I know a number of you have continued questions regarding muscles. Here is my availability this week if you are interested in meeting with me. Please let me know when you plan to come so I can make sure to reserve that time for you on my schedule so that I do not get fully scheduled up.
Tuesday: 9-10am; 2-5pm
Wednesday: 2-3:30pm
Thursday 10-11am; 2-4pm
Friday 9-noon
Here is a coupe resources from one of your fellow students to help you learn and understand what is happening during cross-bridge cycling and covering the sliding filament theory:
I
don't know if you have seen/heard this yet, but this song actually
helps understand the cross bridge cycle.
1. Can you please re-explain the significance behind smooth muscle Passive tension shifting to the left, and how this comes about?
The passive tension curve of smooth muscle shifts to the left because, due to the shape of the muscle fibers, there is some passive tension and stretching of the connective proteins at rest. Therefore, the increase in passive tension happens at a shorter length of the muscle fiber and appears to be a shift to the left of the graph.
Also, where exactly is the optimum length on the graphs you provide, is it at 0?
As the graph indicates, the bottom is a fraction of optimal length (see the length-tension curve in the Skeletal Muscle lecture for details), therefore length 1 would be the optimal length or in other words where the myosin and actin are in optimal interaction with each other. The 'normal working range' of these two muscle types are right around this optimal length.
The example you used involving the urinary bladder expanding during pregnancy was a bit confusing. Can you please clarify?
Why does total tension increase for smooth muscle when compared to skeletal muscle? Is there another example that comes to mind that shows the significance?
It was actually two different examples. I mentioned that both during pregnancy and during the expansion of the urinary bladder that the smooth muscles lining those two structures are stretched. Upon stimulation they need to contract, however, from those long lengths. Remember that total tension is the combination of active and passive tension, so if the passive tension increases at a shorter length, then the total tension will increase accordingly. A benefit of the length-tension relationship of smooth muscle, therefore, is that even at the long muscle lengths there will be enough tension to contract the muscles in order to release urine or during child birth.
2. I would like to know what is the substrate for DHP receptor,
Is it acetylcholine or Sodium?
The DHP receptor is a voltage-gated Ca2+ channel that is also sometimes called the L-type Ca2+ channel. It is activated by a change in membrane potential (just like the voltage-gated Na+ and K+ channels) and opens upon a depolarization of the membrane.
3. DHP receptor is being referred to as a voltage gated calcium channel in
the slides. Is this correct even though no Ca is going through it?
Even though the DHP Receptor does not require Ca2+ to come through it in order to activate the RyR in skeletal muscle, if there is Ca2+ within the T-tubule, the electrochemical driving force would encourage the influx of Ca2+ into the cell through the DHP receptor. As you will see when we cover the cardiac muscle is that Ca2+ influx through the DHP receptor will be required for contraction in that system.
Is it correct to say that if I want to perform more isotonic contractions, I would want more sacromeres in series?
I am unsure of what you are asking. Increasing sarcomeres in series will increase the velocity of contraction, but not necessarily the number of isotonic contractions.
4. The
cross-bridge itself - is it the myosin heads themselves? just a
clarification b/c it seems to be used interchangeably when Myosin heads
BIND to ACTIN (so I got confused and began to think the cross-bridge is
MYOSIN HEADS bound to ACTIN).
The cross-bridge is a cycle of the process where myosin heavy chains (or head groups) bind to actin and then disassociate from actin while utilizing the hydrolysis of ATP. Cross-bridges, therefore, are the attachments that occur between the myosin head groups and actin. It may sometimes be used interchangeably with the myosin head group themselves, as some people talk about mysoin cross-bridges as the head groups (and if I did I apologize). This interchangeableness is probably due to the fact that this cycle happens on and off continuously under physiological conditions. By definition, however, it is the actual interactions between myosin and actin are the cross-bridges, but it is a cycle of connections that is the cross-bridge cycle that is the physiological event that happens.
5. I
was doing the practice quiz and I cant seem to understand why the
correct answer to question 13 is what it is. Any way you can explain? Im
having issues.
