Hey, do you ever wonder mid-rep how
exactly all this works? Like if your
whole body, even your muscles, are made
up of just trillions of tiny cells, how
do they all work together to lift all
this weight? Your strength actually
comes down to an incredible kind of
modular precision. All of your muscles
across your whole body are in a way
millions and millions of repeats of the
same handful of structures. By going
down to the molecular level and building
up the mechanism of your muscles protein
by protein, you can get an incredible
view of the sheer coordination it takes
just to keep you up and moving. The
gears and levers that make up your
muscle fibers trace their history back
billions of years before life was even
multisellular. By remixing a few
structural proteins and assembling them
in just the right way, our cells can
accomplish incredible amounts of work
with very little input. But let's just
get right into it. Crack some creatine
and settle in for this one, folks. Let's
start exploring the sarcomir.
tattoos, and papercraft molecules that celebrate your biochemistry. But anyway,
let's get right into how your muscles
work. And I'm going to do the best I can
to speedrun through the anatomy to get
to the cool stuff at the molecular
level. So, yeah, the basics. All of our
motion is powered by our muscles, whose
main job is to contract and get shorter.
Every movement comes from muscle tissue
pulling on some part of your skeleton,
with most muscles coming in pairs so one
partner can pull the other one back
after a contraction. Moving further
down, that contraction requires an
incredible amount of coordination to
make sure opposing forces don't
accidentally rip your cells apart or
anything. So, muscles are made of very
unique cells called meioytes. You
normally imagine cells that look like
this, right? They're very square or very
round, but always like roughly the same
length and height. Muscle cells are some
of the most specialized tissue known to
nature, and they only care about getting
shorter and longer. Therefore, these
cells are long, thin fibers that are the
result of lots of progenitor cells
fusing together, which means that one
muscle cell actually has several nuclei
running the show here in tandem.
Underneath the surface, these cells are
just bundles of protein fibers called
myofibbrals, which are surrounded by
support structures like transverse
tubules and the cycloplasmic reticulum,
with most of the rest of the space in
here getting absolutely stuffed with as
many mitochondria as possible. You know,
to power all the movement that happens
in here. But now we're getting to the
good stuff. So if we briefly switch to
an electron microscope view of these
myophibbrals, you're going to start
understanding what makes these cells so
powerful. Each myophibbral is incredibly
well organized. I mean, look at these
bands of protein. They line up almost
perfectly across several different
myophibbrals. That's because each fiber
inside every muscle cell is just the
same fundamental unit repeated over and
over. This region, dark band to light
band to dark again, is a single
structure called a sarcomir. Across a
single muscle, every sarccomir is pretty
much exactly the same. But different
muscles and muscle types might have
slightly different sarccomirs with
slightly different sizes. Either way, as
your muscles grow, they're basically
just stacking up new sarcomirs. So, if
you learn how one single sarccomir
operates, you basically know how the
entire muscle works. So, if we zoom all
the way in, we can finally start
exploring the proteins that power all
this movement. Behold the sarcomir. Down
here at the molecular level, it honestly
feels like we're in a dense forest more
than anything with long thin filaments
and elastic connectors towering over us.
A sarcomir is three main components
repeated over and over again. Basically,
we've got the thick filaments in red,
thin filaments in blue, and then a
supporting cast of structural proteins
holding everything together. If you want
to skip the rest of this video, all you
need to know is that the thick filaments
power muscle contraction by using all
these little heads to grab and pull the
thin filaments down like this, thereby
making the whole sarccomir contract
lengthwise. But come on, how does that
even work? Let's keep going. The middle
of the sarccomir is, get this, the M
band. This is also the dead center of
these thick filaments and their mesh of
support proteins. Basically, two
identical thick filaments sprout out of
the spot facing away from each other.
Trunk to trunk, butt to butt, soul to
soul, whatever you want to say. Moving
outwards, we get to the A band. Probably
the best defined area of the sarcomir,
where the thick and thin filaments
overlap with each other. And honestly,
this is where the magic happens. But
hold on, moving a little further out is
the I band, which is just the thin
filaments and the elastic connector
proteins holding everything together,
which eventually gives way to another
super dense region. Behold the Z disk,
the border between two sarccomirs. Here,
a bunch of molecular scaffolding glues
the thin filaments of two neighboring
sarcimeirs together while providing an
anchor for the elastic connectors of
both adjacent sarccomirs as well. Now,
this whole thing has been a glorified
two-dimensional side view. If we look at
this thing from the bottom up, we can
see that a bunch of thick and thin
filaments are organized around each
other in kind of like repeatable layers.
