Physiology of Muscle Contraction: Flashcards
Troponin: how it works
-Troponin, or the troponin complex, is a complex of three regulatory proteins (troponin C, troponin I, and troponin T) that are integral to muscle contraction in skeletal muscle and cardiac muscle, but not smooth muscle
-Troponin has 4 calcium-binding sites.
- 4 Ca2+ bind to the troponin C in skeletal muscles (C = calcium binding) site of the troponin
- In the heart, Troponin C only binds to 3 Ca2+ ions
- when Troponin C binds to calcium, it changes conformation which turns off troponin I.
- conformational change in Troponin C drags the tropomyosin out of the binding site of the myosin-binding site so that myosin and actin can interact
- myosin head then binds to actin, making cross bridges which is what causes the forced generation due to ATP consumption.
- Myosin will break down ATP and myosin pull the thin filament by grabbing the two actin filaments from opposite sites towards one another
- Troponin I is a marker for muscle breakdown. its an intracellular protein and should not be in the blood. if found in the blood, that means that there has been some sort of lysis of muscles cell which is leaking troponin.
Total Troponin I = marker for total muscle breakdown
Cardiac Troponin I = marker for myocardial infarct
cross-bridge cycling
- Its a Molecular cycle of actin-myosin interaction
- Its the Mechanism of Contraction at Molecular level
- cross bridge cycling is the same thing as a molecule contraction of sarcomeres
- contraction depends on the binding of myosin heads to thin filaments (actin) at specific binding sites
- in resting-state of the sarcomere, myosin heads are blocked from binding to actin by tropomyosin, which occupies the specific binding sites (in F-actin double helical groove)
Force generation vs. sarcomere length
- on the X-axis, you have the striated spacing of a muscle.
- if you look at the spacing between the thick filaments, you have an idea of how far apart they are (how open the sarcomeres are)
- the graph at the bottom represents how long a sarcomere is. going further right (the sarcomere is wider), it’s less contracted. on the Y-axis is tension, maximal amount of force generated. As you have an increasing widening of striation, you go from almost no force being generated to a larger and larger amount of force that can be generated until you reach an optimum reach of the sarcomere where maximal force is generated.
As the sarcomere gets larger and larger, less and less force is possible. when there is maximum sarcomere length, the sarcomere si so spread out that there is no way for the cross-bridges from the myosin filament to interact with actin because the thin filaments don’t extend far enough to overlap with the myosin head.
As you shorten the sarcomere, it increases the number of cross-bridges that can interact with the actin filament.
Until you are able to get to point B and C (see image), the acting and myosin cannot interact. this is where you have a maximum level of overlap where all of the cross-bridges are able to overlap.
but when you start to get even shorter i.e C-D, there is an interference between thin filaments and myosin head because there will be incorrect directionality.
As you get closer and closer, you get more and more interference so there is less possibility for interaction until the thick filament crashes into the Z lines and no force will be generated.
Cross Bridge Cycle (illustration)
This involves 4 stages;
- Myosin releases actin
- Myosin head cleaves ATP
- Myosin binds actin.
- Power stroke
*At the end of the cross-bridge cycle, state 4, you have the myosin head already fully pivoted so its all the way forward so it’s already dragged the actin filament along. it’s very difficult for actin and myosin to detach because ATP is required. the first time in other to reset the cycle is for the myosin head which is currently binding ADP to release ADP and form and ATP instead. once the ATP binds to the myosin head, it can then bind to the actin and likewise the myosin head is able to go back to its original position so its no longer stuck in the finished position.
*The myosin head leaves ATP into ADP + Phosphate, it goes into a high energy state. This is when its able to join to an actin filament and pulled. but the actin filament cannot be grabbed because it has troponin on its binding site, its only when there is calcium that the myosin head will release it phosphate and still hold on to ADP.
