Force Generation Research Articles

Neuromusculoskeletal Modeling and Force Prediction: Verification Through Experimental Neuromuscular Dynamics

Abstract Purpose Neuromusculoskeletal (NMS) function is influenced by the interactions between neural and musculoskeletal systems. Age-related changes in motor unit morphology contribute to changes in motor control and force production with advancing age; however, a better understanding of the underlying mechanisms between force production and motor unit reorganization and their interrelationships is needed to develop targeted therapies and interventions to age-related changes. Direct experimental measurement of these neuromuscular changes is challenging due to ethical and logistical constraints and the complexity of isolating individual motor unit contributions in vivo, particularly across time. Computational modeling provides a complementary approach which can help bridge this gap. The objective of this study is to develop a computational framework for predicting dorsiflexion force profiles through the translation of experimental motor unit recordings into simulated musculoskeletal responses. Methods This study presents the development of a combined NMS model that integrates experimental motor unit recordings into a musculoskeletal simulation framework. Specifically, the NMS model predicts dorsiflexion force profiles by translating experimental data from high-density electromyography recordings into simulated subject-specific motor unit discharge characteristics and simulated muscle responses. The NMS model incorporates a detailed motor neuron pool simulation and a finite element musculoskeletal model, allowing for physiologically accurate representation of motor unit discharge characteristics, muscle force generation, and force variability. Results The accuracy of the simulated force profiles in predicting the experimental force were 10.25 N and 0.95, respectively, for average root mean square error and R2 values. Results demonstrate strong agreement between simulated and experimental force profiles and motor unit recordings. Conclusion By bridging the gap between computational and experimental approaches, this study aims to enhance understanding of NMS dynamics and support the development of personalized treatment strategies for neurodegenerative disease patients.

LATS1/2-Integrin Axis Confers Tumor-Generated Forces That Activate Neighboring Fibroblasts.

Tumors generate various forces during growth and progression, which in turn promote tumor development. Although fibroblasts are considered the primary force generators in the tumor microenvironment, recent studies have shown that cancer cells also generate considerable tensile forces. However, the roles that these forces play in the tumor microenvironment and the pathways regulating this process remain largely unknown. Here, we demonstrated that the Hippo pathway-associated kinases, LATS1/2, in cancer cells are essential for collective force generation and fibroblast activation via extracellular matrix-mediated cell-cell interactions. In murine breast cancer 4 T1 spheroids, the deletion of LATS1/2 dampened force generation and disrupted reorganization of the surrounding collagen matrix. LATS1/2-mediated mechanical forces of tumors are required for fibroblast activation and differentiation into mechanoresponsive fibroblasts. Mechanistically, LATS1/2 regulate tumor force generation through the expression of collagen receptor integrins. Our findings not only identify the Hippo pathway as a critical regulator of tumor force generation but also suggest potential strategies for targeting it in cancer therapy from a mechanobiological perspective, offering new avenues in the fight against cancer.

The elementary step that generates force and sinusoidal analysis in striated muscle fibers.

The elementary step that generates force by cross-bridges (CBs) in striated muscles is reviewed. A literature search focused on models with validating data to verify a CB scheme; models without substantiating data were briefly mentioned or not included. Experimental data include those carried out under the isometric condition in muscle fibers and single myofibrils, along with results from single molecule and stopped-flow studies. These results suggest that force is generated before phosphate (Pi) is released, and the same force is maintained after Pi is released. These studies assumed that Pi is released from myosin. Some results from isotonic experiments are also reviewed, but the data lack the effect of Pi (or a weak effect). Studies with X-ray crystallography and cryo-electron microscopy suggested that force is generated after Pi release from the active site, and Pi is trapped at the secondary site before it is released to the solution. Thus, the difference in the definition of the "Pi release step" must have caused a controversy. It can be concluded that the results from physiological/single molecule studies and cryo-EM/crystal studies complement each other quite well. With isometric experiments, several perturbations are used to generate force transients: length change, chemical change, pressure release, and temperature increase. A small length change includes sinusoidal waveforms, and a large length change includes 10-20% release/restretch. Chemical perturbation includes [Pi] changes. With temperature studies it was shown that the force generation step is endothermic, indicating heat is absorbed. This is qualitatively explained by a hydrophobic interaction between actin and myosin, and by a cleft closure of myosin.

Modulation of striated-muscle contractility by a high-affinity myosin-targeting peptide.

Modulation of striated-muscle contractility by a high-affinity myosin-targeting peptide.

