Molecular Mechanism of muscle contractility - Part 1

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Summary

The video delves into the intricate molecular mechanisms involved in muscle contraction, specifically focusing on troponin and its role in the process. It explains how troponin, with its three subunits, interacts with other proteins like tropomyosin and actin to regulate the availability of binding sites for myosin heads. When calcium binds to troponin, it causes a shift in tropomyosin, exposing the binding sites and initiating the contraction cycle. The video also elaborates on terms like 'power stroke', 'crossbridge cycling', and 'rigor mortis', explaining their significance in muscle physiology.

Highlights

Troponin interacts with tropomyosin and actin to facilitate contraction. 🤝
Calcium binding leads to conformational changes necessary for muscle action. ⛓️
The power stroke mechanism is integral to muscle movement. ⚡
Rigor mortis illustrates the importance of ATP in muscle relaxation. 🕒
Myosin heads function independently during the contraction cycle. 🔄

Key Takeaways

Understanding muscle contraction at a molecular level involves proteins like troponin, tropomyosin, and myosin. 🧬
Calcium plays a crucial role by binding to troponin to facilitate muscle contraction. ⚙️
The 'power stroke' is essential for the conversion of chemical energy to mechanical energy. 💪
Rigor mortis provides insights into the biological process post-mortem due to the unavailability of ATP. 💀
Each myosin head operates independently, functioning as long as ATP is available. 🔋

Overview

In this intriguing video, the mechanics of muscle contractility are explored, starting with the role of the protein troponin. This multi-subunit protein is key in muscle contraction processes, interacting intricately with other proteins such as tropomyosin and actin. When calcium binds to troponin, it triggers important shifts in these protein structures, leading to the exposure of sites needed for muscle contraction.

The video outlines the 'power stroke' in detail—a process where chemical energy from ATP is converted into mechanical motion. This transformation is crucial for muscle movement, as the myosin heads attach, pivot, and pull the actin filaments. The insight into how a single stroke of a myosin head results in muscle movement is vividly depicted.

Additionally, a fascinating aspect of muscle physiology—rigor mortis—is discussed. This natural occurrence post-death provides a deeper understanding of ATP's role in muscle relaxation. The interdependence of various proteins during muscle contraction and relaxation stages is made clear, emphasizing on how each myosin head works independently but relies on the availability of ATP to function effectively.

