20110107 Lecture 6 7 8 9 notes.txt

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  • started here on 01/07/11 at 11AM.


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Organization of a muscle

  • Muscle cells (fibers) are bundled together into a fasiculus.
    • Has a connective tissue covering called the endomesium.
  • Many fasiculi make the whole muscle.
    • Has a connective tissue covering called the perimesium.
    • Has a second connective tissue covering called the epimesium.
  • Parallel arrangment of contractile proteins and filaments, then myofibrils, then cells that give the striated pattern.

Skeletal muscle

  • striated
  • Fibers are multinucleate and peripheral
    • Shoved to the side by the contractile apparatus.
  • Fibers can be really long in order to run the length of a bone or joint
  • Large: 90 microns in diameter
  • Highly specialized because it has evolved to simply move the skeleton
  • Voluntary muscle, meaning upper central nervous system effort determines how the muscle will behave.

Voluntary versus involuntary

  • Voluntary and involuntary are becoming more blurred than expected.
  • As an example:
    • We will voluntarily decide to get up and leave.
    • But once we're distracted while headed to lunch, we stop voluntarily commanding each step; it becomes involuntary.
    • We consiously decide to initiate muscle contraction and arcs but then various spinal cord reflex behaviors kick in.
  • Even the reflex arcs are "trained behavior" (somewhere between voluntary and involuntary) which may have to be relearned after being bedridden.

Cardiac muscle

  • Highly evolved, specialized.
  • Same filamentous ultrastructure in the cells, thus the same striated pattern.
  • Cells are much smaller than skeletal.
  • One or two, centrally located nuclei.
  • Smaller diamter
  • Different regulation of contraction (because of smaller diameter)
    • Ca++ doesn't have to diffuse very far as it does in the large muscle cells....
  • Has intercalated discs
    • Joins neighboring cells
    • Provides mechanical coupling through desmosomes
    • Provides chemical coupling through gap jxns
      • Thus provides cardiac tissue the ability to act as a synsytium
  • Involuntary: spontaneous activity
    • "Under myogenic control"
    • We don't have to decide to have it beat.

Smooth muscle

  • The name is a misnomer
    • When we first looked at muscle under the microscope, it was the one type in which there were no striations.
    • However, EM and x-ray diffraction have revealed that
      • the ultrastructure (actin and myosin) are the same as in cardiac and skeletal
      • the attachment proteins that connect the contractile apparatus with the cell membrane and cytoskeleton are less well organized than in skeletal and cardiac cells
  • Spindle shaped
  • Single, large, centrally-located nucleus
    • Nucleus is large because smooth muscle has multiple functions: contraction and synthesis of many materials.
  • Quite plastic: can move between major functions, being mostly contractile and then changing to become mostly synthetic.
  • Found in the walls of all hollow organs other than the heart.
  • There are many subtypes, depending on the organ.
  • Cells can be as small as 2 microns, usually around 7 microns.
    • Not very big or long.
  • Can go through hyperplasia.
  • Can go through hypertrophy readily (thus size can vary quite a bit).
  • Some have gap jxns, some don't.
  • Generally thought of as involuntary.
    • "Biofeedback" and such has shown that we can exert some conscious control, though.

Skeletal muscles

  • Arranged across articulated joints.
  • Arranged in antagonistic pairs.
    • This is because the contractile apparatus can only shorten, not elongating so we must have a counter-acting muscle to elongate.
    • So when one muscle shortens, the other lengthens.
    • Relaxation of muscle is a passive event brought about by the elastic recoil of the molecules that make up the cells.
  • We will talk about modes of contraction in the future.
  • There are many myofibrils in each myofiber (muscle cell).
  • The sarcoplasmic reticulum overlies the contractile apparatus, as well as mt.
    • Skeletal muscle is the hight energy producing / using organ of the body.
    • Skeletal muscle is responsible for generating body heat.
  • The sarcolemma (cell membrane) invaginates to generate a T tubule system and a axonal tubule system.
    • In some places the T tubules come into close proximity with the sarcoplasmic reticulum; this is important for muscle activation.

