3-dimensional geometries. Importantly, patterned photocreasing of filament arrays drives autonomous spinning to form linked filament bundles that are highly entangled and structurally robust. In individual filaments, photocreases unlock paths to arbitrary, 3-dimensional curves in space. Collectively, photocrease-mediated bundling establishes a transformative paradigm enabling smart, self-assembled mesostructures that mimic performance-differentiating structures in Nature (e.g., tendon and muscle fiber) and the macro-engineered world (e.g., rope).
... Second, skinned cardiac fiber or intact cardiomyocyte preparations do not allow for the amount of detail that myofibril mechanical tests may give, such as the resolution of the two stages of cardiac muscle fiber relaxation. [71] Being therapeutic bioactive compounds, fish proteins perform organic activities. Native proteins include a few bioactive peptides that prevent from irritation, hostile to diabetics, and anti-hypertension activities. ...
Statement of Retraction
We, the Editors and Publisher of the journal International Journal of Food Properties, have retracted the following articles:
Waseem Khalid, Muhammad Sajid Arshad, Noman Aslam, Muhammad Majid Noor, Azhari Siddeeg, Muhammad Abdul Rahim, Muhammad Zubair Khalid, Anwar Ali & Zahra Maqbool (2022) Meat myofibril: Chemical composition, sources and its potential for cardiac layers and strong skeleton muscle, International Journal of Food Properties, 25:1, 375-390, DOI: 10.1080/10942912.2022.2044847
Since publication, the Editor-in-Chief of the journal was contacted by a representative of Central South University who requested the retraction of this article on behalf of one of the co-authors due to flaws and errors in the manuscript.
Further investigation conducted by the Publisher in collaboration with the Editor-in-Chief identified concerns with regards to the authorship and article content. The corresponding author listed in this publication has been informed about this decision. The authors do not agree with the retraction.
We have been informed in our decision-making by our editorial policies and the COPE guidelines.
The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.
... In addition to the decrease in the rate of P i release, the decrease in the kinetics of force development operated by MAVA in psoas myofibrils can be also explained by comparing the relations between the kinetics of force development and the level of force modulated by the drug or by the free [Ca 2+ ] (Fig. 7 A). Several rather-accepted models of contraction regulation suggest that Ca 2+ affects the kinetics of force development in an indirect way (i.e., by modulating the availability of actin regulatory units for the interaction with myosin; Brenner, 1988;Poggesi et al., 2005;Stehle et al., 2009;Campbell, 2014). By analogy, the decrease in the number (N a ) of myosin heads functionally available for interacting with actin (at full Ca 2+ activation) would cause a drop in force as force in the sarcomere is settled by the product of the intrinsic force per cross-bridge times the total number of functionally accessible actin-interacting heads N a and the duty ratio (Spudich, 1994). ...
... Interestingly, in human ventricular myofibrils, MAVA, at drug concentrations around IC 50 , induced a significant increase in slow k REL and then on the apparent rate of cross-bridge detachment (g app ; Fig. 7 C). This direct kinetic effect in the presence of MAVA may be due to alterations of the ADP release steps (Stehle et al., 2009;Stehle and Iorga, 2010;Walklate et al., 2016), as already suggested in human ventricular strips from measurement of viscoelastic stiffness (Awinda et al., 2020). ...
... t LIN is shortened and k LIN increased by high phosphate concentrations but lengthened by MgADP indicating a close relationship of this process with the product release step of the crossbridge cycle (Tesi et al., 2002). The interpretation of the relaxation curve and its relationship to heterogeneous sarcomere lengthening was fully described by Stehle et al. (2009). Both k LIN /t LIN and k REL are altered by physiological and pathological perturbations that affect thin filament relaxation rate such as cardiac TnI phosphorylation or HCM related mutations (Song et al., 2013;Vikhorev et al., 2014). ...
... The addition of video microscopy allows sarcomere length to be measured, enabling accurate sarcomere length adjustments, for instance when measuring length-dependent activation. During relaxation these observations have shown transient heterogeneous shortening of sarcomeres in a myofibril which has important implications for the structural changes behind the relaxation process (Stehle et al., 2002(Stehle et al., , 2009). ...
Contractility, the generation of force and movement by molecular motors, is the hallmark of all muscles, including striated muscle. Contractility can be studied at every level of organization from a whole animal to single molecules. Measurements at sub-cellular level are particularly useful since, in the absence of the excitation-contraction coupling system, the properties of the contractile proteins can be directly investigated; revealing mechanistic details not accessible in intact muscle. Moreover, the conditions can be manipulated with ease, for instance changes in activator Ca²⁺, small molecule effector concentration or phosphorylation levels and introducing mutations. Subcellular methods can be successfully applied to frozen materials and generally require the smallest amount of tissue, thus greatly increasing the range of possible experiments compared with the study of intact muscle and cells. Whilst measurement of movement at the subcellular level is relatively simple, measurement of force is more challenging. This mini review will describe current methods for measuring force production at the subcellular level including single myofibril and single myofilament techniques.
