The two mutations of actin–myosin interface and their effect on the dynamics,structures, and functions of skeletal muscle actin

Congenital myopathy is a broad category of muscular diseases with symptoms appearing at the time of birth. One type of congenital myopathy is Congenital Fiber Type Disproportion (CFTD), a severely debilitating disease. The G48D and G48C mutations in the D-loop and the actin–myosin interface are the two causes of CFTD. These mutations have been shown to significantly affect the structure and function of muscle fibers. To the author’s knowledge, the effects of these mutations have not yet been studied. In this work, the power stroke structure of the head domain of myosin and the wild and mutated types of actin were modeled. Then, a MD simulation was run for the modeled structures to study the effects of these mutations on the structure, function, and molecular dynamics of actin. The wild and mutated actins docked with myosin showed differences in hydrogen bonding patterns, free binding energies, and hydrogen bond occupation frequencies. The G48D and G48C mutations significantly impacted the conformation of D-loops because of their larger size compared to Glycine and their ability to interfere with the polarity or hydrophobicity of this neutralized and hydrophobic loop. Therefore, the mutated loops were unable to fit properly into the hydrophobic groove of the adjacent G-actin. The abnormal structure of D-loops seems to result in the abnormal assembly of F-actins, giving rise to the symptoms of CFTD. It was also noted that G48C and G48D did not form hydrogen bonds with myosin in the residue 48 location. Nevertheless, in this case, muscles are unable to contract properly due to muscle atrophy.     

Index for estimation of muscle force from mechanomyography based on the Lempel–Ziv algorithm

The study of the amplitude of respiratory muscle mechanomyographic (MMG) signals could be useful in clinical practice as an alternative non-invasive technique to assess respiratory muscle strength. The MMG signal is stochastic in nature, and its amplitude is usually estimated by means of the average rectified value (ARV) or the root mean square (RMS) of the signal. Both parameters can be used to estimate MMG activity, as they correlate well with muscle force. These estimations are, however, greatly affected by the presence of structured impulsive noise that overlaps in frequency with the MMG signal. In this paper, we present a method for assessing muscle activity based on the Lempel–Ziv algorithm: the Multistate Lempel–Ziv (MLZ) index. The behaviour of the MLZ index was tested with synthesised signals, with various amplitude distributions and degrees of complexity, and with recorded diaphragm MMG signals. We found that this index, like the ARV and RMS parameters, is positively correlated with changes in amplitude of the diaphragm MMG components, but is less affected by components that have non-random behaviour (like structured impulsive noise). Therefore, the MLZ index could provide more information to assess the MMG–force relationship.     

A contact model to simulate human–artifact interaction based on force optimization: implementation and application to the analysis of a training machine

Musculoskeletal multibody models are increasingly used to analyze and optimize physical interactions between humans and technical artifacts. Since interaction is conveyed by contact between the human body and the artifact, a computationally robust modeling approach for frictional contact forces is a crucial aspect. In this contribution, we propose a parametric contact model and formulate an associated force optimization problem to simultaneously estimate unknown muscle and contact forces in an inverse dynamic manner from a prescribed motion trajectory. Unlike existing work, we consider both the static and the kinetic regime of Coulomb’s friction law. The approach is applied to the analysis of a leg extension training machine with the objective to reduce the stress on the tibiofemoral joint. The uncertainty of the simulation results due to a tunable parameter of the contact model is of particular interest.     

