Force Generation Research Articles

Grip force release is impaired in parkinson's disease during a force tracking task.

The controlled release of grasping forces underlies skilled dexterous interactions with objects. While declines in force generation and maintenance are well documented in people with Parkinson's disease (PwPD), limited data exist related to how PD impacts the motor control of grasping force release. The aim of this project was to determine how PD impacts grip force release relative to the generation and maintenance of force. It was hypothesized that PwPD would exhibit global deficits in force control relative to controls but would perform disproportionately worse during the controlled release of grip force. Ten PwPD and 10 age-matched controls completed a force-tracking paradigm requiring grip force generation, maintenance, and release. Compared to controls, PwPD were less accurate (i.e. less time within target range), had greater error (i.e. greater relative root mean squared error), and had more trial-to-trial variability in error during grip force release. Ongoing studies are examining the potential neural mechanism(s) underlying of force release impairments in PD, and the relationships between PD severity, manual dexterity, and force release declines.

Macrophages excite muscle spindles with glutamate to bolster locomotion.

The stretch reflex is a fundamental component of the motor system that orchestrates the coordinated muscle contractions underlying movement. At the heart of this process lie the muscle spindles (MS), specialized receptors finely attuned to fluctuations in tension within intrafusal muscle fibres. The tension variation in the MS triggers a series of neuronal eventsincluding an initial depolarization of sensory type Ia afferents that subsequently causes the activation of motoneurons within the spinal cord1,2. This neuronal cascade culminates in the execution of muscle contraction, underscoring a presumed closed-loop mechanism between the musculoskeletal and nervous systems. By contrast, here we report the discovery of a new population of macrophages with exclusive molecular and functional signatures within the MS that express the machinery for synthesizing and releasing glutamate. Using mouse intersectional genetics with optogenetics and electrophysiology, we show that activation of MS macrophages (MSMP) drives proprioceptive sensory neuron firing on a millisecond timescale. MSMP activate spinal circuits, motor neurons and muscles by means of a glutamate-dependent mechanism that excites the MS. Furthermore, MSMP respond to neural and muscle activation by increasing the expression of glutaminase, enabling them to convert the uptakenglutamine released by myocytes during muscle contraction into glutamate. Selective silencing or depletion of MSMP in hindlimb muscles disrupted the modulation of the stretch reflex for force generation and sensory feedback correction, impairing locomotor strategies in mice. Our results have identified a new cellular component, the MSMP, that directly regulates neural activity and muscle contraction. The glutamate-mediated signalling of MSMP and their dynamic response to sensory cues introduce a new dimension to our understanding of sensation and motor action, potentially offering innovative therapeutic approaches in conditions that affect sensorimotor function.

A Simplified Estimation of Spindle Dynamic Compliance from Current Measurement for Contactless Electromagnetic Excitation

Abstract Dynamic stiffness during spindle rotation is important in the performance evaluation of machine tools. A method for measuring dynamic compliance, which is the reciprocal of dynamic stiffness, using a load generator in uniaxial and unidirectional was investigated. An electromagnetic force generation model was experimentally constructed using static coil current and load measurements. Using this model, the vibratory force was calculated. The excitation conditions without gap effect were set and the dynamic compliance was estimated by conducting actual vibration experiments. The estimated dynamic compliance was in good agreement with the dynamic compliance obtained from the force measurement, indicating that the proposed method can perform the measurement efficiently.

Structural and functional insights into activation and regulation of the dynein-dynactin-NuMA complex.

During cell division, NuMA orchestrates the focusing of microtubule minus-ends in spindle poles and cortical force generation on astral microtubules by interacting with dynein motors, microtubules, and other cellular factors. Here we used in vitro reconstitution, cryo-electron microscopy, and live cell imaging to understand the mechanism and regulation of NuMA. We determined the structure of the processive dynein/dynactin/NuMA complex (DDN) and showed that the NuMA N-terminus drives dynein motility in vitro and facilitates dynein-mediated transport in live cells. The C-terminus of NuMA directly binds to and suppresses the dynamics of the microtubule minus-end. Full-length NuMA is autoinhibited, but mitotically phosphorylated NuMA activates dynein in vitro and interphase cells. Together with dynein, activated full-length NuMA focuses microtubule minus-ends into aster-like structures. The binding of the cortical protein LGN to the NuMA C-terminus results in preferential binding of NuMA to the microtubule plus-end. These results provide critical insights into the activation of NuMA and dynein for their functions in the spindle body and the cell cortex.

