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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 working very diligently. And now the heart is being
asked to do even more. So what's the answer? 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. 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. And this protein is going to
look a little bit like this. And this is our the 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 as how do you get
more myosin heads working? That's really kind of
the answer to this. If you wanted more force, you
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 have 500? So in any case, how
do you get more going? And really to
answer this then, we have to figure out what it
is that myosin heads need to do their job. So let's start with
two key criteria. So the 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 called actin. So if they're far
away from actin, this whole thing's
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 actin, they have to be close
to the actin going in the right direction. And a second thing is that
they actually need calcium. Calcium needs to
bind troponin C. And why is that? Well, remember troponin C--
I'm going to write trop C, but that's 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. 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 could actually
split this talk into two parts because another issue
is are we talking about end of systole
or end of diastole? Or 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 a time. Nearby actin. So which of these myosin
heads is nearby an 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. I ignored circling
these two and these two. And the reason is
because they are actually nearby actin of
the wrong polarity. And I actually even drew in
the arrow heads on the actin, so you could see what I mean. They're nearby acting 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 the myosin heads? We have 16. So remember criteria
two is about calcium. And now let me throw
out the random number. Let's throw up the number 10. Let's say they're 10 the
calciums, calcium ions kind of floating around. Actually, let me make
it a bigger number just to illustrate another point. Let's say 20 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 calciums that are around. So only 50% bind troponin C.
So what are you going to get? You get 50% times 20. You have 10 calciums
that are going to bind. And actually let me go ahead
and create a dividing line here. You have 10 calciums
that are going to bind. So let me just sprinkle some
calciums, 10 of them in here. And let's see what happens. Let's go one, two. Let's go three. Let's go four, five, six,
seven, eight, nine, and 10. So 10 calciums 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-- Oh
yeah, we've got one here. So we've got a total of
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. But that's not quite even 50%. But let's just 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 we know that
the main strategy-- And 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
think of a 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. 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 calciums 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 calciums 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 five,
10, and basically all of them. All of them are basically near
actin of the right polarity. So unlike before where
some were and some weren't going to be near actin
that they needed to be near. Here all of them are. And then I can draw
calcium binding randomly. And I'm going to draw it binding
all different parts of actin. Now you may think, well, why
is it binding all the way to the left over there? There's no myosin over there? But remember calcium
will just bind troponin C wherever it darn
well feels like. So it'll bind anywhere. And even if myosin's not
there, it'll still bind there. So we've got-- Let's make
sure I've got that correct. I think I've got three more
to go, one, two, three. 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 myosin here,
one here, one here, one here, one here, here. Basically anywhere
calcium is bound, I've got a myosin head working. So now I've got a total
of nine out of 20. So this has actually
gone up considerably. Nine 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 end diastole. And that's all well and good. But what about end 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 contracted down, the idea of stretch is going
to be less relevant here. 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 start with
our first scenario. And I'll call these
top two Scenario As and these bottom
two Scenario Bs. So let's go to Scenario
A for the end systole. Let's start with circling
which ones have myosin heads that are
capable of working. So I've got one
here and five here. And you basically see
how this is 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 a
different color. This whole chunk is
basically blocking, and this whole
chunk is basically blocking because they're
the wrong polarity. Now with 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 a really simple. So let's say 20 calciums and
let's say 50% bind troponin C. Well that gives me the
same number as before. We're going to
get a total of 10. So I've got 10
calciums to play with. And I'm going to sprinkle
those calciums around. I'm going to put maybe one here,
one here, three, let's go four, five, six, seven, let's
go eight, nine, and 10. So how many actually
are going to be working? How many myosin
heads are working? Here we got one here. And then of course, these
don't work, the ones in the middle here. Let me just circle them. These guys are blocked, both
sides so 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. It's actually 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 too hot. That's not too great. And now the strategy the
heart uses in end 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 uses. So let's see how it
plays out if you just increase the amount of calcium. I'm going to double
it to 40, 40 calciums. This is an incredible
number of calciums. And let's say that
50%-- I'm going to keep that number the same. --bind to troponin C. So that
number is about the same. So that leaves me
with 20 calciums. And I can put those 20 anywhere. So I'm going to
sprinkle them around, there's one, two,
three, four, five. I have so many to 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 calciums. 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 these are the only 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 an easy
way to get started. And then we just have
to count things up. And so let's see what we get. I did I really didn't plan this. I am just 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 20. So eight out of 20
is definitely better than what we had earlier. So our strategy has worked. We went from three to eight. And in end 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 mysosins at work.