Rigor Mortis
- ATP depleted after death
- Muscle cell does not resequester Ca2+ into SR. there is an increase in Cytosolic Ca2+ because the muscle has ran out of ATP.
- Ca2+ allows cross-bridge cycle contraction continuously until the ATP and creatine phosphate run out. creatine phosphate is how the cell is replenishing its ATP. it’s like a backup gas tank.
-Without ATP, myosin stops just after the power stroke so that means that the myosin is still bound to actin because you need ATP to release actin. if you don’t have ATP, the myosin head is stuck to the actin.
- Rigor mortis ends when muscle tissue degrades after 3 days
creatine-P = creatine phosphate = a chemical used for storing energy inside the cell. ATP cannot be used for energy storage because the cellular levels of ATP must be kept at a steady level to prevent triggering biochemical reactions. Instead, extra energy in the form of ATP is stored by having ATP donate its high energy phosphate bond to creatine (to make creatine phosphate). When the level of energy in the cell is lower, then creatine phosphate can donate its high energy phosphate bond back to ADP to make ATP.
ATP, creatine phosphate and creatine phosphokinase
- Creatine is found in muscle fibres and it is the backup energy storage house.
- Creatine is phosphorylated to creatine phosphate
- This is how energy is stored in muscle
- When creating cross-bridge cycling, ATP is hydrolysed to ADP + phosphate (Pi) . creatine phosphate can donate a high energy phosphate to ADP to restore it to ATP.
- if you hold on to creatine phosphate, whenever you lose an ATP, you can regenerate it by taking the phosphate from creatine phosphate.
- ATP levels must be kept stable – buffering & regeneration. its the creatine and creatine phosphate levels that vary in the cell whereas ATP and ADP levels generally are kept in a stable range for cellular activity.
- creatine phosphate is made in the mitochondria which is making ATP hence storing much of that energy as creatine phosphate. All of this is catlysed theorugh an enzyme called enzyme creatine phosphokinase (aka CK, CPK)
Extra Note.
Creatine phosphate acts as a “energy buffer” for ATP; when a lot of ATP is formed, instead of accumulating ATP, the cell transfers the high energy phosphate bonds to creatine phosphate (ie it accumulates creatine phosphate), whilst ATP levels remain at homeostatic levels.
Creatine is a small, organic, nitrogen containing molecule
It is a store house for energy in the form of phosphate groups
The phosphates from creatine-phosphate can be transferred to ADP, making it ATP
ATP needs to be regenerated for the contraction of muscle
Energy cannot be stored as excess ATP, because ATP levels must be kept stable
Creatine vs creatinine
•Creatine is a small molecule that can accept high energy phosphate bonds from ATP
•Creatine-phosphate is the above molecule after phosphate has been added to it
•Creatine-phosphokinase (CPK) is the enzyme the adds phosphate to creatine
This is a plasma marker of muscle destruction. It is an intracellular molecule and if detected in the blood, then some cells have lysed and let its intracellular CPK into the blood.
The reason why we are able to detect it is that It is a large molecule detected by antibodies
•Creatine-kinase (CK) is just another name for creatine phosphokinase (above). They are the same thing.
•Creatinine is a diagnostic marker of kidney function. It is a breakdown product of creatine.
Calcium triggers contraction
There are 2 different calcium gradient in every cell.
- Extracellular vs cytosolic free calcium
- Between the sarcoplasmic reticulum and the free calcium
In the cytosol, the free levels of calcium are really low. outside the cell and in the SR, there is much higher levels of calcium.
Efflux of calcium from the sarcoplasmic reticulum to the cytoplasm provides most of the calcium when muscle contraction occurs. -Muscle contraction is dependent on the levels of calcium in the cytoplasm being raised and mots of the calcium comes from the SR. very little calcium come from outside the cell during muscle contraction.
Depolarisation of the cells leads to increased Ca2+
- Depolarisation is usually the cause of an increase in calcium levels
- depolarisation means the cell membrane goes from highly negative inside to positive inside
- Usually, that depolarization leads to an increase in intracellular calcium in the cytosol but that isn’t always the case.
