Cardiac Muscles

Hello All,

I have placed two files on the G-drive (or they will be transferred within a day or two) that are the animations for the slow-response and fast-response action potentials for the heart.  They are HTML files, so please open them within a web browser and they should play.

Here are some questions regarding Cardiac Muscles that I have gotten from you.  Same as previously, I have grouped 'like' questions together and provided a single answer.  Questions are in blue, answers in red.  As always, if there are additional questions you have please feel free to comment on this posting or to send them to me individually!

1.  When you have fast-response AP, the last step, phase 4, resting membrane potential is achieved when you have the inward rectifier channels stay open and allow potassium to leave? I looked up what recitifier channels do and it states how they allow positive charges to move inward or into the cells. This make sense grafically, but in the elcture it says potasssium will efflux. I am a bit confused about what exactly is going on the phase 4.

I have a question regarding the fast-response ventricular/atrial muscle AP. During phase 4, if the the inward rectifier K+ channels are open, doesn't that mean that the K+ are coming in?  Please, correct me if I am wrong, because on the slide it says Efflux. But it makes more sense to me that it should be an influx since the current is inward and that it is maintaining the membrane potential. If K+ is moving out, shouldn't it make the cell more negative and thus hyperpolarize rather than depolarize?

As I mentioned in class, the names of these channels seem quite confusing and you would think an inward rectifier channel would be moving ions into the cell.  In the case of the K+ channels, however, K+ is STILL moving down its electrochemical gradient OUT OF the cell thereby repolarizing the membrane potential.  Therefore, the efflux that is stated in the notes and on the slides IS correct.  These channels are named after activities that they perform in experimental situations and are therefore confusing medically.  As I also mentioned in class, your current understanding of the K+ channels being responsible for repolarization and maintaining the resting membrane potential is STILL correct! 

2.  From the lecture slide, it stated that the Na/Ca exchanger takes in Ca and put out Na.  But I thought it is the other way around?

I am unsure where you have seen that.  On slide 24 it has the arrow for Ca2+ moving out of the cell (against its concentration gradient) and Na+ to be moving into the cell (with its concentration gradient), thereby working as a secondary active transporter.

3.  Does the AP from the slow response and the fast response start at the same time?  

They both start at when the membrane hits threshold, if that is what you are asking, but is that at the exact same moment in time?  No.  Remember that in every system, the neurons, skeletal muscles, and the heart muscle cells, that the action potential is the electrical current that travels.  In the heart, that electrical current is initiated at the pacemaking cells (typically the SA nodal cells) and propagates/travels from there to neighboring cells through gap junctions.  Therefore, the depolarization is spread to the next cell which causes it to reach threshold and the action potential to fire.


4.  For excitation-contraction coupling, is it only the cardiac muscle in the myocardium contracting?

Yes.  As Dr. Yin and Dr. Moore have both mentioned, the conducting cells do not have very much of the contractile proteins contained within their cell membrane.  You need actin and myosin in order for contraction to occur, and it is the myocardium that contains the cardiac muscle cells that contain those contractile proteins that, therefore, allow for contraction to occur.

5.  Is it correct to say that for the same afterload, with increasing preload will result in larger/higher shortening velocity (Vmax)?

Yes, that is certainly another way of interpreting that relationship!

6.  So for the heart, is increasing EDV the same as saying increased in preload?  If this is the case then, increasing EDV (increasing preload) will allow the ventricle to overcome the afterload a lot quicker?

Increasing the EDV is indeed the same as increasing the preload.  Increasing the EDV would, therefore, allow the ventricle to contract against a given afterload quicker (similar to what you stated above).  However, it does not allow the ventricle to overcome a greater afterload any quicker, but simply allows the ventricle to produce enough tension to contract against a greater afterload. 

7. How are Slow L type Ca Channels able to open to produce the plateau phase in the fast response Action Potential (since wouldn’t Ca2+’s Nernst potential approximately equal the membrane potential at that stage in the action potential)?

