Mechanotransduction

In cellular biology, mechanotransduction (mechano + transduction) is any of various mechanisms by which cells convert mechanical stimulus into electrochemical activity.^[1]^[2]^[3]^[4] This form of sensory transduction is responsible for a number of senses and physiological processes in the body, including proprioception, touch,^[5] balance, and hearing.^[6]^[7]^[8] The basic mechanism of mechanotransduction involves converting mechanical signals into electrical or chemical signals.

In this process, a mechanically gated ion channel makes it possible for sound, pressure, or movement to cause a change in the excitability of specialized sensory cells and sensory neurons.^[9] The stimulation of a mechanoreceptor causes mechanically sensitive ion channels to open and produce a transduction current that changes the membrane potential of the cell.^[10] Typically the mechanical stimulus gets filtered in the conveying medium before reaching the site of mechanotransduction.^[11] Cellular responses to mechanotransduction are variable and give rise to a variety of changes and sensations. Broader issues involved include molecular biomechanics.

Single-molecule biomechanics studies of proteins and DNA, and mechanochemical coupling in molecular motors have demonstrated the critical importance of molecular mechanics as a new frontier in bioengineering and life sciences. Protein domains, connected by intrinsically disordered flexible linker domains, induce long-range allostery via protein domain dynamics. The resultant dynamic modes cannot be generally predicted from static structures of either the entire protein or individual domains. They can however be inferred by comparing different structures of a protein (as in Database of Molecular Motions). They can also be suggested by sampling in extensive molecular dynamics trajectories^[12] and principal component analysis,^[13] or they can be directly observed using spectra^[14]^[15] measured by neutron spin echo spectroscopy. Current findings indicate that the mechanotransduction channel in hair cells is a complex biological machine. Mechanotransduction also includes the use of chemical energy to do mechanical work.^[16]

