Model For Mechanosensation Research Articles

A continuum model of mechanosensation based on contractility kit assembly

The ability of cells to sense and respond to mechanical forces is crucial for navigating their environment and interacting with neighboring cells. Myosin II and cortexillin I form complexes known as contractility kits (CKs) in the cytosol, which facilitate a cytoskeletal response by accumulating locally at the site of inflicted stress. Here, we present a computational model for mechanoresponsiveness in Dictyostelium, analyzing the role of CKs within the mechanoresponsive mechanism grounded in experimentally measured parameters. Our model further elaborates on the established distributions and channeling of contractile proteins before and after mechanical force application. We rigorously validate our computational findings by comparing the responses of wild-type cells, null mutants, overexpression mutants, and cells deficient in CK formation to mechanical stresses. Parallel in vivo experiments measuring myosin II cortical distributions at equilibrium provide additional validation. Our results highlight the essential functions of CKs in cellular mechanosensitivity and suggest new insights into the regulatory dynamics of mechanoresponsiveness.

Differences in thick filament activation in fast rodent skeletal muscle and slow porcine cardiac muscle.

There is a growing appreciation that regulation of muscle contraction requires both thin filament and thick filament activation in order to fully activate the sarcomere. The prevailing mechano-sensing model for thick filament activation was derived from experiments on fast-twitch muscle. We address the question whether, or to what extent, this mechanism can be extrapolated to the slow muscle in the hearts of large mammals, including humans. We investigated the similarities and differences in structural signatures of thick filament activation in porcine myocardium as compared to fast rat extensor digitorum longus (EDL) skeletal muscle under relaxed conditions and sub-maximal contraction using small angle X-ray diffraction. Thick and thin filaments were found to adopt different structural configurations under relaxing conditions, and myosin heads showed different changes in configuration upon sub-maximal activation, when comparing the two muscle types. Titin was found to have an X-ray diffraction signature distinct from those of the overall thick filament backbone, and its spacing change appeared to be positively correlated to the force exerted on the thick filament. Structural changes in fast EDL muscle were found to be consistent with the mechano-sensing model. In porcine myocardium, however, the structural basis of mechano-sensing is blunted suggesting the need for additional activation mechanism(s) in slow cardiac muscle. These differences in thick filament regulation can be related to their different physiological roles where fast muscle is optimized for rapid, burst-like, contractions, and the slow cardiac muscle in large mammalian hearts adopts a more finely tuned, graded response to allow for their substantial functional reserve. KEY POINTS: Both thin filament and thick filament activation are required to fully activate the sarcomere. Thick and thin filaments adopt different structural configurations under relaxing conditions, and myosin heads show different changes in configuration upon sub-maximal activation in fast extensor digitorum longus muscle and slow porcine cardiac muscle. Titin has an X-ray diffraction signature distinct from those of the overall thick filament backbone and this titin reflection spacing change appeared to be directly proportional to the force exerted on the thick filament. Mechano-sensing is blunted in porcine myocardium suggesting the need for additional activation mechanism(s) in slow cardiac muscle. Fast skeletal muscle is optimized for rapid, burst-like contractions, and the slow cardiac muscle in large mammalian hearts adopts a more finely tuned graded response to allow for their substantial functional reserve.

A computational model of mechanosensation shows how contractility kits promote the accumulation of contractile proteins at the site of applied stress

A computational model of mechanosensation shows how contractility kits promote the accumulation of contractile proteins at the site of applied stress

State-specific morphological deformations of the lipid bilayer explain mechanosensitive gating of MscS ion channels.

The force-from-lipids hypothesis of cellular mechanosensation posits that membrane channels open and close in response to changes in the physical state of the lipid bilayer, induced for example by lateral tension. Here, we investigate the molecular basis for this transduction mechanism by studying the mechanosensitive ion channel MscS from Escherichia coli and its eukaryotic homolog MSL1 from Arabidopsis thaliana. First, we use single-particle cryo-electron microscopy to determine the structure of a novel open conformation of wild-type MscS, stabilized in a thinned lipid nanodisc. Compared with the closed state, the structure shows a reconfiguration of helices TM1, TM2, and TM3a, and widening of the central pore. Based on these structures, we examined how the morphology of the membrane is altered upon gating, using molecular dynamics simulations. The simulations reveal that closed-state MscS causes drastic protrusions in the inner leaflet of the lipid bilayer, both in the absence and presence of lateral tension, and for different lipid compositions. These deformations arise to provide adequate solvation to hydrophobic crevices under the TM1-TM2 hairpin, and clearly reflect a high-energy conformation for the membrane, particularly under tension. Strikingly, these protrusions are largely eradicated upon channel opening. An analogous computational study of open and closed MSL1 recapitulates these findings. The gating equilibrium of MscS channels thus appears to be dictated by opposing conformational preferences, namely those of the lipid membrane and of the protein structure. We propose a membrane deformation model of mechanosensation, which posits that tension shifts the gating equilibrium towards the conductive state not because it alters the mode in which channel and lipids interact, but because it increases the energetic cost of the morphological perturbations in the membrane required by the closed state.