- the rise in calcium is the ultimate cause of muscle contraction rather than depolarisation. if the cell can depolarise without raising calcium, then there will be no contraction.
How you get from depolarisation to increase in calcium
- Acetylcholine is the neurotransmitter involved. it binds at the neuromuscular junction and that leads to depolarization of the cell membrane which will lead to active nicotinic acetylcholine receptors which allows for an inward current and that is the depolarisation.
- This depolarisation is spread along the cell membrane straight towards the centre of the cell via the T tubules.
- T tubules are the invaginations that are continuous with the cell membrane its part of the cell membrane that dives deep into the cell
- this means that local action potential can trigger calcium influx from terminal Sistani
- terminal Sistani are part of the cytoplasmic reticulum which are listening out for changes in membrane potential
- the action potential goes across the membrane of the sarcoplasmic reticulum
- this then allows calcium efflux into the muscle cytoplasm.
Excitation-Contraction (EC) Coupling
- Excitation is voltage changes across the membrane so its your action potential
- contraction is when the actual sarcomeres contracts
- Excitation-Contraction (EC) Coupling always means how do you get from membrane depolarization to increased levels of Calcium inside the cell cytosol
This depends on 2 main proteins
1. Ryanodine Receptor (RyR) which is in the SR membrane; it’s a calcium release channel. it allows calcium to go out of the sarcoplasmic reticulum into the cytosol. it is triggered by a voltage sensor on the calcium channel. the calcium channels are called L-type calcium channels but are also sometimes called (dihydropyridine receptor). these channels are normally sensitive to changes in voltage and down the voltage changes, these channels change conformation and because the channels are really close to the Ryanodine receptors, the channels can cause the Ryanodine receptors to open.
once you have calcium in the cytosol, you don’t want it to be there forever. that has to reserved by SERCA (smooth endoplasmic reticulum calcium ATPase) against its concentration gradient by using up ATP, so it needs ATP to run.
Tetany: molecular basis
- A muscle twitch is a single contraction of a muscle fibre.
- if you have stimulus and you stimulate the membrane of the cell
- this is time vs tension time in the X-axis and tension in the Y-axis
- for the first moment after the electrical stimulus, nothing occurs in terms of forced generation. this is called the latent period.
- It takes time for the muscle to get its act together for it to contract then after the muscles realise that there has been an electrical charge and it’s supposed to contract. then it will start to generate force and increase its contraction until it gets to a maximal level of contraction force at which point it starts to relax and generate less and less force until it generating no force at all.
- much of the contraction and drive is determined by how calcium is released. during the latent period, it takes a finite amount of time where there is almost no calcium being released. so there is no force generation.
- it takes time for that calcium to build up in the cytosol once the calcium starts to build up, contractions occur during the twitch and more and more calcium leaks out and more contraction occurs until the sarcoplasmic reticulum uses SERCA to pump calcium back into the storage. and that is what caused the relaxation
so a single action potential can cause a calcium release which leads to a twitch.
WHAT HAPPENS IF YOU HAVE FREQUENT STIMULUS?
If you have frequent action potentials, there is insufficient time for calcium resequestration to occur which leads to the summation of contraction.
eg we have this stimulus at D which causes a contraction, this contraction occurs and there is an increase in calcium and more force generation and then SERCA starts to pump back the calcium but then we stimulate the cell again and the calcium isn’t all gone yet and yet we are releasing more calcium from the SR which leads to an increase in force generation. that force generation is diminished until we continue to stimulate and stimulate. the faster and the more often yous stimulate a cell, the less chance it has to recover from the summation.
if you have an enormous number, very rapid rate of simulation, you end up with tetany. tetany is where you reach maximum force generation which means all the myosin heads are busy trying to contract, there is no time for calcium to be pumped back and it reaches the maximum and no further force can be generated. this is a very powerful contraction.