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Hello! I’d like you to think about how I’m doing this right now. Not why I’m doing it, because of course, I’m doing it because I like music and I like science and I like to do both those things at the same time. But how can I play music? How can I be hearing it right now? And how can I walk around and play my guitar at the same time without falling on my face? And what is even sound anyway? These are all good questions. Let’s start with the last one, first. The basic answer to “What is sound?” goes like this: Sounds create vibrations in the air that beat against the eardrum, which pushes a series of tiny bones that move internal fluid against a membrane that triggers tiny hair cells -- which aren’t actually hairs -- that stimulate neurons, which in turn send action potentials to the brain, which interprets them as sound. But there’s a lot more to our ears than allowing us to experience the pleasure of birdsong, or the pain of grindcore. The ear’s often overlooked, but even more vital role is maintaining your equilibrium, and without THAT, you wouldn’t be able to dance or strut or even stand up. And you definitely could not do this! At least not without throwing up. In order to really get to the nitty-gritty of how your ears pick up sound, you’ve got to understand how sound works. The key to sound transmission is vibration. When I talk, my vocal folds vibrate. When I slap this table top, or strum a guitar, those vibrations cause air particles to vibrate too, initiating sound waves that carry the vibration through the air. So this, sounds different than this, because different vibrating objects produce differently shaped sound waves. A sound’s frequency is the number of waves that pass a certain point at a given time. A high-pitched noise is the result of shorter waves moving in and out more quickly, while fewer, slower fluctuations result in a lower pitch. How loud a sound registers depends on the wave’s amplitude, or the difference between the high and low pressures created in the air by that sound wave. Now, in order for you to pick up and identify sounds from beeping to barking to Beyonce, sound waves have to reach the part of the ear where those frequencies and air-pressure fluctuations can register and be converted into signals that the brain can understand. So once again, it all boils down to action potentials. But, how does sound get in there? Your ear is divided into three major areas: the external, middle, and inner ear. The external and middle ear are only involved with hearing, while the complex hidden inner is key to both hearing and maintaining your equilibrium. So the pinna, or auricle, is the part that you can see, and wiggle, and grab, or festoon with an earring. It’s made up of elastic cartilage covered in skin, and its main function is to catch sound waves, and pass them along deeper into the ear. Once a sound is caught, it’s funneled down into the external acoustic meatus, or auditory canal, and toward your middle and inner ear. Sound waves traveling down the auditory canal eventually collide with the tympanic membrane, which you probably know as the eardrum. This ultra-sensitive, translucent, and slightly cone-shaped membrane of connective tissue is the boundary between the external and middle ear. When the sweet sound waves of your favorite jam collide with the eardrum, they push it back and forth, making it vibrate so it can pass those vibrations along to the tiny bones in the middle ear. Now, the middle ear, also called the tympanic cavity, is the relay station between the outer and inner ear. Its main job is to amplify those sound waves so that they’re stronger when they enter the inner ear. And it’s gotta amplify them, because the inner ear moves sound through a special fluid, not through air -- and if you’ve ever gone swimming you know that moving through a liquid can be a lot harder than moving through air. The tympanic cavity focuses the pressure of sound waves so that they’re strong enough to move the fluid in the inner ear. And it does this using the auditory ossicles -- a trio of the smallest, and most awesomely named bones in the human body: the malleus, incus, and stapes, commonly known as the hammer, anvil, and stirrup. One end of the malleus connects to the inner eardrum and moves back and forth when the drum vibrates. The other end is attached to the incus, which is also connected to the stapes. Together they form a kind of chain that conducts eardrum vibrations over to another membrane -- the superior oval window -- where they set that fluid in the inner ear into motion. The inner ear is where things get a little complicated, but interesting and also kind of mysterious. With some of the most complicated anatomy in your entire body, it’s no wonder it’s known as the labyrinth. This tiny, complex maze of structures is safely buried deep inside your head, because it’s got two really important jobs to do: One, turn those physical vibrations into electrical impulses the brain can identify as sounds. And two: help maintain your equilibrium so you are continually aware of which way is up and down, which seems like a simple thing, but it is very important. To do this, the labyrinth actually needs two layers -- the bony labyrinth, which is the big fluid-filled system of wavy wormholes -- and the membranous labyrinth, a continuous series of sacs and ducts inside the bony labyrinth that basically follows its shape. Now, the hearing function of the labyrinth is housed in the easy-to-spot structure that’s shaped like a snail’s shell, the cochlea. If you could unspool this little snail shell, and cut it in a cross-section, you’d see that the cochlea consists of three main chambers that run all the way through it, separated by sensitive membranes. The most important one -- at least for our purposes -- is the basilar membrane, a stiff band of tissue that runs alongside that middle, fluid-filled chamber. It’s capable of reading every single sound within the range of human hearing -- and communicating it immediately to the nervous system, because right smack on top of it is another long fixture that’s riddled with special sensory cells and nerve cells, called the organ of corti. So when your cute little ossicle bones start sending pressure waves up the inner fluid, they cause certain sections of basilar membrane to vibrate back and forth. This membrane is covered in more than 20,000 fibers, and they get longer the farther down the membrane you go. Kind of like a harp with many, many strings, the fibers near the base of the cochlea are short and stiff, while those at the end are longer and looser. And, just like harp strings, the fibers resonate at different frequencies. More specifically, different parts of the membrane vibrate, depending on the pitch of the sound coming through. So the part of the membrane with the short fibers vibrates in response to high-frequency pressure. And the areas with the longer fibers resonate with lower-frequency waves. This means that, all of the sounds that you hear -- and how you recognize them -- comes down to precisely what little section of this membrane is vibrating at any given time. If it’s vibrating near the base, then you’re hearing a high-frequency sound. If it’s shakin’ at the end, it’s a low noise. But of course nothing’s getting heard until something tells the brain what’s going on. And the transduction of sound begins when part of the membrane moves, and the fibers there tickle the neighboring organ of corti. This organ is riddled with so-called hair cells, each of which has a tiny hair-like structure sticking out of it. And when one is triggered, it opens up mechanically gated sodium channels. That influx of sodium then generates graded potentials, which might lead to action potentials, and now your nervous system knows what’s going on. Those electrical impulses travel from the organ of corti along the cochlear nerve and up the auditory pathway to the cerebral cortex. But the information that the brain gets is more than just, like, “hey listen up.” The brain can detect the pitch of a sound based solely on the location of the hair cells that are being triggered. And louder sounds move the hair cells more, which generates bigger graded potentials, which in turn generate more frequent action potentials. So the cerebral cortex interprets all those signals, and also plugs them into stored memories and experiences, so it can finally say oh, that’s a chickadee, or a knock at the door, or the slow burn of an 80s saxophone solo, or whatever. So that’s how you hear. But we’re not done with you yet -- we gotta talk about equilibrium. The way we maintain our balance works in a similar way to the way we hear, but instead of using the cochlea, it uses another squiggly structure in the labyrinth that looks like it’s straight out of an Alien movie -- a series of sacs and canals called the vestibular apparatus. This set-up also uses a combination of fluid and sensory hair cells. But this time, the fluid is controlled not by sound waves but by the movement of your head. The most ingenious parts of this structure are three semicircular canals, which all sit in the sagittal, frontal, and transverse planes. Based on the movement of fluid inside of them, each canal can detect a different type of head rotation, like side-to-side, and up-and-down, and tilting, respectively. And every one of the canals widens at its base into sac-like structures, called the utricle and saccule, which are full of hair cells that sense the motion of the fluid. So by reading the fluid’s movement in each of the canals, these cells can give the brain information about the acceleration of the head. So if I move my head like this, because I’m, like, super into my jam, that fluid moves and stimulates hair cells that read up and down head movement, which then send action potentials along the acoustic nerve to my brain, where it processes the fact that I’m bobbing my head. And, just as your brain interprets the pitch and volume of a sound by both where particular hair cells are firing in the cochlea and how frequent those action potentials are coming in, so too does it use the location of hair cells in the vestibular apparatus to detect which direction my head is moving through space, and the frequency of those action potentials to detect how quickly my head is accelerating. But things can get messy. Doing stuff like spinning on a chair, or sitting on a rocky boat, can make you sick because it creates a sensory conflict. In the case of me spinning around on my chair, the hair cells in my vestibular apparatus are firing because of all that inner-ear fluid sloshing around — but the sensory receptors in my spine and joints tell my brain that I’m sitting still. On a rocking boat, my vestibular senses say I’m moving up and down, but if I’m looking at the deck, my eyes are telling my brain that I’m sitting still. The disconnect between these two types of movement, by the way, is why we get motion sickness. It doesn’t take long for my brain to get confused, and then mad enough at me to make me barf. Aaand I’m sorry that we’re ending with barf. But, we are. Today your ears heard me tell you how your cochlea, basilar membrane, and hair cells register and transduct sound into action potentials. You also learned how different parts of your vestibular apparatus respond to specific motions, and how that helps us keep our equilibrium. Special thanks to our Headmaster of Learning Thomas Frank for his support for Crash Course and for free education. Thank you to all of our Patreon patrons who make Crash Course possible through their monthly contributions. If you like Crash Course and want to help us keep making great new videos like this one -- and get some extra special, interesting stuff -- you can check out patreon.com/crashcourse Crash Course is filmed in the Doctor Cheryl C. Kinney Crash Course Studio. This episode was written by Kathleen Yale, edited by Blake de Pastino, and our consultant is Dr. Brandon Jackson. Our director is Nicholas Jenkins, the script supervisor and editor is Nicole Sweeney, our sound designer is Michael Aranda, and the graphics team is Thought Café.

