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Dascher Branch-Elliman [Basic Tissues] {conference number 5} Muscle Physiology by Professor Sciff

2/18/2010

Okay. Today Im going to be spending two hours talking about muscles. This is my punishment for not coming in Thursday, Ive got to give the same lectures four times. But for each of you, only once. And the slides and conference type stuff that Dr. wishe was planning to do hell be doing next Monday, so you wont be missing anything, dont worry. Now muscles is a very interesting tissue because it does stuff than you can see. And that makes it uh useful in terms of, you can try things and you can visualize the outcomes. The muscle contracts it generates force and stuff like that. So this is what Im going to be talking about. Now, as Dr. terracio already gave you, youve got the muscle fiber. Im going to start out talking about skeletal muscles. There are 3 different basic types of muscle that were going to be talking about: skeletal, cardiac smooth. Im starting out with skeletal muscle because theres a lot of fundamental material that can be discussed solely on the topic of that. And as Dr. terracio discussed what youve got is within each muscle fiberand remember the fiber is the cellyou have these internal units running parallel to the fiber called fibrils. And each fibril is made up of a linear sequence of sarcomeres. So this is a z disc. People who do histology tend to think about it as a z line, but if you think about it a muscle fiber is a long cylinder so its really a disk. When youre looking at a flattened preparation on a slide, it looks like a line. And attached to these z disks are a number of thin filaments and in between the thin filaments there are thick filaments or rods. And the rods, let me try a slightly different color, interweave with the filaments this way. They are of course thicker. If you were to take a look at where the over lap is, say from here to here, through the A band, where this major overlapwhat you would see is a hexagonal array of the thin filaments, one, two, three, four, five, six. Thats a hexagon, right? But then you can build another hexagon next to that hexagon, and another one next to that one, and another one over here. So, you can see that these are really hexagons, here, here, here, here, here. Of course the lines connecting them dont exist, but were very good at naming things that dont exist, weve discussed that already. And, but, its sort of like tiling a floor with hexagonal tiles, which used to be the standard for bathrooms and some kitchens, back in that, about a hundered years ago, little white hexagons. You have to go to a really old house to see bathrooms with little white hexagon tiles, but thats the way it was. And the thick filaments, the rods, are right present in the center of each hexagon of thin filaments. So each rod is surrounded by 6 thin filaments. This one is surrounded by these six. Each one of these thin filaments is surrounded by three rods. If you were to continue this pattern over a very large surface area, what you would find is how do the number of thick rods and thin filaments compare? And well just do a couple here like this. How many rods per thin filament or how many thin filaments per rod? Its two to one. Its hard to see immediately, but if you draw a line like this, at this angle, and look at each stripe, youll see a pattern of rod-thin-thin-thick-thin-thin and so on going on along. So theyre clearly as twice as many thin filaments as rods. The thin filaments attach to the z discs. And they are made up of a protein called actin. And actin, the actually actin unit is a little globular unit called G actin because its globular. And these globular proteins sort of string together like a string of pearls, but its a bit more than that. Because its really like two

strings of pearls. You have another one here next to it. But its a little bit more to it than that. Because if you take your two strands of pearls and give them a little twist. So that they form a little helix wrapping around each other with one 180 degree turn per every seven G actin units. You wind up with this sort of twisted double helix formation which is referred to as F actin, where each one of these is a G actin. Okay The thick filaments or rods are made of a thick filament called myosin. And myosin looks something like this: you have a straight segment and then another segment that bends off at an angle and then you have sort of a pair of globular heads: two little globs there. And you line them up, they line up to form this rod next to each other. Head head, another one here, head head. And they also go in other directions. and some of them are in the opposite direction. So that there is a thin here that is only straight segments in the middle of this rod protein. And what you end up with as you put these all together is a thick rod with these side arms with heads coming off, that and a flat plane. Because after all, each rod is in the middle of a hexagon of actin filaments and so the side arms that branch off these myosin molecules head toward the actin molecules so theres a sort of six fold symmetry here . so heres your structure and here are the heads out here. And the other thing you have to know about the myosin is that these heads out at the end of side arms are have enzymatic activity as ATPases. In other words, these heads can bind an ATP, split it, spit out a phosphate, spit out an ADP, and that leaves it with some energy which it can do something. And thats the whole point of muscle. Because what happens is you start off with a myosin side arm (heres a myosin molecule, heres an ATPase). So it picks up an ATP and it has a very high affinity for ATP. So in general you wont see any myosins that dont have anything bound to them. They always have to have something bound to them and usually its an ATP if ATP is available. So the myosin picks up an ATP and it kind of stretches it a little bit. Remember that you