Chapters

00:00 - 00:30: Introduction The chapter titled 'Introduction' begins with music.
00:30 - 01:30: Troponin and Tropomyosin The chapter titled 'Troponin and Tropomyosin' discusses the structure and function of the proteins troponin and tropomyosin in muscle contraction. The transcript elaborates on how these proteins relate to F-actin and G-actin, describing the formation of a double helical structure. Troponin and tropomyosin are positioned along the actin filaments, with troponin playing a crucial role in muscle contraction by binding to calcium ions, facilitating the movement of tropomyosin away from actin's active sites, allowing for myosin head binding and muscle contraction.
01:30 - 02:00: Role of Calcium in Muscle Contraction The chapter discusses the role of calcium in muscle contraction, focusing on the interaction between actin and myosin. It explains the position of specific molecules, including G-actin and how its myosin binding site is typically occupied. Troponin, another protein, plays a critical role in muscle contraction and is noted to be made up of three subunits.
02:00 - 03:30: Crossbridge Cycling and Power Stroke The chapter delves into the complex interactions within the muscle contraction mechanism, focusing specifically on the role of troponin and its three subunits. Each subunit has a distinct function: one binds to tropomyosin, another to actin, and the third to calcium ions. This intricate setup is central to the muscular process of crossbridge cycling and the subsequent power stroke mechanism.
03:30 - 05:30: Rigor State and ATP Role This chapter explains the structure of the muscle fibers, particularly focusing on the role of F actin, tropomyosin, and the binding sites for the myosin head. It details how tropomyosin covers the binding sites on actin and reveals how calcium binding to troponin causes tropomyosin to move aside, allowing muscle contraction to proceed.
05:30 - 07:00: Role of Titin and Troponin Subunits This chapter examines the role of titin and troponin subunits in muscle contraction. It explains how the binding site on actin is exposed, allowing for the binding of the myosin head, which is essential for muscle contraction. Tropomyosin acts as an inhibitor of this interaction. It is displaced from the binding sites when troponin pulls it away, a process that is activated by calcium. The chapter hints at further details to be discussed regarding how calcium activates troponin in the following slides.
07:00 - 09:00: Actin and Myosin Interaction This chapter focuses on the interaction between actin and myosin, particularly through the mechanism known as crossbridge cycling. It begins with a basic visualization or animation of the molecular components involved, such as the head of the myosin and the actin filament, along with their relative positions to the Z membrane. The chapter explains how the actin is anchored to the Z membrane and highlights the role of calcium in facilitating the interaction with the myosin molecules.
09:00 - 11:30: Overlap and Force Generation The chapter 'Overlap and Force Generation' focuses on the mechanics of muscle contraction, particularly how the proteins actin and myosin interact. It explains that the 'troomin' (possibly referring to the troponin-tropomyosin complex) moves away to allow binding. Myosin heads bind to active sites on the actin filament. Once bound, the myosin undergoes a power stroke, pulling the actin filament towards the Z line, contributing to muscle contraction.
11:30 - 12:30: Independent Action of Myosin Heads The chapter discusses the independent action of myosin heads. It begins by setting the scene with a discussion on the myosin filament, focusing on an individual myosin molecule. The key point highlighted is the ability to identify two heads in the molecule, where one head is already bound to an actin molecule—a crucial step in the muscle contraction process.
12:30 - 26:00: Coordination and Conclusion The chapter discusses the initial step in a process termed the 'power cycle,' emphasizing its transient nature. This initial state is referred to as the 'rer state' or 'ryer state,' which is a critical phase concerning the myosin's structure. Specifically, it pertains to the myosin crossbridge located on the head, highlighting the protein's affinity in this arrangement.