Because of how elastic and pliable our
muscles have to be, the details here are
kind of fuzzy. But at the basic level,
these muscle filaments are arranged in
this repeating hexagonal pattern. Every
thick filament is more or less 45 nmters
away from the thick filament next door,
while the thin filaments fill in the
gaps. All right, cool. That's the lay of
the land. Nice. We've got the shape of
things down pretty good. But how does
all this work? That's kind of like why
we're here, right? And you know what?
Surprise. We're actually going to have
to go down one more level and break
these filaments into their component
parts, which is going to tell us
everything we need to know about how
your muscles contract. But first, a
anyway, let's get back to building this sarcimeir. Here we are where we can
finally unpack the mechanics of how
sarccomirs work. Again, at a high level,
these structures contract when the
meiosin heads on the thick filament pull
the thin filament toward the Mline. This
system has been fine-tuned over the last
billion years or so. I mean, both actin
and meiosin are ancient proteins that go
back to the dawn of ukarotic life and
our days as single-sellled blobs
floating around the ocean. And coming
up, we're going to see how these
individual proteins create an incredible
system for so much motion. So, let's
break it down. First up is the thin
filaments. They basically hold the whole
sarccomir together and are like the
medium that's being contracted
throughout your muscles. The star of the
show here is in blue. It's the versatile
actin protein that's pretty much
ubiquitous across all life. Actin is a
wonder. Your cells are constantly
pumping out these little subunits. And
when activated, they can spontaneously
polymerize into these cool little
filaments. And even cooler, they can
also spontaneously depolymerize on the
back end as well. As the title implies,
actin is from your cytokeleton. So, it's
going to provide some structure and some
rigidity throughout your cells. But your
body also uses actin's ability to
polymerize and depolymerize on demand as
a way for folks like your white blood
cells to move around. And I mean, look
at them go, right? All those little like
tentacles, right? They're probably
membrane protrusions being driven by
actin polymerization. This stuff is
incredibly fast, but the role actin has
in muscles is a little different. We
want our actin here to stick around and
polymerize in the right way at the exact
right length and not fall apart at
random. So, your muscle cells are going
to build some support structures around
actin to make it a filament and not
something super dynamic that breaks
apart too much. First up, your muscle
cells build this little yard stick
called nebulin. Nebulin doesn't look
like much, but it's one of the single
largest proteins your body builds on a
regular basis. And if that makes you ask
what the biggest one is, uh, sit tight.
That's coming up in like seconds, right?
Nebulin's job is to act as a scaffold
for actin to polymerize around instead
of letting actin get all dynamic and
depolymerize on a whim. Nebulin
stabilizes actin in its filament form,
keeping your muscles from breaking apart
for no reason. This gives Nebulin the
power to determine sarcimeir length, but
more on that towards the end of the
video, actually. And the thin filament
is further stabilized by this coil,
tropomyiosin. And sure enough,
tropomyiain also has a really important
job outside of stability, working in
tandem with this last protein called
troponin. But let's build the rest of
this sarccomir before we get ahead of
ourselves. Before we head down to the
thick filament and the main event of
this video, really, I may as well
mention what is objectively the coolest
protein in your muscles since it's also
up here. Anyway, these cables are copies
of the same protein, Titan, which is
incredible in its sheer mass. What
you're seeing right now is actually
three copies of Titan that surround a
single thick filament. A single Titan
chain is one singular protein coded for
by the single longest gene in your DNA.