Contractile apparatus

  • A sarcomere is the smallest unit of contraction; each can cause contraction.
    • Runs one z-line to the next z-line.
  • A z line is made up of the structural proteins that attach the thin filaments.
  • The m line holds the thick filaments
    • The thick filaments interdigitate with the thin filaments.
    • In the center of the sarcomere
  • When we found these patterns with EM, we didn't know hwo muscles contracted.
  • So when we saw the striated pattern under relaxed and contracted conditions, we saw a difference.
    • This showed us that the distance between the z lines shortened and that the less-dense area in the middle (m line) got shorter.
    • They saw no buckling of the filaments.
    • So we knew that the movement wasn't due to the structural change of the filaments but due to the movement of the filaments along one another.
  • The h line is the less dense line in which the m line sits.
  • I bands are the parts of the sarcomere where there are only thin filaments--no overlap with thick filaments.
  • A bands contain the length of the thick filament (all parts, even those that overlap with the thin filament).
  • So when we go from relaxed to contracted:
    • Z line shortens
    • H zone shortens
    • A band does not change

A closer look at the contractile apparatus

  • We found that the thick filaments have globular heads and they touch the thin filaments during contraction.
  • So thin moves along the thick.
  • And the globular heads seem to have something to do with the movement of thin along thick.

A molecular look at the contractile apparatus

  • Finally we found that the thin filament had actin and some regulatory proteins (tropomyosin and troponin).
    • The filament is composed two strings of globular actins.
    • There are about 7 g-actins (globular actins) for every half turn of the filament.
    • Tropomyosin is found in a 1:7 ratio on g-actin.
    • Troponin is found at the same ratio: 1 / every 7 g-actin.
      • This is a trimeric protein: troponin I (inhibitory), troponin T (associates with tropomyosin), and troponin C (binds Ca+).
    • This whole unit is anchored on the z line proteins and point away from the z line into the sarcomere.
      • This provides a polarity.


  • The molecular structure of the thick filament:
    • Has a similar double-alphahelix arrangment as the two strands of polymerized g-actin in the thin filament only it uses myosin.
    • Myosin is made up of 2 heavy chains and 4 light chains:
      • Heavy chains have a globular head with a tail; these dimerize (the heads in the same end) that then associate with other dimers in an antiparallel form.
      • Light chains are much smaller and associate with each heavy chain (2 per heavy), near the neck region between the globular head and the tail.
        • Two light chains are called "essential light chains" (17 kda)
        • Two light chains are called "regulatory light chains" (in smooth muscle), "don't know what they do, could be left over from evolution" (striated muscle); (20 kda).
          • Smooth muscles pre-date the striated muscles by a great amount of time.
          • Smooth muscles come from the very first vascular systems of small critters.
    • This entire 6 chain structure lies in parallel with many others, forming polarity along the heavy chain.
      • Half of the heads face one direction and half the other direction.
      • This causes polarity in the H zone.

A full picture of the mechanism

  • In addition to seeing the change from contraction, we noticed that when the sarcomere shortens (H zones), cross bridges formed between the thin and thick filaments and they seemed to make and break as it occurred.
    • We also found that the force produced in contraction was proportional to the number of crossbridges so we decided the cross bridges has much to do with contraction.
  • The amount of shortening that occured in the sarcomere was also shown to be proportional to the amount of shortening of the entire muscle.

Activating skeletal muscle

  • This is all called the sliding filament theory.
    • All the evidence supports this theory and none refutes, so we will be calling it a law soon enough.

Getting the signal from the neuron

  • So we still wondered about the biochemistry of how we activate a muscle to contract.
  • Motor neurons turn on skeletal muscles:
    • AP travels the neuron
    • Neruon branches
    • Neuron releases ach (acetyl choline) in the motor end plate
      • These are specialized regions of the sarcolemma of the muscle cell.
  • The motor end plate region of the muscle cell is rich in ach receptors.
  • The receptor binds the ach.
  • An end plate potential (EPP) occurs in the muscle.
  • The EPP escalates until it triggers an AP in the muscle.
    • This occurs when vgnc are opened on either side of the end plate.
  • Then an AP is propagated down the whole muscle fiber.
    • This occurs in the same way as we learned for neurons: vgnc, then delayed K+ channels to repolarize.

Distributing the AP through the myofiber to the contractile apparatus

  • As the AP runs down the length of the membrane, it also travels down the T tubules (an axial array, into the interior of the cell).
    • The fluid in the T tubule is extracellular.
  • Some of the T tubule membranes touch the sarcoplasmic reticulum membrane.
    • Here, the AP down the T tube triggers the sarcoplasmic reticulum to open Ca+ channels.
  • Ca+ is stored in sarcoplasmic reticulum cisternae.
    • Located where the T tuble touches the sarcoplasmic reticulum.
  • At the T tubule jxn with the sarcoplasmic reticulum:
    • There are dihydropurine receptor and the ryanidine receptor (whcih bind their chemicals, respectively).
      • Dihydropurine receptor is in the sarcolemma of the T tubule.
      • Ryanidine receptor is in the membrane of the sarcoplasmic reticulum.
    • The ryanidine receptor is the Ca+ channel
    • On arrival of the AP, the dihydropurine receptor and its foot (which bridges the gap between the T tubule and the SR) changes conformation.
    • This causes a change of conformation in the ryanidine receptor, too, and thus opens the Ca+ channels.