Molecular Mechanism of muscle contractility - Part 1 Transcription

00:00 - 00:30 [Music]
00:30 - 01:00 so you know what I'm talking about right I'm talking about uh troponin okay troponin means what let's let's again go back to the F actin Okay g actin put together put together put together okay and then two rows okay and then the twist form of Helix okay and then each one has a site where the myin head can bind okay and then there are two more proteins one is called as tropomyosin which is a double helix here there are two of them one is here one is is here
01:00 - 01:30 and to go all along and they are occupying a position such that on each G actin where the site where myosin is supposed to bind is occupied so is The Binding site on the G actin molecule available to the head of the myosin no it's not available okay then there is yet another molecule which is called as troponin yet another protein troponine what do you call it as troponin now this this troponine is actually made up of three subunits how many subunits did I
01:30 - 02:00 say three subunits three Subs one binds to tropomyosin so troponin binds to tropomyosin three subunits one of them binds to what proin good the second one binds to actin okay and the third one binds to calcium whenever it is available so what am I talking about I'm talking of troponin made of how many subunits three one of goes to actin okay one of goes to tropomyosin and one is there for the for the calcium ion to bind now how this
02:00 - 02:30 works we'll see shortly okay now we are looking at the same thing we are looking at the F actin is there and tropomyosin is there if you see carefully here there's a circle and the circle there's that dark patch there dark patch is the site where the myosin head is supposed to went but it's covered you can see all this that that tropomyosin is covering but whenever on the troponin the calcium the calcium binds something very interesting happens what do you expect the tropomyosin to move away and once the trom move away moves away then The
02:30 - 03:00 Binding site is exposed and then it is just ready for the head of the masin molecule to bind with its sight are you getting the argument so who is who is who is inhibiting the interaction it is the tropomyosin okay why would tropomyosin be displaced okay it would be displaced because troponin will pull it away why would troponin pull it away because calcium needs to activate it okay now why would calcium activate it I will we'll see that shortly in a couple of slides so now we are ready to see the entire what they call you know know
03:00 - 03:30 crossbridge cycling what do I mean by crossbridge cycling now I'm trying to animate something here this is my what what is this and this is the head of the masin okay and this is the act are you okay so far and the Z membrane somewhere there okay and this this is this is acting is going all the way and sticking on to the Z membrane are you okay so far very funny okay but this is z this here and this is the m molecule okay when calcium becomes available okay and then
03:30 - 04:00 the troomin moves away are you with me troomin moves away okay then it can bind so what has happened is on the actin on the actin there's one g g guy sitting here on that there's active site okay now where the myin head is bound okay now once it is bound it under goes through a stroke Power Stroke what do I call it as in power stroke it moves this way it moves this way it moves this way now this actin molecule is scking onto this Z membrane here it will pull it will pull the actine towards the Z membrane
04:00 - 04:30 got the you got the now I'm going to show the same phenomena in I'll try to explain it in this slide so let's go to the top and in the top we have a position okay now we remember at the top we have here is a myosin filament good in the masin filament we are now focused on a single myosin molecule and of that molecule can you identify the two heads there please two heads are there and out of the two heads we find that one head is already sticking on to the actin molecule on very on binding s so they
04:30 - 05:00 are already together now this is about step number one we'll start here and come back to the same point which means we'll complete a cycle which we'll call as a power cycle okay it is a transient state it is just it's just holding on for the for very little time and this position is called as rer state r i g o r okay this rer is very important called as so that state is called as ryer state which part of the head okay the myosin has a crossbridge on the head there is the side this so This protein which is sitting here as an affinity for
05:00 - 05:30 the G protein site and they are together good good good now before I go ahead I just want to ask one one thing if I if this were the tail tail of what the myin molecule tail tail tail tail the neck hello and neck and then the head okay and the head is bent and I'll I'll draw your attention to the fact that the head is bent at an angle Which is less than 90° about an acute angle are you okay so far it's an acute angle mind you it's an acute angle this is an acute angle so these are the two heads this is the neck and the neck has yet another pecularity
05:30 - 06:00 you know four more proteins are sitting on the neck hello what do you call them as very good very good what do you call them as light chain light chain so you have you have four four light chain molecules and the B and somewhere a little behind that is a site where ATP by ATP can bind ATP can bind and what is the pecularity of the part of the protein which is sitting there in the in the at binding site it is it is atps what is it it is atps okay so so just imagine imine how big the molecule must