have ATP sort of into ADP and then the third phosphate, the gamma phosphate is stretched out a bit so its about to break it off and do an ATPase job on this, but not quite. It holds the ATP in this sort of partly stretched position at the end, its still strictly speaking an ATP here, and then what? Well given this arrangement with the myosin having six arms going out toward different actins, and the six actins surrounding each myosin, it looks as though the actin might have something to do with turning on the ATPase enzymatic activity, and it does. Because if you now look at the F actin, this filament here, each of the actin subsunits has a binding site or receptor on the outside. And theres one here on this strand of the double stranded sort of binding site or whatever for the myosin. So now what? Well, the myosin is sitting there with an ATP attached to it, and it attaches to one of these binding sites of the actin. So here you have the myosin with the ATP and heres the actin and the myosin binds to the actin. The act of binding as soon as this myosin combines to this actin is essential creating a bridge from this myosin rod to the actin filament and these are called cross bridges because they cross the gap between actin and myosin And as soon as the myosin with its ATP attached bidns to the actin, that act of binding and the actin somehow turns of the ATPase of the myosin. So the myosin then splits ATP into ADP plus inorganic phosphate. So what youve started out with is a myosin that had an ATP attached to it, that myosin bound to the actin to form actin-myosin-ATP but then the ATP got hydrolyzed so you got a phosphate and you got an ADP released and now what youre left with is an actin bound to a myosin. And myosin also has a very strong affinity for actin, so it would tend to stay bound. But remember that youve just hydrolyzed an ATP molecule into ADP and phosphate. That gives this thing some energy and what does

it do with that energy? What it does with the energy is it bends the arm. Now if the myosin has grabbed on to the actin and hydrolyzing the ATP it bends the arm, its going to pull the actin. And thats how muscle contracts. The myosin forms a bridge to the actin, these crossbridges bend using the energy from the ATP, so that pulls the actin filament this way and it pulls this actin filament this way because the other one is bending that way to the right. And that pulls the z line or z disc and that pulls this z disc so the two z discs come closer together and the sarcomere gets a little shorter. And thats how you turn this chemical energy that had been in the form of ATP, into an actually chemical movement. The sarcomere got shorter Okay, so youve done this once then what? Well as we were discussing with synapse and all other subjects. Im going back, Im talking about neuro, but were the same people. Once you have done this once, grab on, pull. Now youve gotta go back to where you were before at some point. Right? Youve got to undo this and go back to the previous status. So whats going to happen here? Well if you are only talking about one cross bridge forming, one myosin side arm, it grabs the actin, it pulls the actin, and then if its going to let go, it lets go. The sarcomere is going to go back to its original length again. But were not talking about just one cross bridge, we are talking about a whole bunch of them in six different directions. so now what you do, is one of them forms a bridge, bends, splitting the ATP, and pulls an arm and then another arm in another direction reaches another actin, grabs on, splits the ATP, uses that energy to pull. Meanwhile this one can let go, go back to its original status, grab on to the next actin along that strand, pull and move on. Its sort of like everybodys favorite old gym activity climbing the rope. Picture a one arm person climbing a rope, you cant do it. He reaches up, grabs, pulls, as soon as he lets go hes sitting of the floor, but with two arms, in this case 6 arms, and in that case 6 ropes as well, you grab, you pull, then this one can grab and pull and you let go and the first one can grab and pull again so all of these six arms in six directions times how many there are coming out of this overlap length, its like hand over hand over hand over hand, so youre continuously shortening the sarcomere and the muscle contracts. So each of these myosin arms is going through a cycle. It has an ATP, it grabs an actin, it splits the ATP into ADP plus phosphate, with that energy it bends the elbow so to speak and then at some point its going to end up wanting to let go, reach out again and repeat the cycle. So heres where youre starting out. This is whats referred to as a cross bridge cycle. You have youre myosin with ATP attached plus actin gives you actin-myosin-ATP. You lose a phosphate, you lose ADP, by the way it happens in that order. First you lose the phosphate and then it spits out ADP. And youre now left with the actin bound to the myosin. This myosin now wants to let go of the actin, to go back to here, where it will grab on to a different actin, maybe the next unit along this strand, to repeat this cycle. But myosin doesnt like to be alone. Its perfectly happy to be bound to actin, but in order to go back to this state here, youd need to add an ATP. Now, in a muscle fiber, a skeletal muscle fiber, theres lots of ATP. Youre muscle fibers have lots of mitochondria, theyre making ATP, so theyve got all sorts of ATP lying around. The cytoplasmic concentration of ATP is actually pretty high, surprisingly high, at least I was surprised. Maybe youre not surprised. Youve got a concentration of ATP in the cytoplasm of about 1 millimolar. I would have expected a lot less, micro or nano molar, but its one millimolar ATP. So with all this ATP around the myosin can pick up an ATP and let go of the actin in sort of a swap. So now you are back to myosin ATP and now it picks up a different actin and it does this again and now youre moving along the rope.