L-type Ca2+ channels are a voltage-gated Ca2+ channel that are initiated to open around the threshold value (same as the voltage-gated Na+ channels and voltage-gated K+ channels that we studied in the neuronal action potentials).  They are slower to open, however, and take awhile to open.  By the time they open the Na+ channels have already opened and inactivated and one type of K+ channel has already opened causing the 'notch phase' of the cardiac muscle action potential.  The equilibrium potential for Ca2+, however, is typically VERY positive (around +100 mV) and at that point in the AP the membrane potential, due to the movement of Na+ into the cell and then some K+ out of the cell, is positive, but not as positive as the equilibrium potential for Ca2+.  Therefore, the electrochemical driving force for Ca2+ at that point is still for Ca2+ to come into the cell.  So, when the L-type Ca2+ channels open, Ca2+ influxes, counteracting the efflux of K+ and that causes the plateau phase.

8. I would like to clarify: are dihydropyridine receptors a type of L-type Ca channel or are they completely interchangable terms? Or am I completely mistaken and they are not related? 

I just had a quick question regarding the dihydropyridine receptor. Is this receptor the actual L-type Calcium or T-type Calcium channel or one of the two or is it a separate entity all by itself?  

L-type Ca2+ channel and dihydropyridine receptors are completely interchangable terms.  There are two different types of Ca2+ channels in the heart that we have discussed, the L-type Ca2+ channel and the T-type Ca2+ channel.  The DHP receptor is another name for the L-type Ca2+ channel and is the SAME CHANNEL as the L-type Ca2+ channel.  Therefore, it would be accurate to alternatively say that there is the T-type Ca2+ channel (present in those cardiac cells that have automaticity), and there is the L-type Ca2+ channel otherwise known as the DHP Receptor that is present in all cardiac cells of the heart.

Smooth Muscles and other Muscle Questions

Hello All,

First off I would like to share a resource that one of your fellow classmates found for you.  It is an animation that helps explain the cross-bridge cycle:
http://highered.mcgraw-hill.com/sites/0072495855/student_view0/chapter10/animation__breakdown_of_atp_and_cross-bridge_movement_during_muscle_contraction.html

Secondly a correction.  NOTE:  On Slide 19 (and others) the Ca2+ ATPase on the membrane of the sarcoplasmic reticulum shows that it is pumping Ca2+ out of the sarcoplasmic reticulum.  However, this arrow is an error and should be going in the other direction causing Ca2+ to be pumped INTO the sarcoplasmic reticulum.

Here are some more questions remaining about Muscle Physiology:


1.  I'm a little bit confused about a question that appears to have two possible correct answers:
When comparing the contractile responses in smooth and skeletal muscle, which of the following is most different?
Correct->The role of calcium in initiating contraction
The source of energy used during contraction
The mechanism of force generation
Also possibly correct?->The source of activator calcium
The nature of the contractile proteins

In skeletal muscle the source of activating calcium is the SR.
In smooth muscle, it is both the SR and the ECM.
Am I correct in my assessment?

Your assessment regarding where the Ca2+ comes from is definitely correct.  Obviously the question above has an amount of 'judgement' associated with it in that it asks what is the 'most different'.  Therefore, the correct answer must also have some judgement associated with it.  Therefore, you would have an argument for that also being correct.  Overall, however, it is important that you can differentiate where the Ca2+ comes from to initiate contraction in both muscle types.

2.  Synaptotagmin is the calcium-binding regulatory protein.  When intracellular calcium levels rise, it binds to the regulatory protein, synaptotagmin (picture 3 in the sequence). I'm having trouble understanding the sentences above in purple. If synaptotagmin is the calcium binding reg protein when intracellular calcium levels rise, it binds to itself or another regulatory protein?

 

Calcium comes into the intracellular space of the presynaptic cell and binds to synaptotagmin.  Calcium is the 'it' that binds to the regulatory protein which is called synaptotagmin.

 

3.  Here was an exchange on your blog:

[6. Regarding #13 on the study quiz:  I understand why E is correct, but would A be correct if the world myoplasm was replaced with the word sarcoplasm?

 

13.  Repetitive stimulation of a skeletal muscle fiber will cause an increase in contractile strength because repetitive stimulation causes an increase in what?