Titan in our muscle cells is 34,300ish
amino acids long. Just incredibly
massive. By comparison, a more average
protein like hemoglobin is only about
550 amino acids when you add up all the
subunits together. So, we are on just an
incredibly massive scale. And you know
what? Quick tangent. I was going to make
a whole thing out of the fact that Titan
is the largest peptide known to science
and how cool that is that it's, you
know, invertebrate muscles. But then two
years back, this team out of the Scripps
Institute in San Diego ruined the fun by
uncovering an even more massive protein
PKzilla that's 30% more massive than
Titan while also somehow being cooler
and uses all that unmodelable heft to
help this one algae build this really
intense looking toxin or whatever. I
mean, honestly, that just kind of feels
like its own video, though. But anyway,
don't let Titan's outsized reputation
intimidate you. This structure is
manageable once you peek under the hood
because instead of being like 34,000
distinct little puzzle pieces making up
this cable, it's basically just the same
three protein domains repeated a bunch
of times. And to be even more real with
you, it's just these imunoglobulin and
fibonnectin domains that get copy pasted
like a few hundred times while Titan is
synthesized. The fibonnectin domains
provide rigidity and structure. While up
in the eye band, these imunoglobulin
units fold and unfold, allowing Titan to
act kind of like a molecular spring,
absorbing some of the tension and force
from the stress of contraction. Titan
spans the whole length of the sarccomir
with a single Titan cable anchored to
the Mline and Z disc. The tension and
elasticity that Titan brings to the
table helps hold the sarccomir together.
And that spring action allows Titan to
help pull the sarcimeir back to the
relaxed state after muscle contraction,
which gives our motion a ton more power
and flexibility compared to folks like
insects and other critters who lack
Titan in their muscles. But getting back
down to the bioam real quick, what's
cool is that these links actually
provide elasticity in a few different
ways. First up, the actual individual
links in these chains will bend together
a little like this when your muscles are
relaxed. And then these kinks will
straighten out as your muscle contracts
more and more. And this is where it gets
wild because according to certain
models, some of these amunoglobulin
domains can unfold completely into a
straight line when the cable is under
enough tension, which makes Titan even
springier. Our bodies can use these
different levels of elasticity to
accomplish so much extra work. But I'll
need to save those for a part two where
we improve this sarccomir model with
better simulations of how Titan works.
Make sure you comment if that deep level
of biopysics is something you actually
want to see. I mean, that's the only way
I'll be able to put myself through the
pain of that level of modeling. Anyway
though, for now, just remember that
Titan is a long elastic cable that has a
couple of distinct regions where these
imunoglobulin and fibonnectin domains
will repeat in a certain pattern. That's
going to be important to have in mind
when we round things out by making it
all the way down to the thick filament.
Which, speaking of which, let's just get
down there now. The meiosin filament.
Finally, we're getting to the meat of
this thing. The core of your muscles are
built around these thick filaments,
which mainly are a rotating stack of
these long meiosin molecules. Our
muscular meioins come in pairs with long
winding tails that wrap around each
other, which are both capped off by a
motor domain attached to a flexible
neck. These meiosin domains kind of
helically stack on top of each other,
which is how we build our thick
filament. The average meiosin filament
is going to have around 294
of these meiosin molecules stacked on
top of each other with two kind of
identical copies branching out trunkto
trunk from the mline. There's one last
super cool detail about how this all
comes together, but I'm going to save
that for the end. For now, let's get to
the main event. Let's see how these
meiosin motors pull on the actins inside
that thin filament. And to do this,
let's get out of this big simulation and
zoom in on the interaction between one
meiosin and a nearby thin filament. What
we're about to see is the power stroke
cycle for these meiosin motors. Stick
with me here. We're just going to level
up through it. Ready? So, how exactly
does meiosin bind and move these long,
thin filaments? As always, it comes down
to one of the most important maxims in
all biology. Structure equals function.
And meiosin is able to pull on actin
thanks to a repeated sequence of very
subtle shape changes. Shape changes that
are powered by everyone's favorite
energy currency, adenazine triphosphate
or ATP. And you know what? We're just
going to start at the very end of the
last power stroke. Meiosin has just
finished pulling this actin molecule up
a little bit, but it's still bonded to
this actin unit. We really don't want to
stay stuck like this for long because we
don't want to jam up the rest of the
sarccomir as the muscle continues to
contract. Luckily, the mitochondria that
are crammed up against these sarccomirs
are just flooding this area with ATP,
which means a fresh energetic molecule
of this stuff is going to quickly find
and bind with the little pocket on the
back of our spent meiosin right here.