Okay. What happens if you dont have that ATP there? Well under what conditions would you not have ATP in the cell? If youre dead? Well youre making it constantly so, if youre alive. So the only time, well, the most obvious time when you run out of ATP is when youre dead and the myosin doesnt let go of the ATP and the muscle gets rigid. This is whats known as rigor mortis, the rigor of the dead person, the dead. And for a certain period of time this muscle remain locked and rigid. If you sometimes if you go swimming in excessively cold water, the low temperature might inhibit the function of mitochondria in your legs and create a situation of deficiency in your mitochondria here and the muscle will cramp. Sometimes known as a charley horse. When this happens, consider it natures way of giving you a preview of death. Because if it prevents you from getting out of this cold water youre swimming in, it will indeed be a preview of death. The line from Sandra bullock in gravity. We all die, but not today. (giggle) something like that. Anyway. So youve got this concentration of ATP. Now if you think about it for a bit, youre mitochondriaif youre suitably healthy and reasonably warmare constantly metabolizing stuff and producing ATP. So the rate of production of ATP is fairly steady. However, when you are lying and resting you are not using up ATP so youd expect the concentration of ATP to go up. When you are doing a lot of rigorous work, say shoveling snow, uh youre concentration of ATP goes down. Or youd expect it to. To keep the concentration of ATP in a skeletal muscle and cardiac muscle at this I millimolar, or this constant concentration, you have this sort of buffer system, sort of like buffers that keep pH at a reasonably constant level depending on your metabolism shifting around. So what happens in your muscle cells, skeletal muscle, have a compound in them called creatin, which is able to pick up a phosphate maintaining the high energy phosphate bond that ATP has. So essentially what youve got here is creatin plus ATP can transfer this high energy phosphate of the third phosphate, the phosphate bond of the third phosphate, the gamma phosphate to the creatin, which will produce creatin phosphate, put a little twiddle there for uh the high energy phosphate bond, plus ADP . And this goes both ways. So the creatin that muscle has, and skeletal and cardiac muscles both have it, um acts as a sort of buffer if youre resting and your mitochondria are cranking out a lot of ATP, this reaction moves left to right and the phosphate gets transferred to creatin and you have lots of ADP and your mitochondria has that as a substrate. On the other hand, suppose you are doing a lot of vigorous exercise. This uses up the ATP in your muscle. And you want to keep this concentration and your one millimolar, so you run this reaction right to left. You take your creatin phosphate and transfer it to an ADP to make more ATP and maintain the ATP concentration. So this is a sort of a buffer to maintain ATP concentration. Okay So, here we have the ATP which enables this whole cross bridge cycle to keep cycling. And then this generates muscle contraction because the sarcomeres keep getting shorter and shorter each time you go around. Now wait a minute. One of the characteristics of skeletal muscle that you see in all your textbooks is that its voluntary. We can decide whether to contract or not contract or relax or not relax a particular skeletal muscle. So, if we are want to be able to control this muscle, you cant do that with just the system I described here of just the ATP being used to make a crossbridge and it just keeps going and going and going. You have to have a way of turning it off if you decide to relax that muscle. So theres a bit more to the thin filaments than this. And that is you have an additional protein called tropomyosin. That actually lies along side the actin filament and blocks the binding sites. So if you were to take like a cross section through this here. Lets take a cross section here. What you would see is:

actin, actin, binding site, binding site. Then tropomyosin sort of blocking the binding site, which causes the muscle to relax. Okay so weve managed to control this constant contracting only to shift the problem one step in the opposite direction. This russle with the tropomyosin blocking the binding sites means the muscle cant contract because the myosin cant bind to this actin binding sites So what youve got now is you add on, heres another one. This tropomyosin run about 7 actin, G actin units, long. And then theres another tropomyosin that begins here and goes for seven. And so on and so on. But lets just look at this seven unit object. At one end, Ill just draw three little circles here. You have a trio of proteins called troponin. Or as Dr. Wishe tends to pronounce it troponin. Youll get to that on Monday. And the troponin triad, three different proteins, has the following properties: theres a troponin M which binds to tropomyosin, theres a troponin I which is an intermediate between the two other troponins and then theres a troponin C, which is the one Im going to be paying attention to here. C. C. the troponin C binds CALCIUM. Calcium ions, in they are in the cytoplasm can binds reversibly to troponin