6. As you were explaining the functions and contractions of Smooth Muscle (SM), you mentioned that SM did not contain any Troponin with in it's Actin complex. Now, as I understand Tropomyosin is located covering the G-Actin active site for Myosin to bind, so what moves Tropomyosin away from the active site to allow the Myosin (Activated by the MLCK) to bind to Actin and initiate the cross-bridge cycle? So if their is no troponin in smooth muscle, but their is still tropomyosin, then how does the tropomyosin move out of the myosin binding sites after the myosin light chains are phosphorylated?
Tropomyosin's role in smooth muscle is not entirely clear. It does NOT cover up the myosin binding sites on on actin, but it is present. Therefore, it does not need to be moved away in order for actin to interact with myosin. The only necessary step needed for actin to interact with myosin in smooth muscle is for the myosin light chains to be phosphorylated by the calcium-calmodulin complex.
7. How is it that extracellular [K+] decreases the likelihood of a muscle contraction? The ability for K+ to leave the cell would decrease correct? How does that affect the ability of Na+ from coming into the cell?
Remember that increasing the extracellular [K+] causes a depolarization in the resting membrane potential (due to the fact that an increase in extracellular [K+] depolarizes the equilibrium potential for K+ and as the resting membrane potential is VERY determined on the equilibrium potential for [K+]. If the membrane potential depolarizes there is an initial drive for the Na+ channels to open. However, there is not a drive for repolarization from that action potential. Therefore, the Na+ channels will get stuck in their inactivation phase (as they need repolarization to go from inactivated to closed) and not allow subsequent action potentials. As you know that contraction of skeletal muscles requires an action potential first (initiated from the NMJ), so if that cannot happen then there will not be a contraction.
8. To transition from isometric to isotonic could you just decrease the load to be less than the force generated by the muscle or increase the force by the muscle to be greater than the load the muscle is acting on?
An isometric contraction, by definition, is a contraction that is constant-length. Therefore, the initial increase in tension that occurs in a muscle fiber up to that of the load and that equal to the load where it keeps the length constant are isometric. Isotonic contractions, by definition are constant tension. All additional energy goes into doing work on the object to move it by either shortening the muscle fiber or lengthening the muscle fiber. So, in a nutshell, yes. Isometric contraction happens initially and can be followed by an isotonic contraction by changing the all additional energy into moving the fiber after creating enough tension in the muscle fiber to equal that of the load.
9. In terms of glycogen stores for use in aerobic ATP production, I was under the impression that the body is unable to store up very much glycogen. I thought we had enough glycogen to last us just enough time to get the fatty acid oxidation pathway mobilized and by the time it kicks in to start burning fat, the liver stores of glycogen are nearly depleted (which if I remember correctly was around 30-45 minutes). The slide stating that liver stores would last for 16-20 miles of a marathon seems to indicate otherwise. I was wondering if you could assess/correct my understanding of it?
I think you are confusing two components and two points I made. Per the notes section this is what it says about glycogen vs. glucose as sources of ATP energy for the muscle:
It is my understanding, therefore, glycogen utilized without oxygen through glycolysis is used up quite quickly, but when you are utilizing oxidative phosphorylation, the depletion rate of glucose/glycogen is much longer. That is why during a sprinting exercise you will fatigue much more quickly (in addition to the build up of lactic acid), while running a marathon you can last much longer. I understand that as a physiologist, my complete understanding of the biochemistry may be somewhat lacking. Therefore, I would encourage you to also consult Dr. Smolanoff or Dr. Meissenberg for further clearance on this topic (and feel free to teach the rest of us upon further clarification).
I'm a bit confused on the external geography of the muscle fiber. According to Dr. Yin's amazing drawing in one of the slides, it shows the satellite cells surrounding the muscle fiber with the external lamina further out surrounding the satellite cells. Is this correct? How can the muscle fiber bind to the external lamina through the dystrophin + associated protein complexes if there is an entire layer of cells between the muscle fiber and the external lamina?
Remember that satellite cells do not completely surround the muscle fiber under the external lamina. Therefore, in some locations you will have satellite cells and in other locations you will have the dystrophin complex between the thin and thick filaments and the external lamina. Additionally, there are T-tubules and sarcoplasmic reticulum surrounding these components in much of the space as well.