And this is one of the magic pieces of
biochemistry. Almost every single thing
that happens to any protein is going to
change its shape a little bit. That's
how dynamic things are down here. And
therefore, even the little nudge from
this ATP is going to change the shape of
our meiosin head just subtly enough to
help it dislodge from this actin
filament, freeing it up to start the
next power stroke cycle. And this is the
cool part that makes the power stroke so
automatic and so fast. Letting go of
this actin is going to release a little
tension inside this motor. This
confirmation is perfectly primed to
hydraulyze this ATP. This terminal
phosphate group at the end will pop off
which to oversimplify releases a burst
of energy that the surrounding meiosin
motor domain can use to change shape.
And meiosin can only move one way when
charged by an ATP burst like this. That
energy will throw meosin's lever arm
into the primed position. That burst of
energy is going to the meiosin
domain back down to the prime state,
readying it to grab onto the next actin
molecule down the chain. And this brings
us to the real magic of meiosin and the
secret sauce that makes your muscles
work. You hear about ATP in biology all
the time. ATP is constantly moving
energy around your cells by getting
hydrayed, popping this phosphate group
off and releasing that burst of energy.
For a lot of proteins, ATP slots into a
binding pocket like the one inside
meiosin right here, transfers its energy
and is then immediately released. But in
meiosin, when ATP the motor back,
it actually gets stuck in the binding
pocket here. Sure, this meiosin head is
now under a lot of tension, but that
tension can't get released because this
adenazine diphosphate ADP and the
phosphate it just released are jamming
the works up in here. Maybe this sounds
clumsy, but it's a brilliant way to make
sure that these meiosins don't burn
through cellular energy for no reason.
Instead, think of this like, I don't
know, a mouse trap. We're effectively
storing the energy from ATP until the
exact moment we need it, which is when
this meiosin comes in actual physical
contact with an actin. There's a great
binding spot for meiosin in this groove
on actin right here. And attaching to
that actin will change the moto domain's
head just enough to pop out this little
phosphate which again allows all that
tension to kick the meiosin lever arm
here down which for physics reasons is
going to actually shove the motor and
actin up which is the actual power
stroke of this cycle. As soon as the
power stroke here finishes a new ATP can
slot in and free meiosin from its bonds
to actin and start the cycle all over
again. And this system by itself is
incredibly powerful and beyond
versatile. This automatic interaction
between actin and meiosin powers
cellular shape changes, cell division,
some motor proteins, and a whole host of
other jobs all throughout the whole
ukareotic domain. Now, yes, this is
complicated, but the complexity here
allows for one last incredible layer of
control. Because if binding to actin
automatically activates these meiosin
motors and you know actin is kept within
binding distance of meiosin basically at
all times in these near crystallin
sarcomirs then like how do our cells
keep meiosin from just power stroking
all the time. You know I kind of wish I
had rewarded that but uh I'm in too deep
now. So let's just keep going because
this is the best part of the video. This
rocks. We get to put the whole thing
together. Now, let's focus back on the
thin filament and check in on the last
piece of this puzzle. Remember, our thin
filaments aren't just raw actin here.
They're stabilized by these winding
coils of tropomyiosin. Actually, coiled
coils of tropomyiosin, but whatever. And
those coils are occasionally studded
with these troponin complexes we glossed
over earlier. Now, troponin controls the
real magic of the sarcomir. And here's
how. Turns out tropomyiosin isn't just
stabilizing our thin filaments. It's
also actively blocking the part of the
actin molecule that meiosin can bind to
during an activity. These meiosin motors
are just endlessly teased, forever
caught in that post ATP tension with
nowhere to bind. All tension, no release
until you actually decide it's time to
flex something. When it's actually time
for a muscle to contract, your nervous
system is going to send an impulse
directly to that muscle. That nerve
contact is directly connected to all
those little tubes that surround the
myophibbrals we discussed earlier. And
once that signal arrives, the
cycloplasmic reticulum here turns on the
pumps and floods the myophibbral with
calcium ions. Once inside the sarcimeic
space, that calcium will bind to
troponin, which will activate and change
its shape pretty sharply. That shape
change is going to pull tropomyiosin
away from actin's binding cleft,
allowing meosin to actually contact the
filament and roll through the power
stroke cycle. Meanwhile, at the exact
same time, there are pumps between the
sarcomir and the cycloplasmic reticulum
that are constantly pumping calcium out
of the myophibbral, which keep the, you
know, contract signal short and to the
point. But yeah, I mean, that's the main
gist of it. Vertebrates like us have
re-engineered cytokeleletal proteins to
massively increase the amount of
leverage we have over the outside world.