Ear

Air pressure changes in the ear canal cause the vibrations of the tympanic membrane and middle ear ossicles. At the end of the ossicular chain, movement of the stapes footplate within the oval window of the cochlea generates a pressure field within the cochlear fluids, imparting a pressure differential across the basilar membrane. A sinusoidal pressure wave results in localized vibrations of the organ of Corti: near the base for high frequencies, near the apex for low frequencies.^[17] Hair cells in the cochlea are stimulated when the basilar membrane is driven up and down by differences in the fluid pressure between the scala vestibuli and scala tympani. This motion is accompanied by a shearing motion between the tectorial membrane and the reticular lamina of the organ of Corti, causing the hair bundles that link the two to be deflected, initiating mechano-electrical transduction. When the basilar membrane is driven upward, shear between the hair cells and the tectorial membrane deflects hair bundles in the excitatory direction, toward their tall edge. At the midpoint of an oscillation the hair bundles resume their resting position. When the basilar membrane moves downward, the hair bundles are driven in the inhibitory direction.^[18]

Skeletal muscle

When a deformation is imposed on a muscle, changes in cellular and molecular conformations link the mechanical forces with biochemical signals, and the close integration of mechanical signals with electrical, metabolic, and hormonal signaling may disguise the aspect of the response that is specific to the mechanical forces.^[19]

Cartilage

One of the main mechanical functions of articular cartilage is to act as a low-friction, load-bearing surface. Due to its unique location at joint surfaces, articular cartilage experiences a range of static and dynamic forces that include shear, compression and tension. These mechanical loads are absorbed by the cartilage extracellular matrix (ECM), where they are subsequently dissipated and transmitted to chondrocytes (cartilage cells).