Stochastic force generation in an isometric binary mechanical system.

Accurate models of muscle contraction are necessary for understanding muscle performance and the molecular modifications that enhance it (e.g., therapeutics, posttranslational modifications, etc.). As a thermal system containing millions of randomly fluctuating atoms that on the thermal scale of a muscle fiber generate unidirectional force and power output, muscle mechanics are constrained by the laws of thermodynamics. According to a thermodynamic muscle model, muscle's power stroke occurs with the shortening of an entropic spring consisting of an ensemble of force-generating myosin motor switches, each induced by actin binding and gated by inorganic phosphate release. This model differs fundamentally from conventional molecular power stroke models that assign springs to myosin motors in that it is physically impossible to describe an entropic spring in terms of the springs of its molecular constituents. A simple two-state thermodynamic model (a binary mechanical system) accurately accounts for muscle force-velocity relationships, force transients following rapid mechanical and chemical perturbations, and a thermodynamic work loop. Because this model transforms our understanding of muscle contraction, it must continue to be tested. Here, we show that a simple stochastic kinetic simulation of isometric muscle force predicts four phases of a force-generating loop that bifurcates between periodic and stochastic beating through mechanisms framed by two thermodynamic equations. We compare these model predictions with experimental data including observations of spontaneous oscillatory contractions (SPOCs) in muscles and periodic force generation in small myosin ensembles.

Cytoskeletal activation of NHE1 regulates mechanosensitive cell volume adaptation and proliferation

Mammalian cells rapidly respond to environmental changes by altering transmembrane water and ion fluxes, changing cell volume. Contractile forces generated by actomyosin have been proposed to mechanically regulate cell volume. However, our findings reveal a different mechanism in adherent cells, where elevated actomyosin activity increases cell volume in normal-like cells (NIH 3T3 and others) through interaction with the sodium-hydrogen exchanger isoform 1 (NHE1). This leads to a slow secondary volume increase (SVI) following the initial regulatory volume decrease during hypotonic shock. The active cell response is further confirmed by intracellular alkalinization during mechanical stretch. Moreover, cytoskeletal activation of NHE1 during SVI deforms the nucleus, causing immediate transcriptomic changes and ERK-dependent growth inhibition. Notably, SVI and its associated changes are absent in many cancer cell lines or cells on compliant substrates with reduced actomyosin activity. Thus, actomyosin acts as a sensory element rather than a force generator during adaptation to environmental challenges.

Effect of acute fatigue on force generation accuracy and repeatability in youth athletes

The study aimed to evaluate the acute effect of the incremental running test on the accuracy and repeatability of submaximal force generation in adolescent athletes (biathletes and runners) with different training regimes. The isometric force generation was assessed in biathletes and runners by examining left and right elbow extension (LEE; REE); flexion (LEF; REF); left and right knee extensions (LKE; RKE) before and after the test. The mean force of 10 sub-maximal targeted force pulses (Fmean) and force variability parameters: standard deviation and coefficient variation were used for accuracy and repeatability estimation. Biathletes generated forces more accurate and exhibit better repeatability of produced forces than runners. Mean force measured in fatigue conditions, for both groups, did not vary significantly from rest measurements. Before testing biathletes exhibited significantly lower REE and LEE, and after testing lower REF and LEF variability than runners. After testing there was a significant drop of variability in elbows flexion but not extension and RKE in biathletes. Insignificant downward trend of variability parameters were found in runners. The presented findings corroborate sport-specific force generation ability alteration in response to exhaustive effort. Tracking force generation over time may be useful in the monitoring of training loads and specific training adaptations.

Differential Effects of Confinement on the Dynamics of Normal and Tumor-Derived Pancreatic Ductal Organoids.

Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the epithelia comprising the ductal network of the pancreas. During disease progression, PDAC tumors recruit fibroblasts that promote fibrosis, increasing local tissue stiffness and subjecting epithelial cells to increased compressive forces. Previous in vitro studies have documented cytoskeletal and nuclear adaptation following compressive stresses in two-dimensional (2D) and three-dimensional (3D) environments. However, a comparison of the responses of normal and tumor-derived ductal epithelia to physiologically relevant confinement remains underexplored, especially in 3D organoids. Here we control confinement with an engineered 3D microenvironment composed of Matrigel mixed with a low yield stress granular microgel. Normal and tumor-derived murine pancreas organoids (normal and tumor) were cultured for 48 h within this composite 3D environment or in pure Matrigel to investigate the effects of confinement on morphogenesis and lumen expansion. In confinement, tumor organoids (mT) formed a lumen that expanded rapidly, whereas normal organoids (mN) expanded more slowly. Moreover, a majority of normal organoids in more-confined conditions exhibited an inverted apicobasal polarity compared to those in less-confined conditions. Tumor organoids exhibited a collective "pulsing" behavior that increased in confinement. These pulses generated forces sufficient to locally overcome the yield stress of the microgels in the direction of organoid expansion. Normal organoids more commonly exhibit unidirectional rotation. Our in vitro microgel confinement platform enabled the discovery of two distinct modes of collective force generation in organoids that may shed light on the mutual interactions between tumors and the microenvironment. These insights into in vitro dynamics may deepen our understanding of how the confinement of healthy cells within a fibrotic tumor niche disrupts tissue organization and function in vivo.

Quantum dot-based thermometry uncovers decreased myosin efficiency in an experimental intensive care unit model.

Critical illness myopathy (CIM) detrimentally affects muscle function in ICU patients, with a dramatic loss of muscle mass and function where the loss in specific force exceeds the loss in muscle mass (maximum force normalized to muscle cross-sectional area). The preferential loss of the molecular motor protein myosin, representing the hallmark of CIM, exhibiting a significant negative impact on the specific force generation by the muscle. Interestingly however, the preferential myosin loss is a relatively late event, and a specific loss in force generation capacity, is observed prior to the myosin loss. In the current study, employing an optimized cadmium telluride quantum dots (QD) mediated-thermometry approach to assess the efficiency of the myosin, we were able to determine the loss in specific force generated by the muscle, prior to the preferential loss of myosin. Reduction in QD fluorescent intensity correlates with greater heat loss, reflecting inefficient myosin function (less mechanical work performed and more heat loss on ATP hydrolysis by myosin). A significant decrease in myosin efficiency was observed in rats subjected to the ICU condition (immobilization and mechanical ventilation) for 5 days using an established experimental ICU model not limited by early mortality. Thus, qualitative myosin changes preceding quantitative myosin loss offer a mechanism underlying the early loss in specific force generation capacity associated with CIM and opens a venue for future CIM intervention strategies.

In-vivo stress measurements in kitesurfing and wakeboarding: implications on load control and preventive approaches - an in-vivo field study.

The trend sports kitesurfing and wakeboarding are increasingly gaining popularity. Tricks and high jumps - both in the air and over obstacles - are performed with increasing difficulty. Repeated high loads on the body, particularly when landing after a jump, can lead to overuse and acute injuries directly related to peak forces, particularly in the lower extremities.There is a lack of detailed analyses of these forces resulting from wakeboarding or kitesurfing, although such data would be relevant for the analysis of injury mechanisms and the subsequent development of prevention strategies. This study is the first of its kind in which the loads on the lower extremity during wakeboarding and kitesurfing were subjected to in-vivo measurements during various maneuvers.Six wakeboarders and 12 kitesurfers (6 with loop bindings and 6 with fixed bindings) were investigated (mean age 33.1 ± 9.9 years). Jump height, hang time, acceleration, and the maximum vertical ground reaction force of both feet during takeoff and landing were recorded by means of sensor insoles (Moticon, Germany) on the feet of the athletes and simultaneously by a height and acceleration sensor (PIQ Sport Intelligence) on the board. A statistical analysis was performed.The data showed that wakeboarders were exposed to higher loads than kitesurfers, with significant differences occurring only between wakeboarders and kitesurfers with loop bindings and between kitesurfers with loop bindings and fixed bindings. High mean forces occurred during the landing of wakeboarders (rear foot 24.24 N/kg ± 8.82; front foot 20.33 N/kg ± 5.05) compared to kitesurfers with loop bindings (rear foot 12.09 N/kg ± 5.6; front foot 12.23 N/kg ± 4.92) as well as partially in kitesurfers with fixed shoe bindings (front foot 13.61 N/kg ± 5.92). Forces during lift-off were comparable in the rear foot (wakeboarders, kitesurfers with fixed bindings, kitesurfers with loop bindings 14.17 ± 6.37 vs. 16.39 ± 4.99 vs. 14.72 ± 5.13 N/kg). Similarly, despite the higher average acceleration force of the wakeboarders (4.16 g ± 1.02), there was no statistically significant difference (p = 0.166) compared to the kitesurfers.The in-vivo forces acting on the lower extremities during wakeboarding and kitesurfing are high (highest absolute values of 3012 N and relative values of 31.71 N/Kg). In addition, fixed boot bindings allow for the generation of higher forces than strap bindings. The results of our study have important implications on load control and preventive approaches in these two sports.