06:00 - 06:30 be how subunits must be so at one end it has got that protein can combine with another protein which is which is sitting on the which is on the F actin there it can bind and another part where it can combine with the ATP molecule and now we have an interesting situation in which the ATP molecule combines where it will combine on this side which is the ATP binding site now with every little thing there's going to be a configurational change in the in the protein molecule now what configurational change is would you expect what difference do you find
06:30 - 07:00 between this state and this state number one ATP has bounded its site are you okay so far now you you see a very interesting thing has happened what is it it is Unbound dissociated what has dissociated from what tell me myosin has dissociated from actin so if you if you don't provide ATP the dissociation won't happen so so as if as if the moment ATP combines at its side there there's a tremendous change on the charge in the molecule as
07:00 - 07:30 a result of that it's it's a slightly different molecule and it loses its affinity and you get this particular stage and then as you can imagine the ATP is bound it has it is bound to its site and that site is atps ATP is going to break away the molecule and soon thereafter you will have a situation what do you have here can you tell me look at the look at that cartoon and tell me hydrolysis so ATP is broken down into ATP and P1 okay Pi are you okay are you okay so far okay so it has has so so the
07:30 - 08:00 en as as a result of hydroly of ATP you have ADP and P are you okay so far then then in the next look look look the neck is still an acute angle the neck is still an acute angle the neck is still an acute angle are you done so far hello now let's move on in The Next Step you see the the uh it binds to here here here as a result of the hydrolysis then you have a similar situation in which very interesting phenomena is happen happening I have been harping on the
08:00 - 08:30 acute acute acute now if you see carefully it is no more acute but it has it has come at a right angle stage okay means it was it was so much bent unfortunately my wrist can't bend so much okay it's much more much more bent and then it becomes so this so This whereas this angle was acute this is more or less so you can see that arrow and this is called as a CO position it is like you have charged the gun you have charged the molecule and this charged molecule here this charged
08:30 - 09:00 molecule means actually what has happened is the energy from the ATP now has been taken by the molecule which molecule the the the the myosin head okay and the myosin head and the myosin head has bound it has taken the energy and the next step is you can can you tell me look at can you tell me the interpretation of this diagram there Pi goes away and the moment Pi goes away then the cocked molecule again goes from a right angle position to the acute angle can you see in that image please
09:00 - 09:30 and in that process in that process this molecule is fish pushed towards towards the Zed membrane so Zed membrane is somewhere here this molecule is anchored on the Zed membrane and and and as a result of the and as a result of the molecule being pulled the the the the actin molecule is be the the two Z membranes on the opposite SES will be am I making sense hello hello hello hello are you okay so far sure sure sure sure we are good so far okay this one also just nothing not
09:30 - 10:00 much has happened lot has happened anyway the the ATP is bound there okay and then uh the ATP has been acted upon by the enzyme okay and that enzyme is an is an integral part of the of the of the myosin head okay so far and then the and then so so here ATP has been converted into ATP and P and then here you have as a now as a result of this hydrolysis now the head of the myosin molecule is ready
10:00 - 10:30 to bind it binds okay so far then as a result of that then the next step would be the the P was still there but the p goes away okay so far once p goes away okay so once so at this stage the the can you see that tiny circular Arrow there which means from the acute angle it has gone to so so it it was it was it was very much bent now it is it can become it can now from acute it can go to right angle and and now once the p goes away it goes
10:30 - 11:00 into what you call as the power stroke means as you go from this step to this step again as you go from this step to this step myosin molecule is pulling the actine molecule by a distance of about 10 nanom means chemical energy is converted into mechanical energy did you get the message now very simple and straight are you okay now okay now so uh after that after that
11:00 - 11:30 then in the next step the ADP was here hello now the ADP goes away okay now once the ADP goes away but it still remains bound it Still Remains bound it Still Remains bound it will it will release it means it is in the rer state and it will go away only when the next ATP molecule comes means for a
11:30 - 12:00 single myosin head to interact with a single site on the on the on on the gtin and to pull it pull it once you need one molecule of ATP and then this is how we say that the crossbridge so this is one and on and on every cell there are thousands of um cross Bridges thousands of AC molecules and all put together they'll generate the force which is nothing but the contraction contraction of the muscle
12:00 - 12:30 now look at the cartoon and tell me if I withdraw the ATP from the system Al together artificially imagine for a second if I withdraw what will happen it will stay absolutely correct it will stay it will stay it will stay in this position it will stay in what position it will stay in ryer state are you with me are you with me so far
12:30 - 13:00 after the death of a human being after a period about 40 minutes or 60 Minutes the body becomes absolutely stiff and that state is called as rer mortis mortis refers to death ryer that ryer happens because after the death the ATP is no more available because ATP is no more available the myosin molecules remains attached remains attached to the actin molecule for a very long time okay and that stage and then eventually