Experimental determination of sarcomere force–length relationship in type-I human skeletal muscle fibers

The objectives of this study were to measure the active and passive force–length (F–L) relationships in type-I human single muscle fibers and to compare the results to predictions from the sliding filament model (the “standard model”). We measured isometric forces in chemically skinned fibers at different sarcomere lengths (SLs) in separate maximal activations. The experimental tolerance interval for optimal SL was calculated to be (2.37, 2.95 μm), which included the prediction by the standard model (2.64, 2.81 μm). Average passive slack length was 2.22±0.08 μm, and the passive F–L relationship was well described by an exponential function. Best fit lines were used to estimate the ascending and descending limbs from the active F–L data using the average SL obtained from a digital image of the fiber. The experimental descending limb was also estimated using the shortest SL to address the possible effects of sarcomere inhomogeneity (SI). The experimental slopes of the ascending and descending limbs, 0.42 F_o/μm and ?0.52 F_o/μm (vs. ?0.55 F_o/μm with the shortest SL) respectively, F_o being the maximal isometric force, were significantly less in magnitude than those from the standard model. These results suggested that the difference between experimental and standard models was not fully explained by SI and other factors could be important. The broader experimental F–L curve compared to the standard model implies that human muscle has functionally a wider operating length range where its force-generating capacity is not compromised.     

History-dependent properties of skeletal muscle myofibrils contracting along the ascending limb of the force–length relationship

There is a history dependence of skeletal muscle contraction: stretching activated muscles induces a long-lasting force enhancement, while shortening activated muscles induces a long-lasting force depression. These history-dependent properties cannot be explained by the current model of muscle contraction, and its mechanism is unknown. The purposes of this study were (i) to evaluate if force enhancement and force depression are present at short lengths (the ascending limb of the force–length (FL) relationship), (ii) to evaluate if the history-dependent properties are associated with sarcomere length (SL) non-uniformity and (iii) to determine the effects of cross-bridge (de)activation on force depression. Rabbit psoas myofibrils were isolated and attached between two microneedles for force measurements. Images of the myofibrils were projected onto a linear photodiode array for measurements of SL. Myofibrils were activated by either Ca²⁺ or MgADP; the latter induces cross-bridge attachment to actin independently of Ca²⁺. Activated myofibrils were subjected to three stretches or shortenings (approx. 4% SL at approx. 0.07 µm s⁻¹ sarcomere⁻¹) along the ascending limb of the FL relationship separated by periods (approx. 5 s) of isometric contraction. Force after stretch was higher than force after shortening at similar SLs. The differences in force could not be explained by SL non-uniformity. The FL relationship produced by Ca²⁺- and MgADP-activated myofibrils were similar in stretch experiments, but after shortening MgADP activation produced forces that were higher than Ca²⁺ activation. Since MgADP induces the formation of strongly bound cross-bridges, this result suggests that force depression following shortening is associated with cross-bridge deactivation.     

Multiple stimulations for muscle–nerve–blood vessel unit in compensatory hypertrophied skeletal muscle of rat surgical ablation model

Tissue inflammation and multiple cellular responses in the compensatory enlarged plantaris (OP Plt) muscle induced by surgical ablation of synergistic muscles (soleus and gastrocnemius) were followed over 10 weeks after surgery. Contralateral surgery was performed in adult Wistar male rats. Cellular responses in muscle fibers, blood vessels and nerve fibers were analyzed by immunohistochemistry and electron microscopy. Severe muscle fiber damage and disappearance of capillaries associated with apparent tissue edema were observed in the peripheral portion of OP Plt muscles during the first week, whereas central portions were relatively preserved. Marked cell activation/proliferation was also mainly observed in peripheral portions. Similarly, activated myogenic cells were seen not only inside but also outside of muscle fibers. The former were likely satellite cells and the latter may be interstitial myogenic cells. One week after surgery, small muscle fibers, small arteries and capillaries and several branched-muscle fibers were evident in the periphery, thus indicating new muscle fiber and blood vessel formation. Proliferating cells were also detected in the nerve bundles in the Schwann cell position. These results indicate that the compensatory stimulated/enlarged muscle is a suitable model for analyzing multiple physiological cellular responses in muscle–nerve–blood vessel units under continuous stretch stimulation. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A physiologically based model of pest–natural enemy interactions