  A.  The total duration of cross-bridge cycling

  B.  The concentration of calcium in the myoplasm

  C.  The magnitude of the end-plate potential

  D.  The number of muscle myofibrils generating tension

  E.  The velocity of muscle contraction

 

Yes, exactly! ]


--Of the above choices, the powerpoint showed that (B) is correct...the online version of the study quiz showed that (A) is correct...and in this blog exchange you indicate that (E) is correct...What is correct?? Clearly the pasted question's answer choices are different than what the student specifically asked you about.

I think (A) is correct and (B) would basically mean the same thing as (A) if myoplasm was replaced with sarcoplasm, since an increased duration of cross-bridge cycling would be caused by increased Ca++ in the sarcoplasm...but I want to make sure with you because its appearance on the blog was very confusing.

 

I sincerely apologize for that misleading exchange.  I was saying yes exactly that B would be correct if it said sarcoplasm rather than myoplasm, but E is not correct.  The correct, correct, answer of the question is A.  Repetitive stimulation would lead to an increase in intracellular Ca2+ and that would lead to a continued duration of cross-bridge cycling.  Again, I apologize for not completely answering and addressing the confusion in the question, it appears that by the time you get to question #13 late in the evening my mind is not working at its peak.

 

4.  One more question, will you point out any flaws in my understanding of fatigue?
1. T-tubule conduction failure= lack of AP propagation inhibits SR Ca++ release by DHP-RyR activation
2. Cross-bridge cycle inhibition= high ADP & Pi conc. reduces/inhibits powerstroke since myosin will be less likely to release its ADP & Pi
3. Increased lactic acid & glycogen depletion= Do the acidity and loss of glucose stores result in reduced ATP production, therefore inhibiting myosin heads from releasing actin (a rigor mortis-like effect)?

 

Mainly the high acidity messes with everything that is happening within the cell including the production of ATP, the hydrolysis of ATP by myosin head groups, and the movement of the myosin molecules.  pH is an important component that is tightly regulated typically because changes in it cause proteins themselves to not work properly, therefore it is mainly the change in acidity within the cell that causes muscle fatigue. 

5. Can I use Chapter 7: Muscle / Cellular Physiology / Landowne, as a reading material for this lecture? (This might be an obvious questions, but I am asking since it is not pointed out in the ppt)

 

You may ABSOLUTELY use that chapter as supplemental reading material.  I simply provided some reading recommendations that I thought are helpful, but if you find the information in Landowne helpful to your understanding of muscle physiology, then by all means utilize that as one of your resources.

 

Know that your knowledge building is your own responsibility always in addition to our help as your educators.  Therefore if you ever find a helpful resource that helps you understand what it is that we are teaching you should use your own knowledge to determine if it is a valid resource and if it supplements your knowledge.

 

6. In slide 54, it is stated that "reflex allows stretched muscle to contract"; does that means that the only response of a muscle is contraction when there is a reflex from the spindle? or could it be that also the muscle relaxes? Is this response autonomous in the muscle? or is it integrated in the CNS?

 

In the event that the muscle spindle is activated, a reflex arc will cause the muscle to contract involuntarily.  Typically, however, skeletal muscle contractions are a voluntary activity not involuntary.  Therefore, no a muscle contraction is not only in response to that reflex arc, but that is how it occurs through an involuntary response mediated by the nervous system itself.

 

7.  Do pacemaker only posses the ability to produce and spread APs or do they also have contractile activity?

Smooth muscle pacemaker cells posses the ability to produce and spread APs AND have contractile activity.  In the cardiac system, in contrast, pacemaker cells have very limited contractile properties and do not initiate contraction, but mostly just initiate and propagate APs.  We will discuss those in greater detail within the cardiovascular module.

Skeletal Muscle Physiology

Hello All,

Here's another batch of questions.  This time they are regarding the skeletal muscles:

There have been a lot of email issues today, so I hope I have addressed as many of your questions as possible today.  There will undoubtedly be more tomorrow and by the end of the weekend so there will be additional postings as we clear up those confusions as well.  