13:00 - 13:30 however after their death about 1 Hour 2 Hour 3 hours even whole protein system acting masin molecules they start breaking down once they start breaking down then the body loens again and which which clinical people or medical people say that rer mortis has set in when the body is stiff okay you might have seen this in in in Murder Thrillers when the body is stiff and then after about three or four hours the ryer mortis passes away whereas in the living condition the ryer is a transient state it comes and
13:30 - 14:00 it goes because ATP comes and binds okay but had ATP not been there we so I'm using I'm introducing you to another word rer and rer mortis yeah any yeah go ahead so but uh for to happen there has to be calcium present inside the sides because only then the AC Bing are being available at the at at at the time of at the time time of death whatever was
14:00 - 14:30 available depending on depending on whatever interaction has taken place into actin masin okay it's not possible that there's no interaction happened at the time of death some will be there okay all of them whatever is there okay they will they will sustain why does power stroke has uh has to be coupled with the release of why does the say that again why does the power have to be coupled with the release of oh it is it is the uh it you have to see these in terms of the
14:30 - 15:00 configurational changes that is happening in the in the proteins or in the head okay and it is uh it of course it's a question of evolution it has evolved in such a way that that that this is the way it happens okay you you you can search for the logic okay but but then you can search for logic everywhere okay which is very yeah yeah but because and I I and you as the question 10 times my answer is the answer is in evolution okay this is this is this is the way the things are but if
15:00 - 15:30 you you will you will find some logic I mean after all yeah but the but the stream of the ideas is that that for for the configuration to change from one to other okay this this this ATB comes it under goes this then this then then enzyme acts on this there so it is yes with with uh with cycle on cycle as contraction happens and the Z membranes yes yes uh the spring action of the Titan continuously gets more and more
15:30 - 16:00 compressed right it does every single new ATP that binds and when the head detaches from the actin that spring will want to decompress and expand the uh sarom again the the answer to the question is that spring works much better when you pull it when you pull it so so muscle is 5 in long okay if I pull it the string the spring will stretch and the spring will try to bring it to 5 in again okay so there is a spring in front of me that's spring is 5 in long I'll pull it to 6 in that spring will
16:00 - 16:30 try to bring me bring me back to 5 in but when I compress it to compress it there is not so much load on that are are you am I making sense there uh so when you have when you have a muscle uh that is compressed a flexor that is compressed yes when the extent when the corresponding extensor uh contracts and then you have the flexor expanding uh what how does the cycling
16:30 - 17:00 work then uh okay okay when no no no no okay okay okay okay okay okay I'll come to that when I talk about aine so what you are seeing is when what what happens when the muscle relaxes yeah yeah when muscle relaxes there is no asine coming how it is relevant I'll talk to in five minutes uh there is there's no calcium available very simple very simple the answer to your question is when the the when when no calcium is available when no calcium is available the muscle relaxes that's
17:00 - 17:30 it all you need to do is either provide calcium or don't provide calcium if you want to contract provide calcium calcium calcium calcium is is that is that message fully taken so when so when so so so so so when you when you do this and this way and when this muscle is relaxing that's because the there's no calcium available so so no cross Bridge no actin Meine interaction done great yeah just a followup question does it mean that the S won't revert
17:30 - 18:00 back to it original position by itself like the extension has to bring which one oh no no no no no no no no it it no no it that that you see that's where the other proteins come into picture okay when when the when it is okay what you are seeing is what happens when there's no calcium when there's no calcium then there are no cross Bridges okay and when there are no CR cross Bridges the muscle will go back to its original length of each sarom and and for that other
18:00 - 18:30 proteins play an important role okay protein bring it back bring it back bring it back bring it they have to they have to go back they have to go back otherwise how will you how will you again contact it for the next time so calcium is very important okay so calcium binds where okay listen to this this this is very very interesting I'm talking about troponine mil molecule what am I talking about trop in the troponine molecule
18:30 - 19:00 there are three subunits done okay the real excitement lies in that part which binds with calcium okay others are also important otherwise protein chemistry people will kill me the the the the part that binds with calcium is is very important now that molecule single molecule single molecule single W molecule single subunit of troponin it is it is supposed to bind to calcium single molecule binds with four ions of
19:00 - 19:30 calcium how many ions four ions of calcium how many ions well well there are n number of n number of molecues so you all of them but for a molecule only four four ions of calcium can combine so you have a protein molecule one of the three subunits of the troponine big molecule and there are four sites where calcium can combine now imagine that molecule at the moment to begin with doesn't have calcium so all the four sides are vacant