Chondrocytes sense and convert the mechanical signals they receive into biochemical signals, which subsequently direct and mediate both anabolic (matrix building) and catabolic (matrix degrading) processes. These processes include the synthesis of matrix proteins (type II collagen and proteoglycans), proteases, protease inhibitors, transcription factors, cytokines and growth factors.^[20]^[21]

The balance that is struck between anabolic and catabolic processes is strongly influenced by the type of loading that cartilage experiences. High strain rates (such as which occurs during impact loading) cause tissue damage, degradation, decreased matrix production and apoptosis.^[22]^[23] Decreased mechanical loading over long periods, such as during extended bed-rest, causes a loss of matrix production.^[24] Static loads have been shown to be detrimental to biosynthesis^[25] while oscillatory loads at low frequencies (similar that of a normal walking gait) have been shown to be beneficial in maintaining health and increasing matrix synthesis.^[26] Due to the complexity of in-vivo loading conditions and the interplay of other mechanical and biochemical factors, the question of what an optimal loading regimen may be or whether one exists remain unanswered.

Although studies have shown that, like most biological tissues, cartilage is capable of mechanotransduction, the precise mechanisms by which this is done remain unknown. However, there exist a few hypotheses which begin with the identification of mechanoreceptors.^{[citation needed]}

In order for mechanical signals to be sensed, there need to be mechanoreceptors on the surface of chondrocytes. Candidates for chondrocyte mechanoreceptors include stretch-activated ion channels (SAC),^[27] the hyaluronan receptor CD44, annexin V (a collagen type II receptor),^[28] and integrin receptors (of which there exist several types on chondrocytes).

Using the integrin-linked mechanotransduction pathway as an example (being one of the better studied pathways), it has been shown to mediate chondrocyte adhesion to cartilage surfaces,^[29] mediate survival signaling^[30] and regulate matrix production and degradation.^[31]

Integrin receptors have an extracellular domain that binds to the ECM proteins (collagen, fibronectin, laminin, vitronectin and osteopontin), and a cytoplasmic domain that interacts with intracellular signaling molecules. When an integrin receptor binds to its ECM ligand and is activated, additional integrins cluster around the activated site. In addition, kinases (e.g., focal adhesion kinase, FAK) and adapter proteins (e.g., paxillin, aka Pax, talin, aka Tal, and Shc) are recruited to this cluster, which is called the focal adhesion complex (FAC). The activation of these FAC molecules in turn, triggers downstream events that up-regulate and /or down-regulate intracellular processes such as transcription factor activation and gene regulation resulting in apoptosis or differentiation.^{[citation needed]}

In addition to binding to ECM ligands, integrins are also receptive to autocrine and paracrine signals such as growth factors in the TGF-beta family. Chondrocytes have been shown to secrete TGF-b, and upregulate TGF-b receptors in response to mechanical stimulation; this secretion may be a mechanism for autocrine signal amplification within the tissue.^[32]

Integrin signaling is just one example of multiple pathways that are activated when cartilage is loaded. Some intracellular processes that have been observed to occur within these pathways include phosphorylation of ERK1/2, p38 MAPK, and SAPK/ERK kinase-1 (SEK-1) of the JNK pathway^[33] as well as changes in cAMP levels, actin re-organization and changes in the expression of genes which regulate cartilage ECM content.^[34]

More recent studies have hypothesized that chondrocyte primary cilium act as a mechanoreceptor for the cell, transducing forces from the extracellular matrix into the cell. Each chondrocyte has one cilium and it is hypothesized to transmit mechanical signals by way of bending in response to ECM loading. Integrins have been identified on the upper shaft of the cilium, acting as anchors to the collagen matrix around it.^[35] Recent studies published by Wann et al. in FASEB Journal have demonstrated for the first time that primary cilia are required for chondrocyte mechanotransduction. Chondrocytes derived from IFT88 mutant mice did not express primary cilia and did not show the characteristic mechanosensitive up regulation of proteoglycan synthesis seen in wild type cells^[36]

It is important to examine the mechanotransduction pathways in chondrocytes since mechanical loading conditions which represent an excessive or injurious response upregulates synthetic activity and increases catabolic signalling cascades involving mediators such as NO and MMPs. In addition, studies by Chowdhury TT and Agarwal S have shown that mechanical loading which represents physiological loading conditions will block the production of catabolic mediators (iNOS, COX-2, NO, PGE2) induced by inflammatory cytokines (IL-1) and restore anabolic activities. Thus an improved understanding of the interplay of biomechanics and cell signalling will help to develop therapeutic methods for blocking catabolic components of the mechanotransduction pathway. A better understanding of the optimal levels of in vivo mechanical forces are therefore necessary for maintaining the health and viability of cartilage, preventative techniques may be devised for the prevention of cartilage degradation and disease.^{[citation needed]}