An Airfoil Science Including Causality

Traditional simple explanations of how air flow generates aerodynamic lift neither identify fundamental mechanisms for the generation of lift pressures (i.e. causality) nor account for dissipation losses across streamlines. By comparison, the Navier-Stokes equation explicitly includes pressure dissipation and implicitly includes the mechanism for the generation of lift forces in surface boundary conditions. This paper critically evaluates computational fluid dynamic (CFD) simulation results to better understand how lift pressure generation and dissipation impact lift and drag on airfoils and lifting bodies. Three basic-physics’ principles emerge as fundamentally correct and insightful without the complexities of partial differential equations. Examples are provided on how the insight gained from fundamentally-correct simple explanations are advancing: a) new frontiers in solar and ground-effect aviation and b) insight into lost work and phenomena like boundary layer separation.

Exploring gastrocnemius medialis behavior during gait in children with cerebral palsy across different gait patterns.

Exploring gastrocnemius medialis behavior during gait in children with cerebral palsy across different gait patterns.

Filaments repel while muscles propel: conservation of energy explains length-dependent lattice spacing in sarcomeres.

The radial lattice spacing (LS) of actin and myosin filaments within a sarcomere changes substantially during muscle contraction. While these changes have been phenomenologically attributed to the constant-volume characteristic of lattice unit cells, the underlying mechanism remained unresolved. Here, I present a novel model that, for the first time, explains these observations by invoking the principle of constant internal energy. Based on electrostatic repulsion between charged filaments in an ionic medium, the model predicts length-dependent LS adaptations that maintain an energetic equilibrium as filament overlap varies. The resulting LS behavior closely follows experimental data across a wide range of sarcomere lengths. Rooted in fundamental physics and applicable to different muscle types, this approach provides new insight into the structural dynamics of the sarcomere and its role in muscle force generation.

Jaw muscle architecture in the greater rhea (Rhea americana): Morphological patterns and postnatal ontogeny in an herbivorous bird.

Jaw muscle architecture in the greater rhea (Rhea americana): Morphological patterns and postnatal ontogeny in an herbivorous bird.

Acute Effects of Static Stretching on Submaximal Force Control of the Ankle

Static stretching (SS) is widely used in clinical and sports settings. However, the acute effects on neuromuscular control during dynamic tasks remain unclear. This study aimed to examine the immediate effects of SS on force control using a randomized crossover design. Seventeen healthy young males performed low-range (10–30% of maximal voluntary isometric contraction: MVIC) and high-range (40–60% MVIC) isometric force tracking tasks. In the SS condition, the ankle plantar flexors were stretched for 60 s; in the control condition, the participants remained at rest. The primary outcomes included ankle dorsiflexion range of motion (ROM), musculotendinous stiffness, and the root mean square error (RMSE) of force tracking. Compared to the control group, SS significantly increased dorsiflexion ROM and reduced musculotendinous stiffness. A significant reduction in the RMSE was observed during the force release phase when participants smoothly decreased force output in the high-range task following SS (p = 0.030, d = 0.79), but no significant changes were found during the force generation phase in the high-range task or during either phase (generation or release) in the low-range task. These findings suggest that a brief SS intervention may acutely refine the dynamic force control under high neuromuscular demands. Therefore, SS may enhance motor control in tasks that involve submaximal force modulation.

Prevention of Mercury-Induced Cardiotoxicity After Short-Term Egg White Hydrolysate Supplementation in Rats.

Mercury exposure triggers localized oxidative stress, playing a central role in its detrimental effects, because toxic levels of ROS induce lipid peroxidation, promote protein oxidation and nitration, and nucleic acid oxidation and damage. Egg white hydrolysate (EWH), a functional food, is a protein extract that has promising capabilities against metal-induced cardiovascular damage. However, its potential in preventing the acute effects of mercury exposure remains unexplored. This study evaluated the preventive efficacy of 3days, a short-term EWH treatment against the subsequent acute exposure to HgCl2 in isolated left ventricle papillary muscles. Male Wistar rats were divided into four groups: Control, EWH, HgCl2 and EWH + HgCl2. Animals received filtered water or EWH (1g/kg/day) via oral gavage for 3days as pre-treatment. Subsequently, papillary muscles were isolated, and then HgCl2 and EWH + HgCl2 groups were exposed to 6nM HgCl2 for 60min. Results revealed that acute HgCl2 exposure impaired force generation, positive and negative time derivatives of force, indicating contractile dysfunction. Notably, these effects were absent in the EWH + HgCl2 group. Furthermore, HgCl2 exposure depressed post-rest potentiation, inotropic response protocols to calcium and isoproterenol while the EWH + HgCl2 group exhibited comparable responses to the control group. Besides that, the increase in ROS levels induced by HgCl2 in vitro was prevented by EWH pre-treatment. In conclusion, EWH demonstrated a cardioprotective effect by preserving contractile function, maintaining physiological inotropic responses, and preventing ROS accumulation with a remarkably brief 3-day pre-treatment period, highlighting its potential against the deleterious effects of acute mercury exposure, particularly in unavoidable or unpredictable exposures.