Sarcomere length
Below is a graph of sarcomere spacing (i.e. sarcomere length) vs. tension.
For each segment (e.g. between A-B or between B-C), what is the relative length of the sarcomeric A band to the sarcomeric I band?
In A-B, the I band at the length of A is so long compared to the I band. The I and is the between bit (I filament) whereas the A band is the thick filament in the centre. Keep in mind that the actual length of the A band never changes. It’s the I band that changes as sarcomeres change.
As you have less and less striation spacing, the sarcomere gets shorter and the I and gets shorter.
At the optimum levels, you probably have similar levels of A and I band .
You eventually get to an point where there is no I and and the whole sarcomere is all A band.
contractile properties of muscle cells
Muscle fibres are divided into 2 main types
1. Slow-twitch muscle fibres which are also called (type I or ‘red’ or oxidative) they have a small diam. they are slow and have a lot more ability to maintain long term contraction. the reason that they are red is because they have higher levels of myoglobin (myoglobin only have 1 subunit compared to haemoglobin with 4 subunits).
Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the skeletal muscle tissue of vertebrates in general and in almost all mammals.
The reason why there are so much myoglobin is because in slow twitch fibres there are many mitochondria. mitochondria are essential for producing energy using oxygen and oxidative phosphorylation).
2. Fast-twitch muscle fibres also called (type II fibres or ‘white’).
They are nonoxidative and tend to have a wider diameter
The reason that they are wide is because they have lower levels of myoglobin
These cells tend to get more of their energy from glycolysis (breakdown of glucose into lactic acid)
its is much less energy efficient in terms of producing ATP compared to using mitochondria to go through the citric acid cycle.
*The slow and fast-twitch fibre types differ in :
1. whether they are aerobic (using O2) or anaerobic (not using O2)
2. faster calcium re-uptake (fast twitch fibres)
3. maximum tension produced (fast-twitch fibres )
4. fatigue resistance (slow twitch fibres )
basis of muscle fibre types
Type I fibres are responsible for slow and sustained actions whereas Type 2b fibres are responsible for fast movements.
There are type 2a fibres which are sort of had way between type 1 and type 2b.
distribution of fibre types
muscles contain mixtures of fibre types and the composition depends on what the muscle action is.
In a muscle like the Salius which is primarily a postural muscle. its 80% type I which is a slow-twitch fibre and 20% type 2a. whereas something like Vastus lateralis which is used for something like running is a mixture of type I, IIA, IIX which is quite a fast type of fibre.
The proportion of muscle fibre types can depend on a person’s physical fitness. someone that is inactive is invariably gonna have more slow-twitch fibres in their muscles. Endurance athletes will have lots and lots of slow-twitch fibres whereas anaerobic fibres like sprinters will. have mostly fast-twitch fibres.
exercise and adaptation
Type I fibres are very dark in the stain image, fast-twitch are very light, the in-between is type 2a
gastrocnemius ; the chief muscle of the calf of the leg, which flexes the knee and foot. It runs to the Achilles tendon from two heads attached to the femur. you can see that most of are type 2 fast-twitch fibres.
But in a long-distance runner, it’s a different organisation. there are a lot more slow-twitch fibres.
muscle fibre types summary
You don’t have to memorise the table
types of muscular force generation
- Muscle contraction ≠ (necessarily) muscle shortening.
- the word muscle contraction is used for force generation but muscle contraction doesn’t mean muscle shortening.
- muscle contraction is when the muscle is generating force but if you try and generate a muscle contraction while holding the muscle in place, if you have this isometric force, you are not having muscle shortening even though you have a muscle contraction.
1. Concentric muscle force generation: this is when the muscle is becoming shorter as it contracts. i.e if you throw a ball into the air, you are contracting the bicep and that is causing the bicep to shorten and the whole arm is moving. tips to remember is to remember CONCENTRATION - when you concentrate, then you can contract a muscle and flex it.