Activation of the contractile apparatus by Ca+

  • Now Ca+ has rushed into the cytoplasm.
  • When ca+ is around 10 to the -5 molar, it triggers contraction.
  • Troponin will bind 4 ca+ / molecule.
  • This causes conformational change.
  • This causes strain on tropomyosin such that it moves it's position on actin.
  • This exposes myosin binding sites on actin.
  • Then bridges are formed between actin and myosin.
  • Once below 10 to the -7 we start to relax again.
  • This is a dis-inhibition:
    • Myosin is ready to bind actin at all time.
    • We just turn off the inhibition (tropopmyosin).

The cross-bridge cycle

  • Now that bridges are made we have the cross-bridge cycle.
  • Binding actin causes myosin to release Pi.
  • Then the conformation of myosin head changes relative to it's tail. (power stroke)
    • A 45 degree step in toward the center of the sarcomere, pulling actin with it.
  • Then ADP is lost, which causes another 45 degree step.
  • Then myosin gains affinity for ATP and binds it.
  • Then myosin loses affinity for actin and releases it.
  • Then myosin releases the pent-up kinetic energy in it's neck region and snaps to extension.
  • Then it burns ATP into ADP and Pi.
  • Then it gains affinity for actin.
  • Then it binds actin and loses affinity for Pi.
  • Repeat....
  • The power stroke is the loss of Pi and ADP.

Clearing the AP, stopping the contractile apparatus

  • When Ca+ opens on the sarcoplasmic reticulum, Ca+ dumps from the reticulum (and the cisternae) into the sarcoplasm.
  • When Ca+ rises in the sarcoplasm, ATP-dependent Ca+ pumps are turned on.
    • These are located in the longitudinal region (between the T tubules).
    • These pump Ca+ from the sarcoplasm into the sarcoplasmic reticulum.


  • stopped here on 01/07/11.
  • started here on 01/10/2011 at 11AM.


Moderating strength of contraction: Motor unit summation

  • One way to adjust the strenght of contraction is by motor unit recruitment
    • This is called motor unit summation.

Moderating strength of contraction: Mechanical-temnporal summation

  • The second method is called mechanical-temporal summation.
  • This occurs in a single msucle fiber.
  • When a single AP fires, we get a twicth.
    • Twitches are small in force and short in duration.
    • They are not big enough to do actual work.
  • By increasing the frequency of APs, we can do work.
  • When a second AP comes along before the twitch has relaxed, then they sum.
  • Addition of twitches will increase the magnitude of force and the duration of the response.
  • This is called mechanical summation because the force is added together.
  • This is also called temporal summation because the duration of the response is increased by the change of AP frequency.
  • Tetany is addition of response in response to APs in close frequency.
    • This can cause constant contraction.

Muscle fatigue and contracture

  • Our normal mode of function is called incomplete tetany.
  • Muscle fatigue is a reversible depletion of ATP.
  • After muscle fatigue is muscle contracture.
    • This is when the muscle has been fatigued and cannot then release the myosin head.

Modes of action

  • Muscle can work in several different modes:
    • Isometric (same length):
      • Force produced but no change in length.
      • After having initially lifted something up, we will switch to isometric which simply maintains the position.
      • Cross-bridges are cycling.
    • Isotonic (same force):
      • Here the muscle provides the same amount of force but the length may change (shorter if the tone is greater than the counter force (like the bucket's gravity) or longer if the tone is less).
      • "ton" = force, tension, etc.

Experimenting with muscle mechanics

  • We can attach muscle to a force transducer.
    • This can be an attachment to a rigid support and a transducer.
    • Then a stimulator stimulates the muscle.
    • And the force transducer measures the force over time.
    • This can give us info about the length and force relationship.
      • This can help us understand how pharma affects muscle.
    • This can give us info about the elasticity of muscle.
  • We care about isotonic movement, too.
    • Then we attach the muscle to a lever and a force transducer.
    • Then we load the lever with some load.
      • To keep the muscle from being over loaded, we put a stop in on the lever.
    • We can use electromagnetic levers, too, to observe muscle under changing conditions.
  • The data is force and length over time.
    • Note that on the length curve, higher on the y axis seems to be shorter.