C. troponin C plus calcium, reversible binding to calcium troponin C. okay So if calcium gets high, concentration gets high, that would tend to move this reaction left to right. And most of the troponin C will have calcium bound to it. If the concentration of calcium in the cytoplasm gets low, and Ill get back to what high and low mean, if the concentration of calcium in the cytoplasm gets low, the calcium and troponin C will dissociate and most of the troponin C will not have calcium bound to it. Now the way that troponin C works is this. If the troponin C has calcium bound to it, it tends to move this tropomyosin out of the way. This whole thing, the whole length of it just shifts out of the way when theres calcium bound to troponin C. so now these active binding sites on the actin are uncovered and cross bridges can cycle and the muscle constracts. If on the other hand the calcium concentration in the cell is low, the troponin C is on the non-calcium state and that tends to move the tropomyosin to this position where its covering the binding sites on the actin. And when the tropomyosin is in this position you dont get any cross bridges able to form and there the muscle is able to contract. So, high calcium concentration in the cytoplasm, muscle contracts. Low concentration of calcium in the cytoplasm, muscle relaxes. How low is low? How high is high? In the cytoplasm of muscle fiber, skeletal muscle fiber, just as in almost every cell in your body, calcium concentration is low. About ten to the minus seven molar. So, if the calcium is 10^(-7)M, thats low and the calcium dissociates from the troponin C, the tropomyosin blocks the binding sites, and the muscle relaxes. If the calcium gets high, it will bind to the troponin C, move the tropomyosin out of the way and let the myosin form crossbridges with the actin binding sites. Whats high? So low is 10 to the -7th. High is about, as high as it gets is about ten to the minus five molar. If you look at this equilibrium equation, what you find is that the equilibrium constant for that equation, you find that the equilibrium constant is about two times ten to the minus 6th molar calcium. In other words if the calcium concentration in the cytoplasm is 2 x 10^(-6) M, about half of the troponin C has calcium bound to it and half doesnt. if the calcium is higher than most of the troponin C has calcium bound to it. If the calcium concentration is lower, than most of the troponin C does not have calcium

bound to it, and that in turn regulates the position of the tropomyosin and therefor the availability of the actin binding sites. Okay So now all we have to do to voluntarily control this muscle is to voluntary control the calcium concentration of the cytoplasm in a skeletal muscle fiber. Thats all. So. How do we do that? Well in skeletal muscle, theres virtually no, or no significant, movement of calcium into or out of the cell. And one of the reasons that this is, is that skeletal muscle fibers are enormous cells. Youve got like a millimeter in diameter or and this long. Or this long. So, thats a big cell. And when a cell is that big, the ratio of its surface to its volume is very small. It has very little surface area. If you have very tiny little cells, then theres a lot of surface compared to the volume of the cytoplasm. But if you have big cell, its minimal surface compared to the volume. So what you have in skeletal muscle cells is a very low surface compared to the volume and therefore movement of calcium across the cell membrane is not going to be a major contributor to changing the calcium concentration in a muscle cell. It is, for example, in a nerve ending. That presynaptic nerve ending, where calcium comes in through voltage gated calcium channel and can raise the calcium concentration all the way from 10^-7 all the way to 10^-5, just by coming, because you have an enormous surface to volume ratio, very little volume, in a teeny tiny nerve ending . But here, youve got a big cell and you cant move enough calcium to make a significant difference across the cell membrane. So what basically happens in the skeletal muscle is theres this storage compartment inside the cytoplasm called the sarcoplasmic reticulum. Whenever you hear the word sarco it means muscle. Alright. Sarcoplasmic reticulum is this enormous storage site in between the fibrils, but entirely interior to the cell. And this storage compartment, the sarcoplasmic reticulum or SR can hold a large quantity of calcium. Such that if it releases a large concentration of the calcium into the cytoplasm, it can increase the concentration of calcium from 10^(-7) to 10^(-5). Thats 100 fold increase. On the other hand, it also has a calcium ATPase pumping calcium from the cytoplasm back into the sarcoplasmic reticulum. And, inside the sarcoplasmic reticulum theres a protein calsequestrin that binds the calcium with a very high affinity, so that keeps the free calcium ion concentration from getting too high inside the SR. Okay, so heres youre sarcoplasmic reticulum and heres your cytoplasm and calcium can go out of the sarcoplasmic reticulum or be pumped back in. the pumping back in, here, is a calcium ATPase. The moving of calcium out of the sarcoplasmic reticulum is through a gated channel. Now a calcium channel that