Developmental cues from epicardial cells simultaneously promote cardiomyocyte proliferation and electrochemical maturation.

Developmental cues from epicardial cells simultaneously promote cardiomyocyte proliferation and electrochemical maturation.

Muscle function and electromyography: (almost) 70 years since Doty and Bosma (1956).

Swallowing, and dysphagia, the pathophysiology of swallowing, differ from most motor activities in that they are not readily observable without invasive imaging or measurement. Successful swallowing depends more on the precision of control and coordination with respiration than it does on force or work generation, which differs from many other motor tasks. Electromyography (EMG), an essential method for investigating motor function in general, has become critical to understanding the physiology of swallowing. In 1956, Doty and Bosma published a landmark paper using EMG to describe the motor pattern of a swallow. Since then, the specific methods of bi-polar indwelling electrodes have not significantly changed, but our understanding of muscle and ability to analyze EMG data has grown remarkably. Advances in imaging and quantitative analysis, largely derived from studies of fine motor control of the limbs and locomotion, are a boon to studies of swallowing and have advanced our understanding of neural control. EMG patterns are a direct readout of central motor control and are valuable for determining the evolution of swallowing, the normal physiology of swallowing, and the pathophysiology of dysphagia. The potential for increasing our knowledge of these aspects of swallowing is high, given current advances in EMG technique and analysis. Here, we briefly discuss the current state of our knowledge of the motor control of the swallow, review what we have learned in the past 70 years about the swallow, and end by highlighting how embracing novel technologies and techniques will enable us to further understand the neural control of this critical behavior.

Modeling Epithelial Morphogenesis and Cell Rearrangement during Zebrafish Epiboly: Tissue Deformation, Cell-Cell Coupling, and the Mechanical Response to Stress

Morphogenesis in early development involves complex and extreme deformations in response to intra- and intercellular forces. Zebrafish epiboly, the spreading of the blastoderm to cover and engulf the large yolk cell, is a key early event that sets the stage for the establishment of the body plan, but the way the forces driving expansion are generated and mediated is poorly understood. The enveloping layer (EVL), the thin squamous outer epithelium of the blastoderm, plays a central role. Forces generated in the yolk cell are transmitted through tight junctions to the marginal EVL cells, and then propagate through the rest of the EVL. To understand mechanisms of force generation and transduction during epiboly, we first need a mechanical model of the EVL capable of responding to such forces and undergoing the drastic deformation of epiboly. The expanding EVL more than doubles its surface area and experiences significant shear as it deforms from a thin cap at one pole to become a complete sphere, necessarily requiring extensive internal rearrangement. We constructed an agent-based model of the EVL and its response to exogenous forces using the center-based simulation framework, Tissue Forge. Our model captures the large viscoelastic deformation of the EVL by cell rearrangement, and incorporates algorithmic strategies to accommodate these dynamic changes while maintaining tissue cohesion. Features observed in living embryos, such as the straightening of the initially ragged leading edge, also emerge in the model. We identified two key components required for realistic epiboly in the model: first, a mechanism to enable tissue remodeling by cell rearrangement without tearing the tissue, and second, a negative feedback on the forces driving EVL expansion, to regulate and synchronize the advancement of the EVL margin. We discuss the implications of these findings for the behavior of living EVL and the mechanisms that drive epiboly.

Consolidation of cell-ECM adhesion through direct talin-mediated actin linkage is essential for mouse embryonic morphogenesis

During animal development, cell-ECM adhesion mediated by integrins is required for the assembly and maintenance of tissues and organs. It can either be transient or stable and requires linking integrins to the cytoskeleton. Talin can link integrins to actin either directly through its actin-binding sites (ABSs) or indirectly by recruiting downstream actin-binding molecules. In Drosophila, talin’s ABS3 domain is essential for biological functions, but its role remains unknown in mammalian systems. Here, we investigate the role of direct talin-mediated actin linkage in mammals by generating a mouse model containing point mutations in talin’s ABS3 domain. We find that mutant mice exhibit early developmental defects and die midway through embryogenesis. Primary mouse embryonic fibroblasts generated from mutants form prominent focal adhesions but show defective consolidation and maturation. Adhesion dynamics, cell spreading, actin dynamics and organization, and traction force generation are also impacted in mutants, which affect processes such as cell migration that impinge on multiple events during early mouse embryogenesis. Overall, our work provides key mechanistic insights into how direct coupling of ECM to actin through talin has specific and critical roles in controlling adhesion dynamics required for early mammalian development.