Temporal control of Staphylococcus aureus intracellular pH by sodium and potassium.

Adaptation to environmental change during both colonization and infection is essential to the pathogenesis of Staphylococcus aureus. Like other bacterial pathogens that require potassium to fulfill nutritional and chemiosmotic requirements, S. aureus has been shown to utilize potassium transport to modulate virulence gene expression, antimicrobial resistance, and osmotic tolerance. Recent studies examining the role for potassium uptake in mediating S. aureus physiology have also described its contribution in mediating carbon flux within central metabolism and generation of a proton motive force. Here, we utilize a pH-sensitive green fluorescent protein to examine the temporal regulation of S. aureus intracellular pH by potassium and sodium under various environmental conditions, including extracellular pH and antibiotic stress. Our results distinguish unique conditions and transport mechanisms that utilize these ions to modulate cytoplasmic pH homeostasis, and they identify these processes as a novel mechanism of intrinsic ampicillin resistance in S. aureus.

Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel.

Background: Pancreatic ductal adenocarcinoma acquired resistance to chemotherapy poses a major limitation to patient survival. Despite understanding some biological mechanisms of chemoresistance, much about those mechanisms remains to be uncovered. Mechanobiology, which studies the physical properties of cells, holds promise as a potential target for addressing the challenges of chemoresistance in PDAC. Therefore, we, here in an initial step, assessed the altered mechanobiology of PDAC cells with acquired chemoresistance to gemcitabine and paclitaxel. Methods: Five PDAC cell lines and six stably resistant subclones were assessed for force generation on elastic micropillar arrays. Those measurements of mechanical phenotype were complemented by single-cell motility and invasion in 3D collagen-based matrix assays. Further, the nuclear translocation of Yes-associated protein (YAP), as a measure of active mechanical status, was compared, and biomarkers of the epithelial-to-mesenchymal transition (EMT) were evaluated using RT-qPCR. Results: The PDAC cells with acquired chemoresistance exert higher traction forces than their parental/wild-type (WT) cells. In 2D, single-cell motility was altered for all the chemoresistant cells, with a cell-type specific pattern. In 3D, the spheroids of the chemoresistant PDAC cells were able to invade the matrix and remodel collagen more than their WT clones. However, YAP nuclear translocation and EMT were not significantly altered in relation to changes in other physical parameters. Conclusions: This is the first study to investigate and report on the altered mechanobiological features of PDAC cells that have acquired chemoresistance. A better understanding of mechanical features could help in identifying future targets to overcome chemoresistance in PDAC.

Multi-channel EMG manifestations of upper-extremity muscle coordination imbalance among community-dwelling sarcopenic seniors

BackgroundSarcopenia is an age-related, insidious, crippling but curable degenerative disease if diagnosed and treated early. However, no accessible and accurate early screening method is available for community settings that does not require specialized personnel. One of the hallmarks of sarcopenia is the pathological changes of muscle fiber type composition and motor unit firing patterns. Surface electromyography (sEMG) may serve as an effective tool for detecting differences between healthy and sarcopenic individuals due to its superior wearability and accessibility compared to other screening methods such as medical imaging and bioimpedance measurements, making it ideal for community-based sarcopenic screening. Our study aims to explore sEMG biomarkers that can be used for screening or diagnosis of sarcopenia.ResultsWe collected multi-channel sEMG signals from six forearm muscles of 98 healthy and 55 sarcopenic community-dwelling older adults. Participants performed grasp tasks at 20% and 50% of maximum voluntary contraction (MVC). Hexagons created by various EMG features, normalized with respect to respective MVC, and symmetry analyses were performed to estimate multi-muscle coordination patterns. An innovative index, namely incenter–circumcenter distance of muscle coordination (ICDMC), is proposed to discriminate between the healthy and sarcopenic groups. We utilized non-parametric tests to compare the ICDMC between the two groups, considering a p-value less than 0.05 statistically significant. The results showed that at 20% MVC, ICDMCs from root mean square (RMS), mean absolute value (MAV), slope sign changes (SSC) and wavelength (WL) showed statistically significant differences. More insights of this sEMG manifestation of sarcopenia were revealed by gender- and age-stratifications analyses.ConclusionsOur results demonstrated that there are clear sEMG manifestations of altered muscle coordination in sarcopenic patients. More consistent force generation patterns were observed in the sarcopenic group, especially at lower contraction intensities. The novel ICDMC can quantify differences between sarcopenic and healthy muscle. These results warrant further research to further develop more accessible sarcopenia screening strategies in community settings based on electrophysiological measurements such as sEMG.