NOTE however, that regarding your concerns and questions about the length-tension and force-velocity relationships, please see the video blogs to see if they clarify your confusions regarding these relationships.  If they do not, please comment on those blogs regarding your additional confusions and I will attempt to address clarity on those issues there.  I am omitting the questions that I have already received on this subject on this blog post as those two postings will hopefully help clarify many of those concerns.

1.  Is the DHP a Ca channel and also the Ryanidine Receptor a separate Ca channel?

Or are they both parts of 1 channel

Do both of them cause release of Ca from the SR? or does DHP cause Ca to be released from somewhere else?

 

DHP receptor and the Ryanodine receptor are different proteins.  The DHP receptor is the same thing as the L-type Ca2+ channel and is a voltage-gated Ca2+ channel and is located on the sarcolemma membrane within the T-tubule.  The ryanodine receptor is a ligand-gated Ca2+ channel that is located on the membrane of the sarcoplasmic reticulum.  The ligand that activates it in skeletal muscles IS the DHP receptor, but in both the smooth and cardiac system the ligand is Ca2+ itself.  The do, indeed, together cause the release of Ca2+ from the sarcoplasmic reticulum, but the DHP receptor could allow for Ca2+ to come into the cell through extracellular stores as you will see it does in cardiac muscle cells.

2.  If DHP receptor is permeable to Calcium (because it is a voltage gated calcium channel) then where does the sodium ions that generated the action potential at the NMJ go??? 

 

The sodium ions that enter into the motor endplate of the muscle cell through the nAChR initiate the action potential to occur on the sarcolemma of the muscle cell.  Those ions are shuttled back across the membrane by the Na/K ATPase pump just like in the neuron after the AP has finished.  The DHP receptor, in contrast, is located within the T-tubules of the sarcolemma and allow for activation of the Ryanodine receptor and the increase in intracellular Ca2+ concentration initiating contraction.

 

3.  Practice question says:  When skeletal muscle is in its resting state, myosin cross-bridges are directly prevented from binding to actin molecules by which protein?

A.Calmodulin

B.Troponin

C.Tropomyosin

D.Titin

E.Phospholamban

 

tropomyosin clearly covers the binding sites but the ans key says it is titan

help?? 

If the correct answer indicates Titin, it is miss-keyed.  Indeed, tropomyosin directly covers the myosin binding sites on actin.  Remember, however, that troponin is the molecule that keeps tropomyosin in place and without troponin (like in smooth muscles), the tropomyosin does not block the myosin binding sites.

4.  On slide 42 of yesterdays lecture, bullet point #4, is that refering to Ca induced Ca channels?

5.  5.  When comparing the contractile responses in smooth and skeletal muscle, which of the following is most different?

            A.  The source of activator calcium

            B.  The role of calcium in initiating contraction

            C.  The mechanism of force generation

            D.  The source of energy used during contraction

            E.  The nature of the contractile proteins 

I'm having trouble understanding why B is the right answer. The way it seems to me is that the role of calcium in initiating contraction isn't very different (aside from the influence of extracellular Ca in smooth muscle). If calcium is present in high enough concentration you will have contraction in both types of muscles. I think how, or the mechanism of how it occurs, use of different receptors, use of latch bridges, calmodulin etc is very different between the two but not necessarily what calcium does. The way i understand it is that Calciums role is to bind and cause a contraction, its everything else that's different (the how aka mechanism). Any help trying to figure this out or correct my logic would be greatly appreciated, thank you. 

 

In fact your understanding of the differences is exactly what that answer choice is stating.  In skeletal muscles Ca2+ binds directly to troponin initiating cross-bridge cycling to occur while in smooth muscles Ca2+ binds to calmodulin which as a complex is responsible for initiating contraction.  I understand your confusion, but that was indeed what that answer choice was indicating.

6. Regarding #13 on the study quiz:  I understand why E is correct, but would A be correct if the world myoplasm was replaced with the word sarcoplasm?

 

13.  Repetitive stimulation of a skeletal muscle fiber will cause an increase in contractile strength because repetitive stimulation causes an increase in what?