A mechano-sensing mechanism for waving in plant roots

Arabidopsis roots grown on inclined agar surfaces exhibit unusual sinusoidal patterns known as root-waving. The origin of these patterns has been ascribed to both genetic and environmental factors. Here we propose a mechano-sensing model for root-waving, based on a combination of friction induced by gravitropism, the elasticity of the root and the anchoring of the root to the agar by thin hairs, and demonstrate its relevance to previously obtained experimental results. We further test the applicability of this model by performing experiments in which we measure the effect of gradually changing the inclination angles of the agar surfaces on the wavelength and other properties of the growing roots. We find that the observed dynamics is different than the dynamics reported in previous works, but that it can still be explained using the same mechano-sensing considerations. This is supported by the fact that a scaling relation derived from the model describes the observed dependence of the wavelength on the tilt angle for a large range of angles. We also compare the prevalence of waving in different plant species and show that it depends on root thickness as predicted by the model. The results indicate that waving can be explained using mechanics and gravitropism alone and that mechanics may play a greater role in root growth and form than was previously considered.

Structure of the Mechanosensitive Channel MscS Embedded in the Membrane Bilayer

Since life has emerged, gradients of osmolytes over the cell membrane cause pressure changes in the cell and require tight regulation to prevent cell rupture. The mechanosensitive channel of small conductance (MscS) releases solutes and water when a hypo-osmotic shock raises the pressure in the cell. It is a member of a large family of MscS-like channels found in bacteria, archaea, fungi and plants and model for mechanosensation. MscS senses the increase of tension in the membrane directly by the force from the lipids, but the molecular mechanism is still elusive. We determined the lipid interactions of MscS by resolving the structure of Escherichia coli MscS embedded in membrane discs to 2.9-Å resolution using cryo-electron microscopy. The membrane is attached only to parts of the sensor paddles of MscS, but phospholipid molecules move through grooves into remote pockets on the cytosolic side. On the periplasmic side, a lipid bound by R88 at the pore entrance is separated from the membrane by TM1 helices. The N-terminus interacts with the periplasmic membrane surface. We demonstrate that the unique membrane domain of MscS promotes deep penetration of lipid molecules and shows multimodal interaction with the membrane to fine-tune tension sensing.

Feeling Stressed or Strained? A Biophysical Model for Cell Wall Mechanosensing in Plants.

Mechanical signals have recently emerged as a major cue in plant morphogenesis, notably influencing cytoskeleton organization, gene expression, protein polarity, or cell division. Although many putative mechanosensing proteins have been identified, it is unclear what mechanical cue they might sense and how this would occur. Here we briefly explain the notions of mechanical stress and strain. We present the challenges to understand their sensing by plants, focusing on the cell wall and the plasma membrane, and we review putative mechanosensing structures. We propose minimal biophysical models of mechanosensing, revealing the modes of mechanosensing according to mechanosensor lifetime, threshold force for mechanosensor dissociation, and type of association between the mechanosensor and the cell wall, as the sensor may be associated to a major load-bearing structure such as cellulose or to a minor load-bearing structure such as pectins or the plasma membrane. Permanent strain, permanent expansion, and relatively slow variations thereof are sensed in all cases; variations of stress are sensed in all cases; permanent stress is sensed only in the following specific cases: sensors associated to minor load-bearing structures slowly relaxing in a growing wall, long-lived sensors with high dissociation force and associated to major-load-bearing structures, and sensors with low dissociation force associated to major-load-baring structures behaving elastically. We also find that all sensors respond to variations in the composition or the mechanical properties of the cell wall. The level of sensing is modulated by the properties of all of mechanosensor, cell wall components, and plasma membrane. Although our models are minimal and not fully realistic, our results yield a framework to start investigating the possible functions of putative mechanosensors.