allows, if its triggered, allows calcium to leave the sarcoplasmic reticulum and go into the cytoplasm. And. What this channel is called the ryanodine receptor. Remember in neuro I was describing in terms of ionotropic synapses that there are a lot of ligand gated channels, transmitter gated channels, whatever, where the receptor that binds the ligand, that binds the transmitter, is actually part of the channel itself and can increase or decrease permeability to an ion. This is called the ryanodine receptor solely because it also opens and lets calcium through in response to ryanodine. You dont have any ryanodine in your body. Ryanodine is a plant molecule thats toxic, that grows from some plant found down in South America, I dont even remember what. And its not the sort of thing you are likely to be munching on, so you dont have any ryanodine in your system. But just because these channels open in response to ryanodine, theyre called ryanodine receptors. And generally they are abbreviated that way. When we get to autonomic system in neuro next week, Ill be talking nicotinic receptors which is a certin type of receptor that responds to acetylcholine in your body. It also responds to nicotine. Normally, if

youre reasonably intelligent, you dont have any nicotine in your body. If you chose to put nicotine in your body, thats a foolish thing to do. Dont do it. But nicotine is also carcinogenic, but well worry about that, well its not relevant to this. Uh those are called nicotinic receptors These are ryanodine receptors, we dont have any ryanodine in our body. If its indeed a receptor to something, we havent a clue what the normal ligand is. But, what we do know is, that these channels can open and let calcium out, and when they let calcium out, the calcium concentration in the cytoplasm can go from its normal resting 10^-7 up to 10^-5. And then the ATPase pumps it back into the sarcoplasmic reticulum until you are back to 10^-7 again. And as long as you are above 2 x 10 ^-6 M calcium, that is from here to here, the majority of troponin has calcium bound to it, the tropomyosin has been moved aside allowing exposure of the actin binding sites and the myosin side arms can form cross bridges and generate muscle tensions. So all you have to do if you want to voluntary cause a muscle to contract, HA, all you have to do is somehow tell the ryanodine receptors in your sarcoplasmic reticulum to open up and let the calcium out of the sarcoplasmic reticulum and then the muscle will contract. Okay. How do we do that? Well if you look at the structure of a skeletal muscle fiber, you have the outside membrane is the sarcolemma. And periodically there are invaginations in to the interior of the muscle fiber that are called transverse tubules, or T tubules. But if you look at their origin or look at what they are continuous to, you can see two things immediately. One is, probably, structurally they are very similar to the sarcolemma, which is the outside membrane of the muscle fiber because they are just a continuation of the sarcolemma. Right? This is the sarcolemma and this is just a continuation of it.so the T tubule membrane is similar to the sarcolemma. The second thing you notice immediately is that in the lumen of the T tubule is extracellular fluid, sea water. So heres your sea water in here, which has 2 and a half millimolar calcium, among other things, and the sodium and less potassium than inside the cell and stuff like that. And because its the same structurally type membrane as the sarcolemma, it has voltage gated sodium channels and stuff like that, so you can propagate an action potential along it. So if there is an action potential in the sarcolemma, each time it reaches the entrance of a T tubule, it will also propagate into the T tubule. When it gets down in here, what you find is that there is an enlargements (the cisterns of the sarcoplasmic reticulum) that come very close to the T tubules on both sides. They dont actually touch, but theres a very small space in between. So what youve got here is the action potential travels along the sarcolemma, travels down the T tubule, it opens voltage gated calcium channels and some calcium ions from inside the t tubules will move into this little narrow space between the t tubule and the sarcoplasmic reticulum. Normally what comes into a skeletal muscle fiber through the sarcolemma, or through a t tubule, is so small, is terms of calcium that it will not have any significant effect on the calcium concentration in the cytoplasm. However, in this particular special place, whatever calcium is coming in, is coming in to a very restricted volume of cytoplasm. And as the calcium comes in to there, it can locally, possibly have an effect on the calcium concentration right there. And what seems to happen, is that the calcium in this little space between the t tubule and the sarcoplasmic reticulum will act on some sort of calcium receptor on the sarcoplasmic reticulum membrane and send a signal that spread through the sarcoplasmic reticulum and tells all those ryanodine receptors to open up and release calcium into cytoplasm. So the ryanodine receptors open, calcium comes out of here into the cytoplasm and then gradually the calcium ATPase pumps it back into the sarcoplasmic reticulum.