  A.  The total duration of cross-bridge cycling

  B.  The concentration of calcium in the myoplasm

  C.  The magnitude of the end-plate potential

  D.  The number of muscle myofibrils generating tension

  E.  The velocity of muscle contraction

 

Yes, exactly!

 

7.  The Ach binds to receptors on the sarcolema to create an AP but how does the AP move through the sarcolem and into the T-tubule system.  Is the AP propagation into T-Tubules but the same method within the neurons? That being via voltage-gated Na+ channels?

 

Remember that action potentials are movement of ions across a membrane allowing for the propagation of electrical activity along a membrane.  Therefore, the AP propagates along the muscle plasma membrane (sarcolemma) just like it did along the neuronal membrane (axon).  As I mentioned the AP in the skeletal muscle is virtually identical to that of the neuron and is propagated by voltage-gated Na+ and voltage-gated K+ channels.  Those channels are located on the membranes of the T-tubules as well allowing for the propagation of those changes in membrane potential within that area as well.  It is there that the DHP receptors are located.

 

8.  I was doing some practice problems and it says that the temporal summation in a dendrite will reduced if the membrane resistance decreases. I thought it would be reduced if there was higher resistance in the membrane? Can you please explain to me what is the concept behind that? 

 

Remember that a dendrite is the part of the neuronal cell where the graded potentials occur and need to move through the dendrites into the cell body to summate and bring the membrane potential at the axon hillock to threshold.  Therefore, the movement of charges within the dendrites is not a 'given' which is the movement of charges within an axon.  In a dendrite charges want to be 'pushed' towards the cell body to b e summated.  Therefore the decrease in membrane resistance indicates that there is a bigger space for charges to dissipate within the dendrites decreasing the likelihood that the charges will get to the axon hillock.  In an axon, reduced membrane resistance will increase propagation velocity, but the opposite is true within the dendrite.

 

9.  To clarify, those Na+ channels at the postsynaptic membranes are NOT voltage-gated, correct?

 

Post-synaptic membrane receptors are not typically only permeable to Na+.  There are a number of post-synaptic receptors that are mixed-cationic receptors that are permeable to both Na+ and K+ and some are also permeable to Ca2+.  These receptors (ex. nAChR) are ligand-gated NOT voltage-gated.

10.  A question says that T-tubule can carry repolarization to muscle fiber interior, what does that mean?

The T-tubules are sarcolemma membranes that continue from the outside of the cell into the inside of the cell.  Similar to Dr. Yin's balloon analogy, if you poke your finger into a balloon, the balloon itself continues with your finger into the inside.  Just as the depolarization of the action potential can propagate into the interior of the skeletal muscle cell by traveling along this invagination of membrane, so too, therefore would the second part of the action potential, which is the repolarization.

11.  How does increase Ca2+/Na+ exchanger activity shorter duration of skeletal muscle contraction?

 

Na/Ca exchanger is a secondary active transporter that transports Na+ with its concentration gradient (from the outside of the cell towards the inside of the cell) and Ca2+ against its concentration gradient (from inside of the cell towards the extracellular space).  This removal of Ca2+ from the sarcoplasm reduces the Ca2+ able to be bound to troponin, thereby not allowing as many cross-bridge cycles to occur and thereby shortening the duration of the skeletal muscle contraction.

 

12.  Why does longer fiber have higher velocity at isotonic contraction than shorter fibers? 

Each of the sarcomeres shorten individually.  Therefore if you have 10 sarcomeres in a row all shortening at the same speed then the whole length of the muscle will shorten faster than if you had 4 sarcomeres in a row shortening.  Each individually would have the same velocity, but as a whole set the speed they can get to a shortened contractile state is faster.

13.  You mentioned in class that increase of ADP+Pi will inhibit cross-bridge cycling, how is that?  Is it because the lack of hydrolysis of ATP will lead to muscles being stuck in the resting state? 

 

There is a biochemical relationship that exists between the myosin head group that is bound to ADP and Pi and the concentration of those molecules surrounding the myosin head group.  Therefore, if you have more ADP and Pi around, then the myosin head group is less-likely to release those molecules slowing down that step in the cross-bridge cycle.  This has been shown, therefore, to lead to muscle fatigue.