How does the multi-segment foot model influence the joint torque contribution to the generation of ground reaction force during the stance phase of running?

How does the multi-segment foot model influence the joint torque contribution to the generation of ground reaction force during the stance phase of running?

Systematic analysis of structural disorder in the minimal proteome of Mycoplasma pneumoniae.

Mycoplasma pneumoniae (Mpn, class Mollicutes) is both an important human pathogen and a model organism. We performed a proteome-wide investigation of intrinsically disordered regions (IDRs) in Mpn. Compared to other bacteria, a considerable fraction of the Mpn proteome (17%) is embedded in IDRs, which are abundant in membrane, non-essential proteins, as well as in proteins that mediate cytoadherence and virulence. Notably, proteins that form the attachment organelle, a specialized structure, are particularly rich in IDRs. Likewise, analysis of protein architectures indicated that some Mollicute-specific domains are preferentially associated with IDRs. Perusal of proteome-wide data also revealed that, as in eukaryotes, structural disorder associates with higher protein degradation rates and that Mpn IDRs are preferential targets of phosphorylation. When we investigated the ensemble features for Mpn IDRs, we used two predictors and benchmarked the results using coarse-grained simulations. We found that ensemble properties are mediated by similar sequence features as in eukaryotes, so that compact IDRs tend to have high residue stickiness, high hydropathy decoration, and few charged residues. We also found that IDRs in attachment organelle proteins are particularly extended and display high conformational entropy. We suggest that these features are exploited for motility through the generation of an entropic force. In summary, our results suggest that structural disorder contributes to very specialized functions in Mpn. Our data also highlight the functional relevance of IDRs, as the minimal proteome of this model organism displays a considerable level of structural disorder.IMPORTANCEWe performed a proteome-wide investigation of intrinsically disordered regions (IDRs) in Mycoplasma pneumoniae (Mpn, class Mollicutes). A considerable fraction of the Mpn proteome (17%) is embedded in IDRs, which tend to be associated with Mollicute-specific domains and are abundant in membrane, non-essential proteins, as well as in proteins that mediate cytoadherence and virulence. As in eukaryotes, structural disorder associates with higher protein degradation rates, and Mpn IDRs are preferential targets of phosphorylation. The ensemble properties of Mpn IDRs are mediated by similar sequence features as in eukaryotes, and IDRs in attachment organelle proteins display high conformational entropy. We suggest that this feature is exploited for motility through the generation of an entropic force. In summary, we show that structural disorder contributes to very specialized functions in Mpn. Our data highlight the functional relevance of IDRs, as the minimal proteome of this model organism displays a considerable level of structural disorder.

Effects of Neuromuscular Priming with Spinal Cord Transcutaneous Stimulation on Lower Limb Motor Performance in Humans: A Randomized Crossover Sham-Controlled Trial

Background: Lower limb motor output contributes to determining functional performance in many motor tasks. This study investigated the effects of non-invasive spinal cord transcutaneous stimulation (scTS) applied during an exercise-based priming protocol on lower limb muscle force and power generation. Methods: Twelve young, physically active male volunteers (age: 22.7 ± 2.1 years) participated in this randomized crossover, sham-controlled study. The maximal voluntary contraction and low-level torque steadiness of knee extensors, as well as the maximal explosive extension of lower limbs, were assessed before and after the priming protocol with scTS or sham stimulation over a total of four experimental sessions. Further, characteristics of evoked potentials to scTS related to spinal circuitry excitability were assessed in the supine position before and after the scTS priming protocol. The exercise component of the ~25 min priming protocol consisted of low-volume, low- and high-intensity lower limb motor tasks. Results: scTS priming protocol tended to increase or maintain maximum isometric torque during knee extension (4.7%) as well as peak force (0.2%) and rate of force development (6.0%) during explosive lower limb extensions, whereas sham priming protocol tended to decrease them (−4.3%, −3.3%, and −15.1%, respectively). This resulted in significant interactions (p = 0.001 to 0.018) and medium–large differences between scTS and sham protocols. These findings were associated with meaningful trends of some neurophysiological variables. Conversely, priming protocols did not affect low-level torque steadiness. Conclusions: scTS counteracted the unexpected fatigue induced by the exercise-based priming protocol, supporting lower limb performance during maximal efforts. Future studies are warranted to assess the implementation of scTS with optimized exercise-based priming protocols during training and rehabilitation programmes that include high-intensity neuromuscular efforts.