The population dynamic processes in aphids and mites are very similar, because the two groups show strong similarities in their biology. Resource limitation, density-dependent emigration and natural enemies are major factors controlling aphid and mite populations, but an assessment of their relative importance has proven difficult. We used a physiologically based simulation model to investigate the relative impact of the three factors on aphid pest populations. The present simulation model includes winter wheat, three aphid species, Metopolophium dirhodum (Wlk.), Rhopalosiphum padi (L.) and Sitobion avenae (F.) (Hom.: Aphididae) and three parasitoids, Aphelinus abdominalis Dalman (Hym.: Apheliniidae), Aphidius rhopalosiphi De Stefani-Perez and Praon volucre (Hal.) (Hym.: Aphidiidae). We derived and parameterized the model from literature data and validated it against independent field data. The study showed that resource limitation and density-dependent alate production restricts aphid numbers in the field. The mortality due to parasitoids increased late in the season and reduced the peak aphid numbers only moderately. The modelling approach we used is appropriate for simulating other pest–natural enemy systems, such as the spider mite–predatory mite system. Using an object-oriented modelling framework as a template, acarologists can now efficiently develop the simulation model of their choice. This revised version was published online in November 2006 with corrections to the Cover Date.     

Biomechanical characterization of ventricular–arterial coupling during aging: A multi-scale model study

Left ventricular–arterial (VA) coupling has been recognized to be of great significance in understanding both the global and local mechanical performance of the circulatory system. In this study, a closed-loop multi-scale model of the human cardiovascular system is established for the purpose of studying the coupled VA hemodynamic changes during aging. Obtained results show that age-associated changes in arterial properties have some negative but relatively small influences on left ventricular (LV) mechanical performance, whereas they progressively increase LV and aortic systolic pressures, and aortic pulse pressure during aging. Wave analysis reveals that increased aortic characteristic impedance and premature wave reflection induced by arterial stiffening are two coexistent factors responsible for aortic systolic hypertension and increased aortic pulse pressure at old age. In contrast, aortic dilatation can partly counteract the negative influences of arterial stiffening. Coupled LV-systolic and arterial stiffening (a constant VA coupling index) well preserves LV mechanical performance given normal LV diastolic function during aging, but with a concomitant further elevation of LV and aortic systolic pressures. Furthermore, it is found that the states of arterial, LV-systolic and diastolic stiffness can be distinguished by investigating the sensitivity of LV-systolic pressure to various cardiac indices.     

Validation of a fluid–structure interaction numerical model for predicting flow transients in arteries

Fluid–structure interaction (FSI) numerical models are now widely used in predicting blood flow transients. This is because of the importance of the interaction between the flowing blood and the deforming arterial wall to blood flow behaviour. Unfortunately, most of these FSI models lack rigorous validation and, thus, cannot guarantee the accuracy of their predictions. This paper presents the comprehensive validation of a two-way coupled FSI numerical model, developed to predict flow transients in compliant conduits such as arteries. The model is validated using analytical solutions and experiments conducted on polyurethane mock artery. Flow parameters such as pressure and axial stress (and precursor) wave speeds, wall deformations and oscillating frequency, fluid velocity and Poisson coupling effects, were used as the basis of this validation. Results show very good comparison between numerical predictions, analytical solutions and experimental data. The agreement between the three approaches is generally over 95%. The model also shows accurate prediction of Poisson coupling effects in unsteady flows through flexible pipes, which up to this stage have only being predicted analytically. Therefore, this numerical model can accurately predict flow transients in compliant vessels such as arteries.     

Intracellular effect of β3-adrenoceptor agonist Carazolol on skeletal muscle,a direct interaction with SERCA