Hydrodynamic Characteristics of Offshore Wind Turbine Pile Foundations Under Combined Focusing Wave-Current Conditions

In extreme marine environments, the interaction between offshore wind turbine pile foundations (OWTPFs) is critical, and the associated hydrodynamic loads are complex. This study focused on fixed OWTPFs and used computational fluid dynamics (CFD) to numerically simulate the flow field around pile foundations under the combined action of focusing waves and current. The objective was to investigate the influence of different focusing wave and current parameters on the hydrodynamic properties of the pile foundations. The findings indicate the following: (1) When the wave and current directions are opposite, the maximum wave force on the pile foundations is greater than when they are aligned. (2) Large-amplitude focusing waves around pile foundations generate secondary loads, which are nonlinear and lead to a rapid increase in the wave force. These secondary loads are short-lived and particularly prominent near the front row of pile foundations. (3) The influence of the group pile effect diminishes under high-amplitude waves, where the wave component dominates the generation of the dimensionless wave force, and the impact of the current on this force decreases.

Force-transducing molecular ensembles at growing microtubule tips control mitotic spindle size

Correct mitotic spindle size is required for accurate chromosome segregation during cell division. It is controlled by mechanical forces generated by molecular motors and non-motor proteins acting on spindle microtubules. However, how forces generated by individual proteins enable bipolar spindle organization is not well understood. Here, we develop tools to measure contributions of individual molecules to this force balance. We show that microtubule plus-end binding proteins act at microtubule tips synergistically with minus-end directed motors to produce a system that can generate both pushing and pulling forces. To generate pushing force, the system harnesses forces generated by the growing tips of microtubules providing unique contribution to the force balance distinct from all other motors that act in the mitotic spindle. Our results reveal that microtubules are essential force generators for establishing spindle size and pave the way for understanding how mechanical forces can be fine-tuned to control the fidelity of chromosome segregation.

Spontaneous breathing-induced lung injury in mechanically ventilated patients.

Recent experimental and clinical studies have suggested that spontaneous effort can potentially injure the lungs. This review summarizes the harmful effects of spontaneous breathing on the lungs during mechanical ventilation in ARDS and suggests potential strategies to minimize spontaneous breathing-induced lung injury. Recent clinical and experimental studies have shown that vigorous spontaneous breathing during mechanical ventilation can potentially injure the lungs due to high transpulmonary pressure, the Pendelluft phenomenon, increased pulmonary perfusion, and patient-ventilator asynchrony. A definitive approach to minimize spontaneous breathing-induced lung injury is the systemic use of neuromuscular blocking agents; however, there is a risk of muscle atrophy. Alternatively, partial paralysis, bilateral phrenic nerve blockade, and sedatives may be useful for decreasing force generation from the diaphragm while maintaining muscle function. A higher positive end-expiratory pressure (PEEP) and prone positioning may reduce force generation from the diaphragm by decreasing neuromechanical efficiency. Several potential strategies, including neuromuscular blockade, partial paralysis, phrenic nerve blockade, sedatives, PEEP, and prone positioning, could be useful to minimize spontaneous breathing-induced lung injury.

Biomechanical validation of the field-expedient pelvic splint

IntroductionMorbidity and mortality from pelvic ring injuries can be mitigated by early and effective external pelvic stabilisation. The field-expedient pelvic splint (FEPS) is a recently described technique to improvise an...

A Novel Ungrounded Haptic Device for Generation and Orientation of Force and Torque Feedbacks.