2. Eccentric contraction (negatives): force during muscle elongation/extension. e.g. when “braking” or when the weight of the object is overwhelming – catching a ball.
•both types of force generation can occur in one behaviour
Proprioception controls force gen based on length and stretch
*if you think about a long jump. during a long jump, just at the moment that you launch yourself, you will extend the knee and that will create a lot of force as you extend the knee.
- As you extend the knew there will be an extension of the muscle and that contraction will be concentric.
- however, you will use the same muscle eccentrically when you land. if you don’t use force and holding the knew in place, it will bend. when people land, they generate a force where the knee actually extends.
Upper vs Lower Motor Neurons
Lower motor neuron disease leads to weakness and muscle atrophy. This means that the lower motor neuron is not sending the signal to the muscle, the muscle responds to the neurons that are stimulating them so the muscle will go huh I’m not receiving any signal then I must not be needed. then the muscle will atrophy.
- Lower motor neuron leaves the spinal cord and goes into the muscle in the PNS.*
- The upper motor neuron starts in the motor cortex send a signal to the motor cortex, crosses over at the decussation and then it will go down to the spinal cord where it is going to synapse with the lower motor neuron which will go out to the body.*
- In upper motor neuron disease, you get spasticity (unexpected contractions) and hypertonia (unusually high levels of contraction) and that is because the lower motor neuron is intact so the muscle that it is receiving information from is capable and is still receiving information from the lower motor neuron. instead, the problem is that the inhibitory fibres that are generated initially from the internal/central nervous system are lost.*
- so the lower motor neuron which is always tempted to give signals to contract somehow is told not to inhibit anything, give it all you have got. so the lower motor neuron will lose control and will be sending lots of signals to the muscles, many of which could have been inhibited because the brain didn’t ask for those contractions.*
Extra notes;
Atrophy = muscle wasting, muscle becomes smaller (and weaker) due to disuse. Often caused by loss of neural input to the muscle fibre.
Upper motor neurone disease = immediately after injury the relevant muscles (usually on the contrlateral side) become flaccid. However, within a few days, the spinal cord makes adjustments (by unknown mechanisms) that result in hypertonia, spasticity, and hyper-excitability. This is presumably due to the loss of inhibitory inputs that normally come from the CNS to the lower motor neurons. It is likely that there are unbalanced stimuli from the spinal cord to the intrafusal vs extrafusal fibres.
Stretch Reflex
STretch reflex/patella reflex. very important for posture and balance.
- the stretch reflex is very important for controlling muscle length.
- it increases muscle force and if you have a patient that doesn’t have a patella reflex , this is known as Westphal’s sign.
- If you have Intrafusal fibres; these are muscle fibres that act as sesnory detectors for how long the muscle is
-extrafusal fibres; located outside the muscles which is force generating contractile fibres.
Westphal’s sign = The absence or decrease of patellar reflex.
Westphal’s sign may indicate damage to femoral nerve (efferent or afferent), receptor damage, peripheral nerve disease, or cerebellar damage, etc
multiple oscillation of the leg following the tap may be a sign of a cerebellar disease.
Flexion for patellar reflex occurs at the level of L4 in the spinal cord
there is an inhibitory interneuron used to relax the antagonistic biceps femoris relating to L2, L3, and L4
Intrafusal fibre = skeletal muscle fibers that serve as specialized sensory organs (proprioceptors) that detect the amount and rate of change in length of a muscle. They constitute the muscle spindle, and they do not generate the contractile force normally associated with muscles. Intrafusal muscle fibers are walled off from the rest of the muscle by a collagen sheath. This sheath has a spindle or “fusiform” shape, hence the name “intrafusal.“
Extrafusal fibres = standard skeletal muscle fibers that are innervated by alpha motor neurons and generate tension by contracting, thereby allowing for skeletal movement. They make up large mass of skeletal (striated) muscle and are attached to bone by fibrous tissue extensions
Stretch Reflex: Patellar
- you have this sensory spindle fibre that detects stretch (length), it doesn’t detect pressure or tone. its responsible for proprioception. its running in parallel to other muscle fibres so when you press with the hammer. it detects stretch and this stretch is normally waiting for a stretch signal to occur where the length in a muscle fibre usually is a sign that something is gone wrong, that the muscle isn’t toned enough.