... That is in line with the work of Tesi, Colomo, Nencini, et al. 2000 where force generation (including rate constant of RFD) and inorganic phosphate release are closely related. The inorganic phosphate release corresponds to the shift in myosin heads and, therefore, a force production, for which changes in calcium concentration do not constitute a limiting factor of RFD (Allen and Westerblad 2001;Stehle, Solzin, Iorga, et al. 2009). Under muscle fatigue, ions H+ as well as inorganic phosphate concentrations increase in the myoplasm, therefore inhibiting the release of calcium in the sarcoplasmic reticulum and consequently the production of force (Allen and Westerblad 2001). ...
The first models of training effects on athletic performance emerged with the work of Banister and Calvert through the so-called Fitness-Fatigue model (FFM). One major drawback of FFMs is that the features stem from a single source of data. That is not in line with the existing consensus about a multifactorial aspect of athletic performance. Hence, multivariate modelling approaches from statistics and machine-learning (ML) emerged.
A research issue arises from the quantification of training Loads (TL) in resistance training (RT) which lack of physiological evidence. In the first study, we provided a new method of TL quantification in RT based on physiological observations. To achieve that, we initially modelled the torque-velocity profiles of fifteen participants during an isokinetic leg extension task and assessed a set of physiological responses to various resistance exercises intensities. Each session was volume-equated according to the formulation of volume load (i.e. the product of the number of repetitions and the relative intensity).
Higher led to greater muscular fatigue described by neuromuscular impairments. Conversely, systemic and local pulmonary responses (measured through oxygen uptake) and metabolic changes (according to blood lactate concentrations) were more significant at low intensities, suggesting different contributions of metabolic pathways.
From these results, we provided a new index of TL based on the neuromuscu- lar impairments observed at exercise. We showed that to exponentially weight TL by the average rate decay of force development rate yielded better correla- tions with any of the significant physiological responses to exercise. In addition, information compressed within a principal component could be a valuable TL index.
In the second study, we provided a robust modelling methodology that relies on model generalisation. Using data from elite speed skaters, we compared a dose-response model to regularisation methods and machine-learning models.
Regularisation procedures provided the greatest performances in both generalisa- tion and accuracy. Also, we highlighted the pertinence of computing one model over the group of athletes instead of a model per athlete in a context of a small sample size.
Finally, ML approaches could be a way of improving FFMs through ensemble learning methods.
In the third study, we modelled acceleration-velocity directly from global posi- tioning system (GPS) measurements and attempted to predict the coefficients of the relationship between acceleration and velocity.
First, a baseline model was defined by time-series forecasting using game data only. Then, we proceeded to multivariate modelling using commercial features. A regularised linear regression and a long short term memory neural network were compared. Finally, we extracted features directly from raw GPS data and compared these features to the commercial ones for prediction purposes.
The results showed only slight differences between model accuracy, and no models significantly outperformed the baseline in the prediction task. Given the multi- factorial nature of athletic performance, using only GPS data for predicting such athletic performance criterion provided an acceptable accuracy. Using time-domain and frequency-domain features extracted from raw data led to similar performances compared to the commercial ones, despite being evidence-based. It suggests that raw data should be considered for future athletic performance and injury occurrence analysis.
Lastly, we developed an athlete management system for long-distance runners. This application provided an athlete monitoring module and a predictive module based on a physiological model of running performance.
A second development was realised under the SAP analytics cloud solution. Team management and automated dashboards were provided herein, in close collaboration with a professional Rugby team.
... Fast kinetic chemomechanical studies on sarcomeric function are possible with subcellular myofibrils (MFs) because they rapidly reach diffusional equilibrium with their surrounding environment and therefore allow activation, as well as relaxation, kinetics to be studied in detail. In addition, functional studies with MFs can provide insights in contractile function of cardiomyocytes (CMs) in the absence of Ca 2+ -handling systems and upstream signaling (Stehle et al., 2009;Stehle and Iorga, 2010;Scellini et al., 2021). Scellini et al. (2021) investigated the inhibitory effect of the drug MAVA on ventricular MFs from human hearts and compared it to fast skeletal MFs from rabbit psoas muscle. ...
... After Ca 2+ removal, the fast, second phase of MF relaxation, having a larger amplitude than the first, slower phase, is characterized by the fast k rel rate constant. This describes kinetics of cross-bridges leaving force-generating states under reduced mechanical load (compared with the first relaxation phase during which sarcomeres remain isometric), because sarcomere lengthening partially releases the serial stress in MFs (Stehle et al., 2003;Stehle et al., 2009). Therefore, the rapid and large drop of myofibrillar force is likely to contribute to the ventricular pressure decay at the onset of diastole, while slow k rel (=g app , the probability of cross-bridges to leave force-generating states), describing kinetics of the first relaxation phase, is related to tension cost (i.e., ATPase/force). ...
... Similar effects are expected from MAVA-treatment, as also proposed in Scellini et al. (2021). Furthermore, cardiac MFs that were partially relaxed to a low level of force (e.g., ≤6% of F max ) showed delayed and slower relaxation (i.e., reduced fast k REL ) than MFs which were fully relaxed (Stehle et al., 2009). Thus, if there is incomplete inactivation of cross-bridges due to elevated diastolic Ca 2+ levels, it feeds back on relaxation kinetics (Stehle et al., 2009;Scellini et al., 2017). ...
Iorga and Kraft discuss a recent investigation on force inhibition by mavacamten in ventricular and skeletal myofibrils.