Carazolol (CZL) is a known agonist of β3 and antagonist of β1 and β2 adrenoceptors (AR), used in the animal production industry to improve meat quality by reducing animal stress and skeletal muscle (SM) proteolysis. Here we sought to better understand the direct effect CZL has on SM. We study CZL effect on calcium (Ca²⁺) regulation by enzymatic activity kinetics of the Ca²⁺-ATPase (SERCA), in isolated sarcoplasmic reticulum (SR) from SM and on the mechanical properties of isolated muscle. In isolated SR from SM previously incubated with 0.03 mM CZL, but absent during SR isolation and during SERCA activity determination, the activity was reduced by 45%. Thermal analysis of SERCA activity with CZL shifted the transition temperature of inactivation (T_i) from T_i = 47 to 44 °C. When isolated SR from fast and slow SM was exposed to CZL, inhibition of SERCA occurred in a dose dependent manner. Slow and fast SM T_i of SERCA shifted to a lower temperature in the presence of CZL and a second transition appears at temperatures <40 °C. In isolated extensor digitorum longus (EDL) and soleus muscles, CZL reduces the contraction force and increases susceptibility to fatigue. However, recovery force after fatigue in either muscle was higher. Our results suggest that Carazolol penetrates the plasma membrane and interacts with SERCA, thus having an important effect on skeletal muscle function. The inhibition of SERCA may lead to a decrement in SR Ca²⁺-release promoting further failure in muscle contraction.     

ProPose: a docking engine based on a fully configurable protein–ligand interaction model

Virtual high-throughput screening of molecular databases and in particular high-throughput protein–ligand docking are both common methodologies that identify and enrich hits in the early stages of the drug design process. Current protein–ligand docking algorithms often implement a program-specific model for protein–ligand interaction geometries. However, in order to create a platform for arbitrary queries in molecular databases, a new program is desirable that allows more manual control of the modeling of molecular interactions.For that reason, ProPose, an advanced incremental construction docking engine, is presented here that implements a fast and fully configurable molecular interaction and scoring model. This program uses user-defined, discrete, pharmacophore-like representations of molecular interactions that are transformed on-the-fly into a continuous potential energy surface, allowing for the incorporation of target specific interaction mechanisms into docking protocols in a straightforward manner. A torsion angle library, based on semi-empirical quantum chemistry calculations, is used to provide minimum energy torsion angles for the incremental construction algorithm. Docking results of a diverse set of protein–ligand complexes from the Protein Data Bank demonstrate the feasibility of this new approach.As a result, the seamless integration of pharmacophore-like interaction types into the docking and scoring scheme implemented in ProPose opens new opportunities for efficient, receptor-specific screening protocols. Figure ProPose — a fully configurable protein-ligand docking program — transforms pharmacophores into a smooth potential energy surface.This revised version was published online in October 2004 with corrections to the Graphical Abstract.     

A stochastic model for the spatial distribution of species based on an aggregation–repulsion rule

The heterogeneity associated with the spatial distribution of organisms is an awkward problem in ecology because this heterogeneity directly depends on the sampling scale. To specify the scope of the influence of sampling scale on the level of species aggregation, we need data sets that entail excessive sampling costs in situ. To find a solution for this problem, we can use models to simulate patterns of organisms. These models are often very complex models that take into account heterogeneity of habitats and displacement or longevity of studied species. In this article, we introduce a new stochastic model to simulate patterns for one taxon and we want this model to be parsimonious, i.e., with few parameters and able to simulate observed patterns. This model is based on an aggregation–repulsion rule. This aggregation–repulsion rule is defined by two parameters. On a large scale, the number of aggregates present on the pattern is the first parameter. On a smaller scale, the level of aggregation–repulsion among individuals is determined by a probability distribution. These two parameters are estimated from field data set in a robust way so that the simulated patterns reflect the observed heterogeneity. We apply this model to entomological data: four Diptera families, namely the Sciaridae, Phoridae, Cecidomyiidae, and Empididae. The field data for the Phoridae family are used to simulate sampling using different trap sizes. We record changes in the coefficient of variation (C) as a function of the sampling scale, and we can suggest to ecologists emergence traps of 0.6 m², in other words a square 77 × 77 cm trap, to obtain a C value under 20%. Received: February 28, 2000 / Accepted: October 14, 2000     

A numerical model of cellular blebbing: A volume-conserving,fluid–structure interaction model of the entire cell