To provide deeper immersion for the user in the virtual environments, both force and torque feedbacks are required rather than the mere use of visual and auditory ones. In this paper, we develop a novel propeller-based Ungrounded Handheld Haptic Device (UHHD) that delivers both force and torque feedbacks in one device to help the user experience a realistic sensation of immersion in a three-dimensional (3D) space. The proposed UHHD uses only a pair of propellers and a set of sliders to continuously generate the desired force and torque feedbacks up to 15N and 1N.m in magnitude in less than 370ms, respectively. The produced force and torque feedbacks are oriented in a desired direction using a gimbal mechanism where the propellers are mounted inside in such a way that a simple structure is obtained. These features facilitate the control of the proposed UHHD and enhance its practicality in various applications. To prove the capability of the system, we model it and elaborate on the force and torque analyses. Next, we develop a robust parallel force/position controller to tackle the structured and unstructured uncertainties. Finally, a measurement setup is manufactured to experimentally evaluate the performance of the UHHD and the controller. The implementation of the controller on the developed UHHD prototype shows that a satisfactory control performance is achievable in terms of offering the desired force and torque feedbacks.

Enhanced attractive force via torsion spring as rotatable tip structure in beam-structure electrostatic chucks

This research aims to replace ball joints of beam-structure electrostatic chucks (BSESC), which are limited by issues such as structural friction and inconsistent operation, thus enhancing the applicability in industrial settings. Torsion springs are used as rotational degree-of-freedom (RDOF) mechanisms at the tip of BSESCs to reduce friction and improve repeatability, while also highlighting the positive relationship between tip rotatability and the attractive force generated. Following the law of conservation of energy, an analytical calculation was performed using a beam-spring-capacitor model to establish the correlation between tip rotatability and the maximum attractive force generated through energy system analysis. An analytical solution was derived, explicitly defining the relationship between tip rotatability and the achievable attractive force. The results were plotted using MATLAB. Experimental validations were carried out by fabricating devices that differed only in tip rotatability, and measurements of the attractive force were taken. Both analytical and experimental results clearly demonstrate a positive relationship between tip rotatability and attractive force generation in BSESCs. The use of torsion springs effectively reduces the energy concentration at the tip, delaying detachment while simultaneously increasing the attractive force, significantly improving the overall performance of BSESCs. These findings provide a foundation for future industrial applications, particularly for automated large-area manipulation of irregularly shaped targets in industries such as screen production and semiconductors.

TRPV4-mediated Mechanotransduction Regulates the Differentiation of Valvular Interstitial Cells to Myofibroblasts: Implications for Aortic Stenosis.

As aortic valve stenosis (AVS) progresses, the valve tissue also stiffens. This increase in tissue stiffness causes the valvular interstitial cells (VICs) to transform into myofibroblasts in response. VIC-to-myofibroblast differentiation is critically involved in the development of AVS. Herein, we investigated the role of mechanosensitive Ca 2+ -permeant transient receptor potential vanilloid 4 (Trpv4) channels in matrix stiffness- and transforming growth factor β1 (TGFβ1)-induced VIC-myofibroblast activation. We confirmed Trpv4 functionality in primary mouse wild-type VICs compared to Trpv4 null VICs using live Ca 2+ influx detection during application of its selective agonist and antagonist. Using physiologically relevant hydrogels of varying stiffness that respectively mimic healthy or diseased aortic valve tissue stiffness, we found that genetic ablation of Trpv4 blocked matrix stiffness- and TGFβ1-induced VIC-myofibroblast activation as determined by changes in morphology, alterations of expression of α-smooth muscle actin, and modulations of F-actin generation. Our results showed that N-terminal residues 30-130 in Trpv4 were crucial for cellular force generation and VIC-myofibroblast activation, while deletion of residues 1-30 had no noticeable negative effect on these processes. Collectively, these data suggest a differential regulatory role for Trpv4 in stiffness/TGFβ1-induced VIC-myofibroblast activation. Our data further showed that Trpv4 regulates stiffness/TGFβ1-induced PI3K-AKT activity that is required for VIC-myofibroblast differentiation and cellular force generation, suggesting a mechanism by which Trpv4 activity regulates VIC-myofibroblast activation. Altogether, these data identify a novel role for Trpv4 mechanotransduction in regulating VIC-myofibroblast activation, implicating Trpv4 as a potential therapeutic target to slow and/or reverse AVS development.