A finite-element model of mechanosensation by a Pacinian corpuscle cluster in human skin.

The Pacinian corpuscle (PC) is the cutaneous mechanoreceptor responsible for sensation of high-frequency (20-1000 Hz) vibrations. PCs lie deep within the skin, often in multicorpuscle clusters with overlapping receptive fields. We developed a finite-element mechanical model of one or two PCs embedded within human skin, coupled to a multiphysics PC model to simulate action potentials elicited by each PC. A vibration was applied to the skin surface, and the resulting mechanical signal was analyzed using two metrics: the deformation amplitude ratio ([Formula: see text], [Formula: see text] and the phase shift of the vibration ([Formula: see text], [Formula: see text] between the stimulus and the PC. Our results showed that the amplitude attenuation and phase shift at a PC increased with distance from the stimulus to the PC. Differences in amplitude ([Formula: see text] and phase shift ([Formula: see text] between the two PCs in simulated clusters directly affected the interspike interval between the action potentials elicited by each PC ([Formula: see text]. While [Formula: see text] had a linear relationship with [Formula: see text], [Formula: see text]'s effect on [Formula: see text] was greater for lower values of [Formula: see text]. In our simulations, the separation between PCs and the distance of each PC from the stimulus location resulted in differences in amplitude and phase shift at each PC that caused [Formula: see text] to vary with PC location. Our results suggest that PCs within a cluster receive different mechanical stimuli which may enhance source localization of vibrotactile stimuli, drawing parallels to sound localization in binaural hearing.

Computational modeling of three-dimensional ECM-rigidity sensing to guide directed cell migration

Filopodia have a key role in sensing both chemical and mechanical cues in surrounding extracellular matrix (ECM). However, quantitative understanding is still missing in the filopodial mechanosensing of local ECM stiffness, resulting from dynamic interactions between filopodia and the surrounding 3D ECM fibers. Here we present a method for characterizing the stiffness of ECM that is sensed by filopodia based on the theory of elasticity and discrete ECM fiber. We have applied this method to a filopodial mechanosensing model for predicting directed cell migration toward stiffer ECM. This model provides us with a distribution of force and displacement as well as their time rate of changes near the tip of a filopodium when it is bound to the surrounding ECM fibers. Aggregating these effects in each local region of 3D ECM, we express the local ECM stiffness sensed by the cell and explain polarity in the cellular durotaxis mechanism.

Ion Channel Conformation and Oligomerization Assessment by Site-Directed Spin Labeling and Pulsed-EPR.

Mechanosensitive (MS) ion channels are multimeric integral membrane proteins that respond to increased lipid bilayer tension by opening their nonselective pores to release solutes and relieve increased cytoplasmic pressure. These systems undergo major conformational changes during gating and the elucidation of their mechanism requires a deep understanding of the interplay between lipids and proteins. Lipids are responsible for transmitting lateral tension to MS channels and therefore play a key role in obtaining a molecular-detail model for mechanosensation. Site-directed spin labeling combined with electron paramagnetic resonance (EPR) spectroscopy is a powerful spectroscopic tool in the study of proteins. The main bottleneck for its use relates to challenges associated with successful isolation of the protein of interest, introduction of paramagnetic labels on desired sites, and access to specialized instrumentation and expertise. The design of sophisticated experiments, which combine a variety of existing EPR methodologies to address a diversity of specific questions, require knowledge of the limitations and strengths, characteristic of each particular EPR method. This chapter is using the MS ion channels as paradigms and focuses on the application of different EPR techniques to ion channels, in order to investigate oligomerization, conformation, and the effect of lipids on their regulation. The methodology we followed, from the initial strategic selection of mutants and sample preparation, including protein purification, spin labeling, reconstitution into lipid mimics to the complete set-up of the pulsed-EPR experiments, is described in detail.

The Functional Organization of Cutaneous Low-Threshold Mechanosensory Neurons

Innocuous touch of the skin is detected by distinct populations of neurons, the low-threshold mechanoreceptors (LTMRs), which are classified as Aβ-, Aδ-, and C-LTMRs. Here, we report genetic labeling of LTMR subtypes and visualization of their relative patterns of axonal endings in hairy skin and the spinal cord. We found that each of the three major hair follicle types of trunk hairy skin (guard, awl/auchene, and zigzag hairs) is innervated by a unique and invariant combination of LTMRs; thus, each hair follicle type is a functionally distinct mechanosensory end organ. Moreover, the central projections of Aβ-, Aδ-, and C-LTMRs that innervate the same or adjacent hair follicles form narrow LTMR columns in the dorsal horn. These findings support a model of mechanosensation in which the activities of Aβ-, Aδ-, and C-LTMRs are integrated within dorsal horn LTMR columns and processed into outputs that underlie the perception of myriad touch sensations.

