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Current time:0:00Total duration:14:30

here's a question for you how can the heart increase the force of contraction in fact in thinking about this kind of put yourself in the position of the heart you know the heart is working very very hard every single day to beat and now if you're the heart let's say this is you and you've got to figure this out you're you're working very diligently and now the heart is being asked to do even more so what's the answer how did you how do you actually increase the force of contraction well you know that there's one form of energy that's being converted to another so that's chemical energy and we think of the molecule ATP when I say chemical energy that's the one I'm kind of thinking about is being converted to mechanical or kinetic energy I'm going to write mechanical energy and this process of going from chemical energy to mechanical energy is creating this kind of force of contraction this is how you're getting the force of contraction and there is a specific protein that's actually allowing you to even do this right this protein is going to look a little bit like this and this is our myosin head in fact not even a whole protein this is a part of a protein so the myosin head is what is actually allowing you to convert chemical energy into mechanical energy and so the question you can actually rephrase is how do you get more how do you get more myosin heads working that's really kind of the answer to this right if you wanted more force need more myosin heads working so if you have let's say I don't know let's say you have 100 myosin heads working then how do you get 200 or if you have 200 how do you get 500 so in any case how do you get more going and really to answer this thing we have to figure out what it is that myosin heads need to do their job so let's start with let's start with two key criteria right so two key things that we know they need one is they need to be nearby actin so we know that they need to be working and nearby another protein call actin so if they're far away from actin this whole thing is not going to work they're not going to be able to do their job and remember that there's this issue of polarity and all I mean by polarity is that actin actually has a certain direction so not only do they have to be close to act and they have to be close to the actin going in the right direction and a second thing is that they actually need calcium right calcium needs to bind troponin C needs to bind troponin C and why is that well remember troponin C I'm going to write trop C blast troponin C troponin C is actually going to move it's going to move tropomyosin out of the way so that's just to kind of remind you of what it does and when tropomyosin is moved out of the way then actin is free to bind myosin so these are the two important kind of things we have to consider right we need to make sure that our myosin is nearby actin and that calcium is binding troponin C let me make a little bit of space I'm going to pull up something that I drew earlier and I thought we can actually split this talk into two parts because another issue is kind of are we talking about end of systole or end of diastole or what what time point are we talking about exactly and of course it's always nice to kind of label this stuff so let's talk about end of diastole on this side and on the other side I'll squeeze in end of systole this will be end of systole so these are the two time points that I think are important to kind of discuss separately in terms of our two criteria which of these are going to meet the criteria well let's go one at a time nearby actin so which of these myosin heads is nearby and actin that it needs to be nearby well those three for sure and then these five are near the correct polarity as well as are these five and these three but now I've actually not circled a couple of things here right I ignored circling these two and these two and the reason is because they are actually nearby actin of the wrong polarity and actually even drew in the arrow heads on the actin so you could see what I mean right there nearby actin going in the wrong direction as opposed to what they would need to bind to so I've got a total of how many blue circled myosin heads we have 16 right so remember criteria 2 is about calcium and now let me throw up a random number let's set up to number 10 let's say there are 10 calcium's calcium ions kind of floating around actually let me make it a bigger number just to illustrate another point let's say 2020 calcium ions floating around and now let's say that they are going to have to bind troponin C well troponin C let's say only binds about 50% of the calcium's that are around so only 50% bind troponin C so what are you going to get you get 50 percent times 20 you have 10 calcium's that are going to bind and actually let me go ahead and create a dividing line here if 10 calcium's that are going to bind so let me just kind of sprinkle some calcium's 10 of them in here let's see what happens so let's go one two let's go three let's go four five six seven eight nine and ten so ten calcium's there and now the question is how many myosins are working so I'm going to just circle or with little red arrows I'm going to point to the myosin heads that are working that satisfy our two criteria so so far we've got a couple there and then we've got this guy here we've got this guy here we've got one here and I think that might know yet we've got one here so we've got a total of seven seven that are working so let me actually just write that seven out of 20 myosin heads are working so that's not too bad that's not quite even 50% but let's just kind of tuck that away and let's say that and we know this we actually redo this with a strategy in mind so the heart actually wants something better than seven and no the main strategy we've talked about this but really not in this context the main strategy for getting more myosin heads working is going to be called stretch so this is kind of if you were to think of one word answer to our initial question how do you get more myosin heads working you basically stretch at least if you're in end of diastole that is the answer right we know that's kind of the key idea so let's now bring up a stretched out version of this and see what would happen so in a stretched out version you have let's say again 20 calcium's here and instead of binding 50% of