Force-length relationship in sarcomeres

  • We now understand that the sliding filament theory is factual.
    • Much of this data came from isometric studies.
  • The passive length tensions curve occurs when stretching muscle with no stimulation.
    • This is just like any material.
    • Measures the compliance or stiffness of the material.
    • This can give us information when comparing disease states with normal states, perhaps in muscular distrophy.
  • We can also stretch the muscle and then maximally stimulate the muscle and then strethc again and stimulate again.
    • This gives the total curve.
  • When you subtract the passive from the active, you get hte total curve.
  • So muscles will provide more and more force as you stretch it and stimulate it until it eventually drops off.
    • This allows us to find the maximal force the muscle can produce.
    • This also demonstrates that the maxiumum force ariseas at the optimal length--where the maximum number of cross bridges can be made.
    • Shorter than the optimal may cause interference with cross bridging by heavy chains.
  • The total curve goes down initially because the thick filaments are overlapping and decreaasing active force but then rises again because passive force is rising.
  • All the sarcomeres have very slightly different force-length relationships, but the average is a nice curve.
  • The optimal sarcomere position is about 2.5 microns.
  • Skeletal muscles generally sits at optimal position in full extension.


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  • sarcomeres are operating in a very short range where the myosin heads overlap on light chains.
  • But a very shore movement of many sarcomeres can have a great effect.

?

  • The slope of the "shortening traces" (at the top), we get the velocity of the shortening.
    • There will be greater velocity with lower loads. 
Didn't get much out of this slide.
  • Bottom left figure won't be tested.

Power output

  • Here velocity is plotted as a function of force.
  • Power output is also plotted as a function of force.
  • When force is zero, power output is zero.
  • Peak power occurs at 1/3 the maximum force.
  • So muscle can do it's maximal / optimal power output when carrying about 1/3 the maximal load it can sustain.
  • The power output is maxiumum when muscle is working at about 1/3 the velocity at which it can shorten.
  • This is useful when you are training athletes and running a moving company.

Energy

  • There is lots of creatine phosphate in skeletal muscle.
    • A storage form of high-energy phosphate bonds.
  • The muscle has to contract and do lots of other cellular tasks.
    • The amount of ATP for other tasks is negligible compared to contraction.
    • Hence we keep creatine phosphate around as a quick store, unless the muscle has been used at high levels.
  • Initially, phosphate comes off creatin and binds to ADP to give a quick sorce of ATP.
  • Later, the muscle has to rely on ATP from glycolysis and ETC.
    • if ETC cannot keep pace, then glycolysis gets rampant.
    • Then there will be lots of production of lactic acid.
      • This can cause water drawn into the muscle; swelling and pain.
      • Thsi can change the local pH (acidotic).
      • This will change the biochemical reactions in the muscle, too.
      • This will cause a different type of cramp than tetany mentioned earlier.
  • Then lactic acid goes away during rest.
  • Then an oxygen debt occurs
    • Phosphate has to be put back on the creatine, etc.
  • Luckily, our heart is generally working harder.
    • And our heart likes lipids and lactic acid for energy and our skeletal muscle likes glucose; a nice partnership.


  • stopped here on 01/10/11 at 12PM.


Muscle types not at fixed lengths

Smooth muscle

  • Spindle shaped cell.
  • Small; as small as 2 microns in diameter.
  • Two functions:
    • Contraction
    • Synthesis
      • Collagen
      • Agonists
      • Etc.
  • Contractile apparatus doesn't give striations:
    • In part because the structures on which actin and myosin chains are anchored are made of globular proteins, not the big wall proteins of striated muscle.
  • The contractile apparatus is arranged at an oblique angle to the longtitudinal axis of the smooth muscle cells.
  • The apparatus (the thin filaments) anchores to dense plaques (on the membrane) and dense bodies (in the cytoplasm).
  • Thin filaments
    • composed of actin
    • face away from their ...? 
Spaced out a bit.
  • We noticed that IFs formed a mesh.
    • This is a cytoskeleton against which the contractile apparatus can work.
    • Necessary because smooth muscle isn't attached to bones.
    • IFs also important for recoil to original shape and length of cell in relaxation.
    • Note that IFs don't play an active role.
Turning smooth muscle on
  • Can be stimulated by:
    • neurogenic control
      • (NTs from nerves) or
      • called neurogenic
    • hormones or
    • locally produced substances
      • (prostaglandins, leukotrienes, angiotensins) or
    • changes in membrane potential
      • (least common) or
    • mechanical stimuli
      • (pressure changes, stretching of cell membrane) or
    • changes in environment
      • (ph, temp, local O2)
      • freezing fingers: smooth muscle has reacted to change in temperature.
  • All non neurogenic stimulated smooth muscles are called myogenic.