- The brain doesn’t know whether the muscles are toned enough to hold the knee in place if the muscle fibre length is too long for the length that the brain thinks that it should be, it needs to know somehow. every time the intrafusal muscle fibre is too long. it is going to send a signal to the brain saying hey this muscle is too login and then the brain will shorten it.
- keeping muscles in tone is so important that not only the brain does this. its done at the level of the spinal cord. it is a monosynaptic reflex. what happens is that you have a detector in the muscle which detects length and when the length is too long, the signal goes from the stretch receptor in the muscle to the spinal cord, it is then detected via an inhibitory interneuron which then sends a muscle to the opposite side to relax. because it is too long. it sends a signal to the muscle in the thigh saying hey you are too long a, you have to shorten. this happens very quickly so it’s a single muscle reflex to maintain proper muscle tone.
Muscle Spindle Reflex: Relevance
•Westphal’s Sign is due to the Absence of this reflex and this is often due to receptor damage or It can be due to femoral or peripheral nerve damage such as peripheral neuropathy.
A neurologistst will have several options as to why this might fail.
-In supper motor neuron disease, you will get hypertonia or spasticity and that is because the upper motor neuron inhibits the inhibitory input to the spinal cord interneurons.
Westphal’s sign = absence of patellar reflex. This can be caused by many conditions including: receptor damage, femoral nerve damage, peripheral nerve disease, disease of the dorsal (sensory) columns of the spinal cord, cerebellar lesions, or lesions in the pyramidal tracts.
Hypertonia = muscle has too much tone involuntarily, so it is contracting when it should not. This can lead to rigidity and ultimately to contractures.
Spasticity = muscle increases its tone involuntarily when the muscle is stretched, so when a clinician tries to passively move the joint, the muscle strongly resists, making the joint rigid. The muscle becomes sensitive to the velocity of change in length. Spasticity usually has resistance in only one direction (ie the clinician can extend the joint, but cannot flex it).
Rigidity = when joint resists movement in all directions.
Tendon Reflex
Spindle reflex is responsible for maintaining tone in muscle so muscle length is normal. the tendon reflex does the exact opposite, it protects muscle from overloading. so instead of an increase in muscle force, the tendon reflex decreases the muscle force causing you to drop the load because if the sensor is firing it, it detects a problem, leading to loss of contraction.
there is a sensor that is detecting whether or not there is too much load. eg you are trying to catch a ball and someone drops something that weight much too much and you are trying to hold it. your muscles will not hold on. they will not break or allow you to rip if you have too much force.
if you have too much force, the tendon reflex will tell the muscle to let go and stop. so even if you’re consciously trying to contract the muscle, you won’t be able to and that is based on the Golgi tendon organ which is inside the tendon itself.
so you have this tendon reflex that can detect if there is too much force pulling on a tendon and that causes the Golgi tendon organ to give a reflex to cause the muscle to stop functioning and stop resisting the force.
the results in the motor neuron being inhibited via an interneuron (interneurons are neurons going from a sensor into the cell and then there is usually a reverse.
interneurons are usually essential for inhibiting.
Tendon Reflex
The sensor for the tendon reflex is the Golgi Tendon Organ. This detects tension, it does not detect length.
the tendon organ is in series with the muscle.
the tendon reflex is often disynaptic and it’s an ipsilateral spinal reflex. so you detect the force on the left and it affects the neurons on the left.