10. I had a question about inhibition of acetylcholinesterase. In your lecture, you discuss that if you inhibit Achase that your muscles will be unable to go through the abs. refractory period after the initial action potential and the receptors will become desensitized and more stimuli will not be able to happen. However, if you have Myasthenia gravis, they give you drugs that inhibit Achase. What am I missing here?
Indeed, this is confusing. Under normal physiological circumstances if you block the acetylcholinesterase you will increase the amount of ACh within the junctional cleft leading to increased depolarization of the motor endplate and continued inactivation of the Na+ channels followed by desensitization of the AChR. However, in the case of Myasthenia gravis, you have antibodies that are attacking the AChR causing the number of channels to decrease. This leads, physiologically, to a depolarization at the motor endplate that does not create an action potential in the skeletal muscle (the 1-to-1 relationship is gone). Therefore, you need to increase the amount of depolarization at the motor endplate by blocking the acetylcholinesterase and therefore increasing the amount of depolarization at the motor endplate. Obviously this is a balance, because if you increase the depolarization too much you will have the result described above, but you need to create enough sustained depolarization in order to activate the action potential, but allow for the second action potential to occur as well.
11. When characterizing smooth muscle based on it's normal contraction state, the esophagus is listed as relaxed. Is this because peristalsis is shut off when not swallowing? This is new for me because I thought it was active all the time.
The activity of the smooth muscle within the gut is quite complex and will be covered in more detail during the GI module next semester. However, it appears that different smooth muscle within different parts of that system are working all the time while others are working only when there is the need to move a bolus of food. Again, more details regarding this, including the specific autonomic nervous system innervation by the enteric nervous system will be covered in more detail next semester.
Can you explain what the L type Ca++ channels were again?
L-type Ca2+ channels are a classification of voltage-gated Ca2+ channel. It is a specific isoform of voltage-gated Ca2+ channel that also includes DHP Receptors. Therefore, the voltage-gated Ca2+ channels on the sarcolemma of skeletal and smooth (and cardiac) muscle are all L-type Ca2+ channels. As we will see in a few weeks, in addition to this type of channel, there will be another isoform of Ca2+ channels (T-type) that will be important in cardiac muscles as well.
Is it correct to state that removal of the phosphate (via MLCK phosphatase) ends the cycle (myosin/actin dissociate).
Yes. This is achieved by lowering the Ca2+ concentration within the sarcoplasm of smooth muscles, and is similar to the Ca2+ disassociation from troponin in skeletal muscles. Both are activated by the removal from Ca2+ from the sarcoplasm, but in smooth muscle there is the extra step that MLCK phosphatase is involved to fully stop the events.
When talking about the Latch state, it states that the removal of the phosphate after myosin and actin attach, causes it. Wouldn't that mean every contraction results in a latch state?
No. The removal of phosphate from myosin by MLCK phosphatase typically happens at the end of a cross-bridge cycle, so while the myosin and actin are not in actual association with each other. In the case where the phosphate is removed from myosin WHILE it is still interacting with actin (so directly after the powerstroke of the cross-bridge cycle), this causes the myosin and actin to stay temporarily stuck together (not undergoing cross-bridge cycling) and causes the muscle to stay in a temporary rigor-mortis like state that is called latch state in smooth muscle (because it is temporary).
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
Please refer to slide # 59 to help with this. This question is directly describing tetanic contraction. An increase in stimulation to the skeletal muscle fiber will cause an increase in the activity of the DHP and therefore RyR receptors and cause to an almost continues release of calcium from the sarcoplasmic reticulum. This will lead to an increase in the concentration of calcium in the sarcoplasm (not myoplasm, myoplasm refers to the contractile components and the Ca2+ surrounds them, it is not 'in' them). This increase in calcium concentration causes the cross-bridge cycling to occur for a longer duration leading to the increase in tension occurring for a longer period of time.
6. As you were explaining the functions and contractions of Smooth Muscle (SM), you mentioned that SM did not contain any Troponin with in it's Actin complex. Now, as I understand Tropomyosin is located covering the G-Actin active site for Myosin to bind, so what moves Tropomyosin away from the active site to allow the Myosin (Activated by the MLCK) to bind to Actin and initiate the cross-bridge cycle? So if their is no troponin in smooth muscle, but their is still tropomyosin, then how does the tropomyosin move out of the myosin binding sites after the myosin light chains are phosphorylated?