  • Activation by NT:
    • Something like NE binds to a receptor
    • PIP2 is split to IP3 and DAG
    • IP3 binds on Sarcoplasmic reticulum
    • CA released
    • Ca pumps activated to pump ca out
      • There is a pump that traverses both the SR and the cell membrane, to bring CA from outside the cell into the SR.
    • There may also be vg-Ca-channels but this is probably a secondary mechanism.


  • Cross-bridge cycling is very slow.
  • Relatively little ATP burned and relatively little heat is generated.


  • Now that Ca is high:
    • Binds to calmodulin, which smooth muscle has lots of.
    • Actin myosing light chain kinase phosphorylates 20 kd myosin light chian. (Check this)
    • Myosin can then bind to actin.
    • Then cross-bridge cycle occurs, just like with skeletal cycle.
    • This will continue as long as myosin light chains are phos (as long as ca_ is high enough to keep myosin light chain kinase active).
  • This is a true activation, not a dis-inhibition.
    • Requires a turning on of myosin in order to make a cross bridge.
  • We also call this a myosin-associated event (as opposed to actin-associated even in skeletal and cardiac muscle).
  • There is no troponin in smooth muscle.


  • Energy expense:
    • We use ATP to phos myosin light chain and to ?
    • But there is also a mode of opperation that is very economical.


  • Biochem and contraction by time:
    • Dots are phos of myosin reg light chain
    • Solid line is velocity of muscle shortening (cross-bridge cycling)
    • Dashed is force production
    • Other line is Ca concentration
  • There is a dissociation of the force production maintenance from signaling. 
Figure out what this means.
Understand this graph.
*Sonds like one point to see is that there is some slow release of actin from myosin because myosin light chain is turned off suddenly, when myosin and actin are still bound and then take a long time to disociate.
  • Bladder example:
    • Letting the bladder fill, adaptation makes stimulus of need to urinate go away as we hold it.
  • Biofeedback example:
    • Pts can reduce blood pressure with feedback but it takes all their cognitive ability.


  • Uterus:
    • Muscle is expanding.
    • Moving up the expansion curve.
    • There's increase cell size.
    • There's more and more force on the cell walls.
    • So the smooth muscle must counteract the force with slow velocity (because fast velocity would cause ejection of the fetus).
    • Note that the slow velocity mode is an ATP-conserving mode, too.
Smooth muscle function
  • Comparison of contraction between smooth and skeletal
    • Smooth muscle has a broad force curve:
      • Means the smooth muscle can act at it's optimum level over a large length spectrum.
    • Smooth muscle also has a greater retention of integrity when stretched.
      • Part of this is provided by IF arrangement, connective tissue arrangement, and the attachment of contractile apparatus to IF cytoskeleton.
    • There are twice as many actin filaments per mysoin filament in smooth msucle.
      • This means more cross-bridges can be made.
      • However, the actual force is lower because the cells are smaller, etc.
  • We have relfexes that keep us from using our muscles at full capacity because it can hurt our skeleton.
    • We also feel pain and that stops us.
    • Hallucinagens can cause pts to not respond to the reflex or pain.
    • Mom lifts car off baby.
    • Men are 600x stronger:
      • Larger muscle mass
      • More dense muslce mass
      • Longer levers
  • Force velocity differences:
    • For the same relative forces, skeletal is exponentially faster.
    • But if you do a force velocity curve for all the different smooth muscles (trachea, gut, epididymas) we would see differences in each:
      • Arteriole is much slower than gut.
      • All of them are slower than skeletal.

Hyperplasia versus hypertrophy

  • Usually we don't have hyperplasia in skeletal muscle.
    • We usually have hypertorphy by increasing the amount of contractile apparatus within each cell.
    • All three types of muscle will respond with hypertrophy to isometric work.
  • Smooth muscle can also undergo hyperplasia:
    • This is mitotic activity
    • This is in response to damage.
    • This occurs via satellite cells which will differentiate into smooth muscle.
  • It is possible to exercise to the point of damaging muscle and then hyperplasia may occur.
  • Athletes have an enlarged heart because of hypertrophy and this is considered normal.


  • stopped here on 01/11/11 at 11:40AM.
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