19:30 - 20:00 are you okay so far now one calcium combines one one I'll go steadily 1 2 3 4 one one when one combines there is a change in the configuration configuration with of the molecule the first one combined with affinity certain Affinity as happens between two bodies two molecules calcium ion versus what and I'll call that Affinity as X whatever it is X some some some value I don't know x value but because one ion of calcium has
20:00 - 20:30 combined okay Affinity has changed as a result of that the second calcium ion combines with affinity which is 2x hello hello so one calcium ion combining with the protein changes the affinity for the next site one has already combined next site Affinity is more so when the second calcium ion combines it influences the affinity for the third now it shows 4X affinity and the next one maybe 10x 20x
20:30 - 21:00 I don't know there's there's there's what this is a phenomena which is very common in Biology one of the amazing phenomenas which have evolved and we call it as cooperativity what do you call it as cooperativity I will again talk about this phenomena when we talk about how the hemoglobin molecule combines with oxygen that molecule so many enzymes show the phenomena of what cooperativity means once it starts going in One Direction its efficiency is is increased many many Folds uh this is a very interesting uh uh
21:00 - 21:30 animation video on the YouTube it tells everything what we have done okay so I I strongly recommend that you spend a few minutes and okay we have actually seen this image but I'm putting this once once again so what are we seeing here we are seeing a direct correlation between the actin myin sliding over and work being done okay now I ask you one very simple question look at the degree of the overlap between actin myin f ments in the image number 1 2 and three and
21:30 - 22:00 what is your observation It Is What It increasing can somebody please explain to me as to what would be the hidden meaning there more overlap means what more overlap means what you are right more no more overlap means more overlap means more opportunities for the myosin head to combine with actin see if look look look look see see this this is the myosin molecule in my traditional masin this is AC and in this
22:00 - 22:30 there are say 100 head myosin heads are you okay so far 100 masin heads I'm just taking arbitrary figures 100 myin heads now how many will be there now more 200 maybe 300 and how many will be there now nil nil you see if there is no overlap between actin masin filaments the muscle is useless it can't contract at all because the the force of contraction or power of contraction is dependent on the number of directly directly dependent on the
22:30 - 23:00 number of how many heads can combine with how many molecules how many of their sites on the on the on the active molecule are you with me yeah are the BIOS heads only present at the edge which one bio are they present only in the Eds of the yeah yeah yeah on the two ends so even if there's a great amount of overlap only that part can B that I didn't get your statement can you say that again please so because the vus said heads are only present on one end on two ends I mean okay overlap
23:00 - 23:30 increases the area of the heads how much it overlaps with acted will remain constant after a certain ex after yeah yeah it will it will it will you see after a certain limit as in this case might be you see and and and once the once it's the overlap is complete then no matter whatever you do okay there won't be any additional Force means what the amount of force that a muscle can generate depends on how many opportunities are there for the head to
23:30 - 24:00 combine with the heads of the myosin to combine with the actin molecule CLE and simple another beauty of the situation is that each head is on its own if you can get my language mean one myin head and second myin head it has nothing to do with one another each each myin head as long as you keep on providing ATP molecule to it it will keep on beating its own at its own frequency it will keep on beating are you getting the argument so just so
24:00 - 24:30 it will go so it will one acting second acting third like you know it is the people often compare you know in Kerala they have boat races you know they they pull the ORS are you following what I'm saying okay they have boat races in in keral very interesting episode you see they they just pull so you just imagine that that ore that ore is the head of the mine molecule and you have to you have to you have to pull it okay so but every ore is independent on its own and as long as every ore gets an an ATP molecule it will go to the
24:30 - 25:00 next available next available molecule on the actin and pull it and pull it and pull it and pull it as as long as as long as calcium is available as long as what calcium is available now how how does the calcium become available is a point that we'll try to sort out so excuse me yeah as you said that each head is independent does it mean that they are not at all coordinated or they are coordinated they are not coordinated that's what I'm saying they are not coordinated ated if a particular head doesn't get ATP it
25:00 - 25:30 won't function but if the next guy gets it will function I mean the cell provides ATP the cell provides Everything But ultimately it is just left to the chance of aead if you get ATP that shall function otherwise you cannot function and one has nothing to do with the other this okay there is no central control that answers your question oh it can any any of can combine any can combine any can combine if it finds if it finds an act in there it and bind there it will work and often
25:30 - 26:00 it [Music] [Applause] works