Tropomyosin's role in smooth muscle is not entirely clear. It does NOT cover up the myosin binding sites on on actin, but it is present. Therefore, it does not need to be moved away in order for actin to interact with myosin. The only necessary step needed for actin to interact with myosin in smooth muscle is for the myosin light chains to be phosphorylated by the calcium-calmodulin complex.
7. How is it that extracellular [K+] decreases the likelihood of a muscle contraction? The ability for K+ to leave the cell would decrease correct? How does that affect the ability of Na+ from coming into the cell?
Please see question number 11 from http://drjphysiology.blogspot.com/2012/06/membrane-potential-student-questions.html for additional guidance.
8. To transition from isometric to isotonic could you just decrease the load to be less than the force generated by the muscle or increase the force by the muscle to be greater than the load the muscle is acting on?
An isometric contraction, by definition, is a contraction that is constant-length. Therefore, the initial increase in tension that occurs in a muscle fiber up to that of the load and that equal to the load where it keeps the length constant are isometric. Isotonic contractions, by definition are constant tension. All additional energy goes into doing work on the object to move it by either shortening the muscle fiber or lengthening the muscle fiber. So, in a nutshell, yes. Isometric contraction happens initially and can be followed by an isotonic contraction by changing the all additional energy into moving the fiber after creating enough tension in the muscle fiber to equal that of the load.
9. In terms of glycogen stores for use in aerobic ATP production, I was under the impression that the body is unable to store up very much glycogen. I thought we had enough glycogen to last us just enough time to get the fatty acid oxidation pathway mobilized and by the time it kicks in to start burning fat, the liver stores of glycogen are nearly depleted (which if I remember correctly was around 30-45 minutes). The slide stating that liver stores would last for 16-20 miles of a marathon seems to indicate otherwise. I was wondering if you could assess/correct my understanding of it?
I think you are confusing two components and two points I made. Per the notes section this is what it says about glycogen vs. glucose as sources of ATP energy for the muscle:
The second source of ATP
mobilized during maximal need comes from anaerobic glycolytic conversion of
glucose to lactic acid. Glucose can come
either from glycogen stored within the muscle cytoplasm, or from the blood
supply. For each glucose molecule, two
ATP molecules are generated. Glycogen
breakdown and anaerobic glucose metabolism, like creatine phosphate energy transfer, occurs in the
sarcoplasm and requires neither oxygen nor mitochondria. At 2.5 moles of ATP per minute, anaerobic
glucose metabolism is less efficient than that of creatine
phosphate (4 moles/min), but it is more efficient than aerobic glucose
metabolism (1 mole/min). Disadvantages
include production of waste products that can potentially produce sore muscles,
and a limited supply of intracellular glycogen, typically enough to maintain
maximum muscle contraction for 1-2 minutes.
Nevertheless, this is ideal for a somewhat longer, intense burst of
muscle activity, as in an 800 meter sprint.
White muscle fibers (section IV)
have relatively more glycogen than do red fibers so are better suited to this
means of producing ATP.
The third source of ATP
mobilized during maximal need is from aerobic metabolism of glucose (via
pyruvic acid) or fatty acid through the Krebs cycle and oxidative
phosphorylation, respectively. Aerobic
metabolism provides the least energy per unit time (~ 1 mole of ATP/min), but
it can generate ATP for periods of intense exercise lasting up to several
hours. Generally speaking, most of the
glucose used in aerobic metabolism is derived from the liver, and can come from
its glycogen storage. There is typically
enough glucose stored as liver glycogen to supply skeletal muscle for hours,
i.e. through 16-20 miles of a marathon, or standing for an hour performing a surgery. Other sources such as ketone bodies and
fatty acids can also be used by muscle cells for aerobic metabolism,
particularly when hepatic glucose reserves run low.
It is my understanding, therefore, glycogen utilized without oxygen through glycolysis is used up quite quickly, but when you are utilizing oxidative phosphorylation, the depletion rate of glucose/glycogen is much longer. That is why during a sprinting exercise you will fatigue much more quickly (in addition to the build up of lactic acid), while running a marathon you can last much longer. I understand that as a physiologist, my complete understanding of the biochemistry may be somewhat lacking. Therefore, I would encourage you to also consult Dr. Smolanoff or Dr. Meissenberg for further clearance on this topic (and feel free to teach the rest of us upon further clarification).