For me, the most important thing that
allows this to work is how perfectly
organized these sarcimeirs are. Don't
forget how they line up so well to
ensure that all these little proteins
end up all working in the same
direction. How do we even pull that off
when living structures can look so messy
in other ways? And this is actually
another one of the superpowers of Titan.
Remember how Titan is just three
different subunits repeated over and
over in different patterns. Down here in
the thick filament, Titan just repeats
these imunoglobulin and fibonnectin
domains in an 11 unit pattern over and
over again. And this 11unit pattern
actually repeats 11 times. Nice. This is
the C type super repeat and evidence
suggests that this acts like a molecular
ruler, giving the tails of these big old
meiosin molecules a place to start
binding. Once that first meiosin
molecule slots in on this first super
repeat from Titan, the rest of the
meiosins can slot into place, stacking
up helically like this. All 294 of them
stacked helically on top of each other.
And the rest of the filaments fall into
line all around it. With Titan and
Nebulin, we added a few extra yard
sticks and controls. And that's going to
help the fuzzy process of cellular life
achieve a kind of incredible rigidity
and specificity. For me, it's incredible
how all this comes together. I love so
much how our cellular structures have
relatively simple rules that build to
fabulous complexity. And like I said at
the very beginning, this system is also
incredibly modular. By organizing the
sarcamir around yard sticks like Nebulin
and Titan, our cells can make incredibly
different muscle types out of pretty
much the same molecular ingredients. If
you've seen my big old video on how DNA
gets transcribed into RNA, you know that
one of our secret superpowers is RNA
splicing. This big complex called the
splyoome modifies RNA as it gets
transcribed from DNA, allowing us to
produce tons of different proteins from
a single DNA sequence. Alternate
splicing of Nebulin and Titan changes
the length of these yard sticks and
therefore the length of the entire
sarccomir. Different lengths and a few
other modifications allow for a
breathtaking variety in muscle types and
jobs. A little added complexity yields
an astonishing amount of extra control.
And gosh, we are able to do just so much
with our own internal variety. That's
the main thing I always want you to take
away from videos like this. Together, we
slog through a whole mess of dense
information, and in the end, we're able
to put things all together and see the
majesty in our biochemical foundations.
Frankly, muscle cells are great in that
these sarcimeirs are organized enough
that it's easier for me to show you just
how jam-packed our cells are with
proteins and structure. It's grounded in
these cells, and we're able to do just
so much with all these little puzzle
pieces. And there's so much more to
explore in these sarccomirs, but here's
a good place to end this first video.
Make sure you hit that comment section
if you want to dive even deeper into
this particular aspect of chemistry. For
now, though, I really appreciate your
time. Thank you so much for watching.
And hey, thanks so much for getting all
the way to the end of this video. If you
like this video, make sure you like and
subscribe so you don't miss future
editions of this series on muscle
structure. At the same time, it would
mean the world to me if you checked out
what we've got cooking over at
patreon.com/clockworkshow.
This year has a lot of great perks in
the works, and I think you're going to
really like it over there. And one bit
of housekeeping. I just want y'all to
keep in mind that so much got left on
the cutting room floor here, too. I
didn't get to talk about creatine or low
duty ratios or anything cool like that.
So, make sure you let me know if that's
something you'll really want to see.
Otherwise, the main thing I want you to
know is how much it helps me when you
make it all the way through a video like
this. Just the act of you hearing these
words right now effectively is carrying
this channel. Thank you so much for
being here. But that's a solid place to
end things. Let me know what your
favorite color is in the comments if you
made it this far. For now though, I just
really appreciate your time and as
always, I'd like to leave you with
peace, love, and as many seat type super
repeats as possible. Everyone, be well.
Thank you so much.