Assessment of the histone mark-based epigenomic landscape in human myometrium at term pregnancy

The myometrium plays a critical role during pregnancy as it is responsible for both the structural integrity of the uterus and force generation at term. Emerging studies in mice indicate a dynamic change of the myometrial epigenome and transcriptome during pregnancy to ready the contractile machinery for parturition. However, the regulatory systems underlying myometrial gene expression patterns throughout gestation remain largely unknown. Here, we investigated human term pregnant nonlabor myometrial biopsies for transcriptome, enhancer histone mark cistrome, and chromatin conformation pattern mapping. More than thirty thousand putative enhancers with H3K27ac and H3K4me1 double positive marks were identified in the myometrium. Enriched transcription factor binding motifs include known myometrial regulators AP-1, STAT, NFkB, and PGR among others. Putative myometrial super enhancers are mostly colocalized with progesterone receptor-occupying sites and preferentially associated with highly expressing genes, suggesting a conserved role of PGR in regulating the myometrial transcriptome between species. In human myometrial specimens, inferred PGR activities are positively correlated with phospholipase C like 2 (PLCL2) mRNA levels, supporting that PGR may act through this genomic region to promote PLCL2 expression. PGR overexpression facilitated PLCL2 gene expression in myometrial cells. Using CRISPR activation, we assessed the functionality of a PGR putative enhancer 35 kilobases upstream of the contractile-restrictive gene PLCL2. In summary, the results of this study serve as a resource to study gene regulatory mechanisms in the human myometrium at the term pregnancy stage for further advancing women’s health research.

Assessment of the histone mark-based epigenomic landscape in human myometrium at term pregnancy

The myometrium plays a critical role during pregnancy as it is responsible for both the structural integrity of the uterus and force generation at term. Emerging studies in mice indicate a dynamic change of the myometrial epigenome and transcriptome during pregnancy to ready the contractile machinery for parturition. However, the regulatory systems underlying myometrial gene expression patterns throughout gestation remain largely unknown. Here, we investigated human term pregnant nonlabor myometrial biopsies for transcriptome, enhancer histone mark cistrome, and chromatin conformation pattern mapping. More than thirty thousand putative enhancers with H3K27ac and H3K4me1 double positive marks were identified in the myometrium. Enriched transcription factor binding motifs include known myometrial regulators AP-1, STAT, NFkB, and PGR among others. Putative myometrial super enhancers are mostly colocalized with progesterone receptor-occupying sites and preferentially associated with highly expressing genes, suggesting a conserved role of PGR in regulating the myometrial transcriptome between species. In human myometrial specimens, inferred PGR activities are positively correlated with phospholipase C like 2 (PLCL2) mRNA levels, supporting that PGR may act through this genomic region to promote PLCL2 expression. PGR overexpression facilitated PLCL2 gene expression in myometrial cells. Using CRISPR activation, we assessed the functionality of a PGR putative enhancer 35 kilobases upstream of the contractile-restrictive gene PLCL2. In summary, the results of this study serve as a resource to study gene regulatory mechanisms in the human myometrium at the term pregnancy stage for further advancing women’s health research.

A new dragon-boat rowing machine with visual motion capture technology

In the existing land-based rowing machine training for kayak, dragon boat, and other water sports in the racing category, there are problems such as not being able to restore the posture and situation of the boat during water sports, which greatly affects the training effect. This study involves a new rowing machine, whose fuselage can swing, thus realistically simulating the rowing action. The seat plate and pedal can be adjusted to adapt to athletes of different heights and body types. The position of the lead rope pole is easy to adjust, simulating the situation of rowing on the left and right sides. The fuselage is connected by hinges and an insertion rod, making it easy to store. The 3D force sensor, three-axis sensor, and camera sensor are used to obtain real-time motion data and images of athletes, which is convenient for understanding the movement pattern and efficiency of force generation after training. In the experimental phase, the machine 3D force sensors, motion sensors, and cameras used to capture real-time data of oar force, motion patterns, and paddling efficiency. The experiments demonstrated that the device provides accurate and comprehensive feedback, facilitating motion correction and performance optimization.