them to troponin c we know more of them are going to want to bind because that's one of the keys with stretching you recall that now troponin C is going to really want to bind to calcium so more of it binds and that's one of the interesting properties of troponin C is that it can actually change its affinity for calcium so 15 calcium's are going to bind now and that's up from just 10 earlier and just like before I'm going to circle the blue myosin heads that are near actin of the right polarity so so far we've got 5 10 and basically all of them right all of them are basically near actin of the right polarity so I'm like before were some weren't some weren't gonna be near actin that they needed to be near here all of them are and then I can draw calcium kind of binding randomly and I'm going to draw it binding all different parts of actin now you might think well why is it binding all the way to the left over there there's no myosin over there I remember calcium will just bind troponin C wherever it darn well feels like so it'll bind anywhere and even if myosin is not there it'll still bind there so we've got let's make sure I've got the correct I think I got three more to go 1 2 3 so now we've got a total of let's say I'm going to draw red arrows next to the ones that are working so we've got one minus in here one here one here one here one here here basically anywhere a calcium is bound I've got a myosin head working so now I've got a total of 9 out of 20 so this has actually gone up considerably right 9 out of 20 are bound so this is actually really really nice to see we've actually using stretch we're able to recruit a couple more myosin heads to work and again these numbers I'm just throwing out so I don't want you to be wedded to the numbers but I want you to get the concept the concept that stretch actually helped us increase the amount of myosin that was converting chemical energy to mechanical force now this is all happening in in diastole and that's all well and good but what about in systole what's happening there well here you can see that basically the end of systole the two myosin actin drawings that I have here look very similar pretty much the same so at the end of systole when everything is kind of contracted down the idea of stretch is going to be less relevant here right I mean that doesn't matter so we really need to think of a new strategy if we want to get more myosin heads working and what is that strategy going to be well let's let's start with our first scenario and I'll call these top two scenario a's and these bottom two scenario B's so let's go to scenario a for the end systole let's start with kind of circling which ones have myosin heads that are capable of working so I've got one here in five here and you basically see how this is kind of going you've got five here and one here and that's because there's so much blockage happening from this whole chunk right here let me draw it in a different color this whole chunk is basically blocking and this whole chunk is basically blocking because they're the wrong polarity now with the criteria two we said you need some calcium binding so what's going to happen there well let's use the same numbers just to keep it really simple so let's say twenty calcium's and let's say 50% bind troponin C well that gives me the same numbers before we're going to get a total of ten right so I've got 10 Cal seems to play with and I'm going to sprinkle those calcium's around I'm going to put maybe one here and one here three let's go for five 6:7 let's go eight nine and ten so how many actually are going to be working how many masts and sir heads are working here we got one here and then of course these don't work right the ones in the middle here let me just circle them these guys are blocked both sides so still still at just one and then I've got one here he's working and then I've got one here he's working now I want to point out I've got calcium here and here but I didn't put an arrow next to those guys because again those myosin heads are near actin but that calcium is actually binding not the nearby actin its actually buying binding to the far actin on the other side so again those myosin heads will not be working so I have a total of three only a total of three so that's not - not too hot right that's not too great and now the strategy the heart uses and n systole is not stretch but increased calcium so if you just increase the amount of calcium then you can actually get a much better outcome and this is the key idea and the key strategy that it uses so let's see how it plays out if you just increase the amount of calcium I'm going to double it to forty forty calcium's this is an incredible number of calcium's right and let's say that fifty percent I'm going to keep that number the same bind troponin C so that number is about the same so that leaves me with twenty calcium's right twenty calcium's and I can put those twenty anywhere so I'm going to sprinkle them around just one two three four five I have so many dude you know kind of bind I've got to just bind everywhere and let's see where this all goes make sure I get 20 out here and let's do something like that so that's 20 calcium's and now let's figure out what we have so we have the same as before these are the myosin heads that are going to be near an actin of the right polarity so there's the label ones that from the get-go we know could potentially work and these other ones we know are going to be blocked by the actin of the wrong polarity so that's that's an easy way to kind of get started and then we just have to kind of count things up and so let's see what we get I really didn't plan this I'm just kind of seeing what I get based on random luck so I've got one two three four and then I've got on this side five six and seven eight so I've pointed arrows to the ones that I think makes sense and you can double-check that to make sure again you're just looking for a blue circled myosin with a calcium on the nearby actin that sounds like a mouthful but I think I got all that out correctly so I've got eight out of twenty so eight out of 20 is definitely better than what we had earlier right so our strategy has worked we went from three to eight and in and diastole went from seven to nine so we're definitely seeing improvements now these are the key strategies and I just want to remind you that it goes back to just doing whatever you can to getting the most myosins at work