Okay, so what have we accomplished here? Now you can control the contraction of this muscle fiber by creating an action potential in the sarcolemma. How do you trigger an action potential in the sarcolemma of a muscle fiber? Well you look at the motor neuron that is presynaptic and synapses on to the skeletal muscle fiber, and this is generally referred to as an alpha fiber and it releases acetylcholine and its myelinated. But when you get down near the end, the myelination stops in that form. The nerve ending sits in a little trough or dish in the membrane of the muscle fiber. This is the muscle. And another schwann cell, one schwann cell, sort of overlies this whole thing. Theres a schwann cell. And sort of seals it in. so that what happens is, well remember when I discussing cholinergic synapses, synapse with acetylcholine in them as the transmitter, that they tend to be very tight, very small gap between cells and here they sort of have an extra bit of sealant here that keeps the acetylcholine, the acetylcholine of course gets broken down by acetylcholinesterase into acetate and choline and the choline is taken into the motor neuron to be used again, weve been through that already. But the key to this, is that an action potential here in the motor neuron will always cause an action potential in the muscle fiber. In other words, transmission across that particular synapse, unlike just about any other synapse in your body, is what we call mandatory, or obligatory. The action potential in the presynaptic cell will always produce a liminal depolarization and therefore trigger a depolarization in the post synaptic cell, which is the muscle fiber. The mechanism for this unique situation is this. Remember I talked about in presynaptic neurons, Im switching from my basic tissue hat to my neuro hat again, you would occasionally see a little depolarization in the post synaptic membrane from spontaneous release of a vesicle full of transmitter, in this case acetylcholine, because there are a few vesicles that have enough kinetic energy to actually hit the membrane and release their transmitter. But lets do some numbers here. In a muscle fiber you have a resting membrane potential of somewhere in -80 to -90 range, they are a little more negative than neurons. And when you have one of these spontaneously released vesicle loads, this causes about a 1 millivolt depolarization. So therefore, if you release the contents of one synaptic vesicle you get about a 1 mV depolarization. Now if the membrane potential of the muscle fiber is say -85 mV, just to pick a number, and to trigger an action potential you need to get it up to -55mV, that would require 30 vesicles to acetylcholine to be released more or less simultaneously. Studies have shown that when an action potential comes along an alpha motor neuron it releases about 350 vesicles full of acetylcholine. Thats more than 10 times the amount that you need. You need thirty and your get 350. Theres always a safety margin, baring pathology that will make sure that the action potential in the motor neuron will always cause an action potential in the muscle fiber. So now all we need to do to get this muscle fiber to start contracting is send one action potential along the motor neuron. And that will produce one action potential in the muscle fiber, and that will cause all of this stuff to go on. So, lets take a look at that one little contraction. You send in one action potential, the calcium concentration of the cytoplasm goes up to ten to the minus five from ten to the minus seven, then it goes down and eventually its back to ten to the minus seven. Thats the calcium. While its above 2 times ten to the minus sixth, the contraction mechanism the actin and myosinis turned on. And then when it gets below two times ten to the minus six the

contraction mechanism is turned off again. Right. Because now youve dissociated calcium from troponin C, and the tropomyosin covers the actin binding sites and so on and so forth. So what happens here? You would expect that while the crossbridges are cycling youre going to get this much tension, none here, it contracts up to a certain level, and it goes back down when you are below that. But what actually happens when you have one action potential? And by the way, just to throw in the vocabulary, when you have one action potential, the muscle contraction that it produces is called a twitch. You dont get this much tension being produced. What happens is the actual muscle tension that you see if you take this muscle and you hook it up to some sort of force transducer measurerer is something like this and then it dies off. A lot less than, it never gets up to here. Why is that the case? Well the reason thats the case is this. Youre not measuring directly the force thats produced by the actin and myosin. What you are measuring is the force thats exerted on the next bone in your elbow joint you know on the radius and ulna. You have an insertion and when you tighten your biceps muscle the radius and ulna bone are pulled, but theyre not pulled directly by the actin and myosin. Actin and myosin pull on a tendon, and the tendon attaches to the periosteal membrane of a bone and whats called the insertion, and thats what gets pulls. But when the sarcomeres start to contract, initially all it does is stretch the tendon. Because the tendon is elastic. If you have, what youre really measuring here is the actin-myosin system producing tension and then you have this elastic, Ill put a little tendon here, and that goes to the reader, measuring the force. And so when you turn on the actin myosin system by putting calcium into the system, this starts to contract, initially its just stretching the spring. And you get the twitch. And then if you turn it off, so soon, you never really reach the full level. Well suppose you say I want to measure the full force that the actni-myosin system is producing. How would I do that? Well the whole idea is, theres a time problem here. Because the time that you spend doing this is you dont give it enough time to tighten up the tendon. The tendon is actually in series with the muscle and the measuring device. So this is referred to as the series elastic component of muscle. And because its in series with (one pulls the other which pulls the other) the elastic component of muscle and it takes time for the series elastic component to be fully stretched out to exert the force that the actin-myosin system is producing. Basically, you are introducing a time constant sort of thing. One way to measure this would be to prolong the high calcium state in the cytoplasm for a long time, then this would continue on up and