In animal cells, blebs are smooth, quasi-hemispherical protrusions of the plasma membrane that form when a section of the membrane detaches from the underlying actin cytoskeleton and is inflated by flowing cytosol. The mechanics behind this common cellular activity are not yet clear. As a first step in the development of a full computational framework, we present a numerical model of overall cell behavior based upon the interaction between a background Newtonian-fluid cytosol and elastic structures modeling the membrane and filaments. The detailed micromechanics of the cytoskeletal network are the subject of future work. Here, the myosin-driven contraction of the actin network is modeled through stressed elastic filaments. Quantitative models of cytoskeletal micromechanics and biochemistry require accurate estimates of local stress and flow conditions. The main contribution of this paper is the development of a computationally efficient fluid–structure interaction model based on operator splitting, to furnish this data. Cytosol volume conservation (as supported by experimental evidence) is enforced through an intermediate energy minimization step. Realistic bleb formation and retraction is observed from this model, offering an alternative formulation to positing complex continuum behavior of the cytoplasm (e.g. poroelastic model of Charras et al., 2008).     

Effects of long-term taurine supplementation on age-related changes in skeletal muscle function of Sprague–Dawley rats

Taurine (2-aminoethanesulfonic acid) is a free amino acid found abundantly in mammalian tissues. Increasing evidence suggests that taurine plays a role in the maintenance of skeletal muscle function and increase of exercise capacity. Most energy drinks contain this amino acid; however, there is insufficient research on the effects of long-term, low-dose supplementation of taurine. In this study, we investigated the effects of long-term administration of taurine at low doses on aging in rodents. In Experiment 1, we examined age-related changes in aging Sprague–Dawley (SD) rats (32–92 weeks old) that O₂ consumption and spontaneous activity decreased significantly with aging. In Experiment 2, we examined the effects of long-term (21-week) administration of taurine on healthy aging SD rats. SD rats were stabilized for 32–34 weeks and divided into three groups, administrated water (control), 0.5% taurine (25 mg/kg  body weight (BW)/day), or 1% taurine (50 mg/kg  BW/day) from age 34 to 56 weeks (5 days/week, 5 mL/kg BW). Our findings suggest that long-term administration of taurine at relatively low dose could attenuate the age-related decline in O₂ consumption and spontaneous locomotor activity. Upon intestinal absorption, taurine might modulate age-related changes in respiratory metabolism and skeletal muscle function via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), succinate dehydrogenase (SDH), cytochrome c (Cycs), myocyte enhancer factor 2A (MEF2A), glucose transporter 4 (GLUT4), and myoglobin, which are regulated by the activation of AMP-activated protein kinase (AMPK). This article examines the mechanism underlying the effects of taurine on age-related changes, which may have potential clinical implications.

     

Influence of experimental conditions on visco-hyperelastic properties of skeletal muscle tissue using a Box–Behnken design

The Mechanical characterization of skeletal muscles is strongly dependent on numerous experimental design factors. Nevertheless, significant knowledge gaps remain on the characterization of muscle mechanics and a large number of experiments should be implemented to test the influence of a large number of factors. In this study, we propose a design of experiment method (DOE) to study the parameter sensitivity while minimizing the number of tests. A Box-Behnken design was then implemented to study the influence of strain rate, preconditioning and preloading conditions on visco-hyperelastic mechanical parameters of two rat forearm muscles. The results show that the strain rate affects the visco-hyperelastic parameters for both muscles. These results are consistent with previous work demonstrating that stiffness and viscoelastic contributions increase with strain rate. Thus, DOE has been shown to be a valid method to determine the effect of the experimental conditions on the mechanical behaviour of biological tissues such as skeletal muscle. This method considerably reduces the number of experiments. Indeed, the presented study using 3 parameters at 3 levels would have required at least 54 tests per muscle against 14 for the proposed DOE method.     