Modeling mechanosensing and its effect on the migration and proliferation of adherent cells

The behavior of normal adherent cells is influenced by the stiffness of the substrate they are anchored to. Cells are able to detect substrate mechanical properties by actively generating contractile forces and use this information to migrate and proliferate. In particular, the speed and direction of cell crawling, as well as the rate of cell proliferation, vary with the substrate compliance and prestrain. In this work, we present an active mechanosensing model based on an extension of the classical Hill’s model for skeletal muscle behavior. We also propose a thermodynamical approach to model cell migration regulated by mechanical stimuli and a proliferation theory also depending on the mechanical environment. These contributions give rise to a conceptually simple mathematical formulation with a straightforward and inexpensive computational implementation, yielding results consistent with numerous experiments. The model can be a useful tool for practical applications in biology and medicine in situations where cell–substrate interaction as well as substrate mechanical behavior play an important role, such as the design of tissue engineering applications.

A molecular model for mechanosensation in Caenorhabditis elegans.

Sensory signaling by chemicals and light are fairly well understood in molecular terms, but the molecules needed for mechanical signaling, which underlies the senses of touch, hearing, and balance, are not known. By analyzing the genes needed for mechanosensation in the nematode Caenorhabditis elegans, we hope to gain this molecular understanding. Six touch receptor neurons respond to gentle touch in C. elegans. Mutations producing touch insensitivity have identified 12 mec (mechanosensory abnormal) genes needed for touch cell function (Chalfie and Sulston, 1981; Chalfie and Au, 1989). Eight of these genes have been cloned by ourselves and others. Two genes (mec-4 and mec-10) encode similar subunits (degenerins) of a channel needed for mechanosensation (Driscoll and Chalfie, 1991; Huang and Chalfie, 1994). Gene interaction studies suggest that many of the remaining mec genes interact with this channel (Huang and Chalfie, 1994; Gu et al., 1996). Predicted protein sequences, gene interactions, and ultrastructural studies of the touch receptor neurons suggest the following model for mechanosensation in these cells (Gu et al., 1996). Mechanosensation requires the degenerin channel formed from MEC-4, MEC-10, and

A new approach to quantitation of whole nerve bundle activity.

ArticleA new approach to quantitation of whole nerve bundle activity.D E Dick, J R Meyer, and J V WeilD E Dick, J R Meyer, and J V WeilPublished Online:01 Mar 1974https://doi.org/10.1152/jappl.1974.36.3.393MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat Previous Back to Top Download PDF FiguresReferencesRelatedInformationCited ByA finite-element model of mechanosensation by a Pacinian corpuscle cluster in human skin17 March 2018 | Biomechanics and Modeling in Mechanobiology, Vol. 17, No. 4Responses of single‐unit carotid body chemoreceptors in adult rats1 February 2001 | The Journal of Physiology, Vol. 531, No. 1Strain-associated differences in hypoxic chemosensitivity of the carotid body in ratsJ. V. Weil, T. Stevens, C. K. Pickett, K. Tatsumi, M. G. Dickinson, C. R. Jacoby, and D. M. Rodman1 May 1998 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 274, No. 5Role of endogenous female hormones in hypoxic chemosensitivityKoichiro Tatsumi, Cheryl K. Pickett, Christopher R. Jacoby, John V. Weil, and Lorna G. Moore1 November 1997 | Journal of Applied Physiology, Vol. 83, No. 5An electronic device for accurate quantification of neuronal mass activity based on a digital integration methodJournal of Neuroscience Methods, Vol. 11, No. 3Inhibition of efferent sympathetic nerve activity by centrally administered paraoxon in the catEuropean Journal of Pharmacology, Vol. 81, No. 1Semicircular Canals: Measurement of Endolymphatic and Cupular Displacements at Threshold8 July 2009 | Acta Oto-Laryngologica, Vol. 93, No. 1-6 More from this issue > Volume 36Issue 3March 1974Pages 393-7 https://doi.org/10.1152/jappl.1974.36.3.393PubMed4814313History Published online 1 March 1974 Published in print 1 March 1974 Metrics