I'm a bit confused on the external geography of the muscle fiber. According to Dr. Yin's amazing drawing in one of the slides, it shows the satellite cells surrounding the muscle fiber with the external lamina further out surrounding the satellite cells. Is this correct? How can the muscle fiber bind to the external lamina through the dystrophin + associated protein complexes if there is an entire layer of cells between the muscle fiber and the external lamina?
Remember that satellite cells do not completely surround the muscle fiber under the external lamina. Therefore, in some locations you will have satellite cells and in other locations you will have the dystrophin complex between the thin and thick filaments and the external lamina. Additionally, there are T-tubules and sarcoplasmic reticulum surrounding these components in much of the space as well.
10. I had a question about inhibition of acetylcholinesterase. In your lecture, you discuss that if you inhibit Achase that your muscles will be unable to go through the abs. refractory period after the initial action potential and the receptors will become desensitized and more stimuli will not be able to happen. However, if you have Myasthenia gravis, they give you drugs that inhibit Achase. What am I missing here?
Indeed, this is confusing. Under normal physiological circumstances if you block the acetylcholinesterase you will increase the amount of ACh within the junctional cleft leading to increased depolarization of the motor endplate and continued inactivation of the Na+ channels followed by desensitization of the AChR. However, in the case of Myasthenia gravis, you have antibodies that are attacking the AChR causing the number of channels to decrease. This leads, physiologically, to a depolarization at the motor endplate that does not create an action potential in the skeletal muscle (the 1-to-1 relationship is gone). Therefore, you need to increase the amount of depolarization at the motor endplate by blocking the acetylcholinesterase and therefore increasing the amount of depolarization at the motor endplate. Obviously this is a balance, because if you increase the depolarization too much you will have the result described above, but you need to create enough sustained depolarization in order to activate the action potential, but allow for the second action potential to occur as well.
11. When characterizing smooth muscle based on it's normal contraction state, the esophagus is listed as relaxed. Is this because peristalsis is shut off when not swallowing? This is new for me because I thought it was active all the time.
The activity of the smooth muscle within the gut is quite complex and will be covered in more detail during the GI module next semester. However, it appears that different smooth muscle within different parts of that system are working all the time while others are working only when there is the need to move a bolus of food. Again, more details regarding this, including the specific autonomic nervous system innervation by the enteric nervous system will be covered in more detail next semester.
Can you explain what the L type Ca++ channels were again?
L-type Ca2+ channels are a classification of voltage-gated Ca2+ channel. It is a specific isoform of voltage-gated Ca2+ channel that also includes DHP Receptors. Therefore, the voltage-gated Ca2+ channels on the sarcolemma of skeletal and smooth (and cardiac) muscle are all L-type Ca2+ channels. As we will see in a few weeks, in addition to this type of channel, there will be another isoform of Ca2+ channels (T-type) that will be important in cardiac muscles as well.
Is it correct to state that removal of the phosphate (via MLCK phosphatase) ends the cycle (myosin/actin dissociate).
Yes. This is achieved by lowering the Ca2+ concentration within the sarcoplasm of smooth muscles, and is similar to the Ca2+ disassociation from troponin in skeletal muscles. Both are activated by the removal from Ca2+ from the sarcoplasm, but in smooth muscle there is the extra step that MLCK phosphatase is involved to fully stop the events.
When talking about the Latch state, it states that the removal of the phosphate after myosin and actin attach, causes it. Wouldn't that mean every contraction results in a latch state?
No. The removal of phosphate from myosin by MLCK phosphatase typically happens at the end of a cross-bridge cycle, so while the myosin and actin are not in actual association with each other. In the case where the phosphate is removed from myosin WHILE it is still interacting with actin (so directly after the powerstroke of the cross-bridge cycle), this causes the myosin and actin to stay temporarily stuck together (not undergoing cross-bridge cycling) and causes the muscle to stay in a temporary rigor-mortis like state that is called latch state in smooth muscle (because it is temporary).
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