Remodeling of calcium handling in skeletal muscle through PGC-1α: impact on force, fatigability, and fiber type

Regular endurance exercise remodels skeletal muscle, largely through the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α promotes fiber type switching and resistance to fatigue. Intracellular calcium levels might play a role in both adaptive phenomena, yet a role for PGC-1α in the adaptation of calcium handling in skeletal muscle remains unknown. Using mice with transgenic overexpression of PGC-1α, we now investigated the effect of PGC-1α on calcium handling in skeletal muscle. We demonstrate that PGC-1α induces a quantitative reduction in calcium release from the sarcoplasmic reticulum by diminishing the expression of calcium-releasing molecules. Concomitantly, maximal muscle force is reduced in vivo and ex vivo. In addition, PGC-1α overexpression delays calcium clearance from the myoplasm by interfering with multiple mechanisms involved in calcium removal, leading to higher myoplasmic calcium levels following contraction. During prolonged muscle activity, the delayed calcium clearance might facilitate force production in mice overexpressing PGC-1α. Our results reveal a novel role of PGC-1α in altering the contractile properties of skeletal muscle by modulating calcium handling. Importantly, our findings indicate PGC-1α to be both down- as well as upstream of calcium signaling in this tissue. Overall, our findings suggest that in the adaptation to chronic exercise, PGC-1α reduces maximal force, increases resistance to fatigue, and drives fiber type switching partly through remodeling of calcium transients, in addition to promoting slow-type myofibrillar protein expression and adequate energy supply.     

A signature predicting relapse based on integrated analysis on relapse-associated alternative mRNA splicing in I–III rectal cancer

Researches focusing on the effects of alternative splicing (AS) on relapse of rectal cancer is little and signature based on the AS is blank. In this study, bioinformatic analysis was performed to identify and analyze the relapse-associated ASs, a signature was also constructed. In conclusion, 829 relapse-associated ASs of 676 mRNA were identified. 603 proteins with 2119 interactions were involved in the PPI (protein-protein interactions) network. 43 relapse-associated ASs and 64 SFs (splicing factors) with 160 interactions were indicated. Finally, we built a robust signature to predict the relapse of I–III rectal cancer with a high AUC (0.98) of ROC at 1 year. Based on the ASs involved in the signature, 4 molecular subgroups that could distinguish the relapse rate in diverse groups were identified. Our research provided an overview of relapse-associated ASs in I–III rectal cancer.     

Deep radiomic model based on the sphere–shell partition for predicting treatment response to chemotherapy in lung cancer

BackgroundThe prognosis of chemotherapy is important in clinical decision-making for non-small cell lung cancer (NSCLC) patients.ObjectivesTo develop a model for predicting treatment response to chemotherapy in NSCLC patients from pre-chemotherapy CT images.Materials and MethodsThis retrospective multicenter study enrolled 485 patients with NSCLC who received chemotherapy alone as a first-line treatment. Two integrated models were developed using radiomic and deep-learning-based features. First, we partitioned pre-chemotherapy CT images into spheres and shells with different radii around the tumor (0–3, 3–6, 6–9, 9–12, 12–15 mm) containing intratumoral and peritumoral regions. Second, we extracted radiomic and deep-learning-based features from each partition. Third, using radiomic features, five sphere–shell models, one feature fusion model, and one image fusion model were developed. Finally, the model with the best performance was validated in two cohorts.ResultsAmong the five partitions, the model of 9–12 mm achieved the highest area under the curve (AUC) of 0.87 (95% confidence interval: 0.77–0.94). The AUC was 0.94 (0.85–0.98) for the feature fusion model and 0.91 (0.82–0.97) for the image fusion model. For the model integrating radiomic and deep-learning-based features, the AUC was 0.96 (0.88–0.99) for the feature fusion method and 0.94 (0.85–0.98) for the image fusion method. The best-performing model had an AUC of 0.91 (0.81–0.97) and 0.89 (0.79–0.93) in two validation sets, respectively.ConclusionsThis integrated model can predict the response to chemotherapy in NSCLC patients and assist physicians in clinical decision-making.