eventually reach the maximum tension because youd have enough timeyoure eliminating the time constantto fully stretch out the tendon. Now, the way you do this is, before you start turning things off, before you get to 2 times ten to the negative sixth, at some point to the left of this point, you produce another action potential. Here was an action potential, heres another action potential, so that sends this up again to ten to the minus five. And as this falls down again, just before it reaches here, and that sends another action potential. The key is youre keeping the calcium concentration about that 2 x 10^-6 level by giving repeated stimuli, repeated action potentials, and that allows the tension to fully stretch the tendon and eventually express the full tension that the actin-myosin system is producing. When you give repeated action potentials, or repeated stimuli to the muscle or to the motor nerve fast enough so that you keep the calcium above that 2 x 10^-6 up to that maximum level, you are producing

something that is called a tetanus. Which has nothing whatever to do with the disease of that name. it goes rather uh cause that deals with a motor neuron cell bodies and triggering spasms of their descending off burst of action potentials, not steady streams of action potentials. So the when you produce a tetanus, if you wait long enough, you can measure the full amount of force that the actin and myosin system is capable of producing . Next item of business. If you measure the amount of force that an actin-myosin system is producing by producing a tetanus, you can fix the length of a muscle, or muscle fiber, at a certain fixed length, so that sarcomeres are at a certain fixed length and see what effect the length of the sarcomere, the initial length of the sarcomere, has on the amount of tension that can be produced. Heres your normal picture of a sarcomere. I just draw a couple of thin filaments and one thick filament. Alright. With a lot of crossbridges here. This is normal. If you make this cell shorter, by a little bit, so that the thin filaments are overlapping. Heres your myosin rod, always the same length. You can still produce crossbridges here, but not in the middle portion because the myosin filaments are not the right distance away. Or else they can sometimes buckle. So, what you get here is the production of less tension under these conditions. If you make it longer, same length and the same myosin rod, now you can only produce a few crossbridges and you wind up getting even less tension. If you make the cell shorter still so that the actin is extremely forced to be short, so that the myosin rods actually bump into the z disc, you are getting no tension at all. If you make this a little bit longer you reach a point where you cant produce any cross bridges whatsoever and you cant produce any tension at all. If you plot the amount of tension you can find in a tetanus versus length of the sarcomere, you end up with something like, if this is call it A B C D E A B C D, youre getting to loose again and E, youre down to zero again. Now, if. This is looking at a single sarcomere, if you average a few thousand sarcomeres is tends to round out, but it still has the same general shape. There is one optimal length here that corresponds to the muscle being able to produce its maximum force. Thats generally labeled the resting length of the muscle. Why is that? Because if your body is, lets just lay it out on the table, hand by your sides, the legs straight. The length of each muscle as it is in your resting body is about what the resting length is. So whenever you start off at your muscle with this length, whatever movement you make you are starting with your muscles at their optimum length to produce that maximum force. Okay. One more things about skeletal muscle and then Ill go on to smooth and cardiac. And that is this. If you look at a chicken, now there was a time when to get a chicken you would go to a farm and Ill take that one and the farmer would chop off the head and hand you a chicken. And removing the internal viscera, and the feathers was your job. Now you get this cleaned polished bird carefully wrapped in plastic in its own little coffin. And but you notice that there are two different types of muscle on this chicken. The breast and wings are whats called white muscle, we generally refer to it as white meat. The thighs and meat, which we generally call dark meat, are red muscle. Now consider the function of these muscles in a chicken. Whats the day to day life of a chicken? Not nearly as fascinating as yours. They dont fly for the most part, a little jump here and there. They mostly walk. And so most of the work thats being done is of the thigh and leg muscle and these never really rest because the chicken is always on its feet. These need a constant source of energy. So the red muscle has three adaptations that let it keep working

without stopping to rest. One is its got lots of mitochondria to produce lots of ATP to produce lots of energy for its constantly contracting and relaxing, contracting and relaxes. So it keeps walking around, it needs lots of mitochondria its got lots of ATP. The mitochondria cant do anything unless you bring oxygen to them. And oxygen comes by way of the blood stream, in fact by way of capillaries. But if you have a capillary here and capillary here, the muscle in between isnt getting very much oxygen, because oxygen doesnt transport very well through tissue. Its not very water soluble, oxygen molecules. You have two adaptations to take care of that, one is your red meat, red muscle, has more capillaries in it. Instead of a capillary here and a capillary here, it has maybe three capillaries in between that so that no muscle cell is very far from a capillary, source of oxygen. A second thing is, even so, you have to be able to get the oxygen from the capillary to the mitochondria within the muscle cell. And just as we have hemoglobin that helps out blood carry oxygen in the blood stream, here in the muscle cytoplasm we have something called myoglobin. Which carries oxygen from the border of the cell, the outside of the cell, to the mitochondria. Myoglobin, more mitochondria and more capillaries. Now there is one thing these three things have in common, they are red. Myoglobin, like hemoglobin is red. Mitochondria tend to have a red appearance under the light microscope, and the additional capillaries bring more blood vessels, which look red. Thats what gives red muscle its color. And the advantage of red muscle is it has an oxidative metabolism and therefore it can keep going for a long time without needing to rest. White muscle on the other hand has few mitochondria, it mostly rests and occasionally does something and then rests again. So it can get away with getting energy from glycolysis alone. It doesnt need much input from mitochondria. And the white muscle can go into whats called oxygen debt, where you convert the pyruvate into lactate and you get this acid situation and you can recover gradually from that by throwing in a couple ATPs to get back to the pyruvic acid which can get back to the mitochondria and the Krebs citric acid cycle. So, white muscle on the other hand, doesnt have the endurance. It has to rest most of the time. But one of the characteristics is that its faster. You could do fast, fine manipulations with your white muscle. Just look at your fingers. They are doing fine manipulation, fairly rapidly, because they are white muscle, but if you had to keep going for a long time, they would get tired. Now Compare your chicken, or yourself for that matter, to a goose. Goose, lets say a Canadian goose, they spend their winter here and then come spring they fly back north. If youve got white muscle the way a chicken does, in your wings, you cant fly 500 miles. Now if youve got white muscle in your arms, you cant fly 500 miles in a stretch either, unless you get into a plane. But with the goose, its all red muscle. The wings, the chest, aerobic metabolism and they can fly for five hundred thousand miles, stopping down once or twice for some chow. So thats the main difference. I remember the goose was always the, If you ever read Dickens, the goose was always the Christmas dinner. Its only the Americans who eat turkey. Anyway, so thats the main difference between white muscle and red muscle. And, by the way, if you ever look at a heart muscle, go to the butcher shop and look at a heart. Thats even redder than red. Because a heart muscle, cardiac muscle, cant stop and rest and take a vacation. Its entitled to one vacation and that doesnt end. So cardiac muscle is even redder than red muscle. Lets compare three types of muscle: cardiac muscle, smooth muscle and skeletal muscle. Just to put them side to side. You have skeletal, cardiac, and smooth. Cardiac muscle cells, as I said before, are very

large. Thats why you need a sarcoplasmic reticulum to take calcium in, take calcium out because theres not enough surface area. So you have very large cells. Smooth muscle on the other hand has very small cells, just these sort of spindle shaped cells with a nucleus in a middle. By the way, the nuclei are in the center is cardiac and smooth muscle and in skeletal muscle they are along the edge and there are multiple nuclei. Large cells, small cells. Because these are small cells, you have a very large surface to volume ratio, and therefore calcium moving in and out across the cell membrane is enough to regulate muscle contraction. So calcium, moves across cell membrane. Where as in skeletal muscle calcium moves to and from sarcoplasmic reticulum. What about cardiac muscle? This is one of those situations where the answer is yes to both. You have calcium moving to and from the sarcoplasmic reticulum and you also have calcium moving to and from the extracellular fluid. And theyre comparable in size, Im not going to say they are exactly fifty: fifty, but they are comparable. Its not just all one way, SR, and its not all the other way, across into and out of the cell, but both, through the sarcoplasmic reticulum and out of and into the cell Skeletal muscle of course exists in red and white versions, and theres also an intermediate that sorts of pinkish. Cardiac muscle is very red, it has an oxidative metabolism. Smooth muscle is generally white, but sometimes you have a, in some of them, you have a major mitochondria distribution, but you dont need myoglobin because the cells themselves are very small. Is there something else I wanted to say? Or else were finally done with this. Let me see. Oh yeah just one more last thing. You notice that skeletal and cardiac muscle are both classified as striated, that means you have you have sarcomeres, distinct sarcomeres that give that sort of striated appearance, its not as distinct in cardiac muscle as in skeletal muscle but its there, definitely there. Smooth muscle is not striated, thats why its called smooth or occasionally in the old British literature they used to call it plain as opposed to striated. Uh, where does the actin and myosin anchor to? And what you have are here are your sort of spindle shaped smooth muscle cell, nucleus in the middle, there are what are called dense bodies generally attached to the membrane although they can be inside the cell and you have actin filaments and myosin rods that attach. You dont necessarily have myosin from one side, myosin from the other side and actin in the middle the way you do in skeletal and cardiac sarcomeres, but here you can have actin from one dense body and myosin from the other and they will interdigitate and contract. now, what sometimes happens is when I describe that length tension curve and you got up to the longer lengths where there was no overlap and therefore no tension being produced in skeletal muscle, youre not going to have that sort of thing in real life in skeletal muscle unless there is real damage because there is enough connective tissue in real life to keep the sarcomere and the cells themselves from stretching that much unless you really do a job on it. Smooth muscle, sometimes in real life, gets stretched enough so that the actin and myosin dont overlap. Uh lets say morning after a party where you consumed large quantities of liquids of various types. You make up in the morning and your bladder is very distended. Youre urinary bladder. Now normally you wake up in the morning ,your bladder is somewhat distended, and as soon as you relax the various sphincters, the muscle contracts, the smooth muscle of the bladder contracts and squeezes the urine out. But here youve got a situation where the bladder is so distended that the actin and myosin are not overlapping at all anymore. And now you relax the sphincters and nothing comes out until you start doing abdominal compressions to squeeze the bladder. Thats because youve stretched the

muscle, just by physiological activity. If you can call drinking that much something physiological. And to the point where the actin and myosin are no longer over lapping and its your bladder is no longer capable of contracting. Once youve managed to expel by abdominal contractions and by applying pressure there by most of the liquid then, the overlap is beginning to occur and the bladder can take over by its self. But that can sometimes take a while. Okay. Have fun people. Thats it.