Editing 20110107 Lecture 6 7 8 9 notes.txt

*started here on 01/07/11 at 11AM.


===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 arrangement of contractile proteins and filaments, then myofibrils, then cells that give the striated pattern.

===Skeletal muscle===
*Skeletal muscle is striated
*Fibers are multinucleate and the nuclei are found on the periphery
**The nuclei are on the sides of the cells because they were shoved to the side by the contractile apparatus.
*Fibers can be really long in order to run the length of a bone or joint.
*Skeletal muscle fibers are large: 90 microns in diameter
**Recall that RBCs are 8 microns in diameter
*Skeletal muscle is highly specialized because it has evolved to a single purpose: 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.
*Cardiac muscle cells have the same filamentous ultrastructure (apparatus, myofibrils, myofibers) as in the skeletal muscle, and thus the same striated pattern.
*Cardiac muscle cells are much smaller than skeletal muscle cells.
**They are shorter and have a smaller diameter.
*Cardiac muscle cells have one or two, centrally located nuclei.
*Cardiac cells have a different mechanism that regulates contraction because of their smaller diameter.
**Because Ca++ doesn't have to diffuse very far as it does in the large muscle skeletal muscle cells, we don't have to have such an intricate t-tubule and sarcolemma system.
*Cardiac cells have intercalated discs
**These discs join neighboring cells.
**Intercalated disks provides mechanical coupling through desmosomes.
**They also provide chemical coupling through gap junctions.
***Gap junctions and the passage of ions allow the cardiac cells to act as a synsytium
*Cardiac muscle is involuntary; it has spontaneous activity
**Because cardiac muscle does not need conscious thought to act, we say that it is under "'''myogenic control'''".
**We don't have to decide to have it beat.
**Myogenic control means that the muscle itself controls it's activity; it originates from the muscle.
**The alternative is neurogenic control.

===Smooth muscle===
*The name "smooth muscle" is a misnomer
**When we first looked at muscle under the microscope, smooth muscle 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 muscle,
***the attachment proteins that connect the contractile apparatus with the cell membrane and cytoskeleton are less well organized than in skeletal and cardiac cells
*Smooth muscle is spindle shaped
*Smooth muscle has a single, large, centrally-located nucleus
**The nucleus is large because smooth muscle has multiple functions: contraction and synthesis of many materials.
*Smooth muscle is quite plastic: it can move between major functions, being mostly contractile and then changing to become mostly synthetic.
*Smooth muscle is found in the walls of all hollow organs other than the heart.
*There are many subtypes of smooth muscle, 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 smooth muscle cells has gap jxns, some don't.
*Generally thought of as involuntary.
**"Biofeedback" and such has shown that we can exert some conscious control.
***However, it was shown that it takes a patients' full cognitive function so it isn't very practical.

===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 high energy producing / using organ of the body.
**Skeletal muscle is responsible for generating body heat.
*The sarcolemma (cell membrane) invaginates to generate a T tubules to form an 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 how 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 zone is the distance between opposite thin filaments.
**It is centered on the M line.
*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 (sarcomere shortens)
**H zone shortens (thin filaments get closer together)
**A band does not change (because thick filaments are constant in length)

===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 alpha helix arrangement 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 (acetylcholine) 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 (voltage-gated Na channels) 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====
*Because muscle cells are large, we have specified structures that help spread the AP and the necessary influx of Ca throughout the cell, not just next to the membrane.
*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).
**Recall that the fluid in the T tubule is extracellular.
*So as depolarization travels down the inside of the cell membrane causing voltage-gated Na channels to open, it follows the membrane which includes the T tubules and brings the AP into the center of the cell where the sarcoplasmic reticulum is located.
**In fact, some of the T tubule membranes nearly touch the sarcoplasmic reticulum membrane.
*The sarcoplasmic reticulum is an important source of Ca because it is in the center of the cell, allowing Ca to influx into the center of the cell as well as from the ECF into the peripheral parts of the cell (across the cell membrane).
**Ca+ is stored in sarcoplasmic reticulum '''cisternae'''.
**Located where the T tuble touches the sarcoplasmic reticulum.
*There are two important receptors at the juction of the T tubule and the sarcoplasmic reticulum:
**Dihydropurine receptor 
***In the cell membrane (sarcolemma) along the T tubule.
***Has a '''foot''' that bridges between the T tubule and the sarcoplasmic reticulum cisternae.
**Ryanidine receptor:
***In the membrane of the sarcoplasmic reticulum.
**'''The ryanidine receptor is the Ca+ channel''' of the sarcoplasmic reticulum.
*On arrival of the AP, the dihydropurine receptor (on the T tubule) '''foot'''  changes conformation.
**We might say that the foot's conformation is voltage dependent.
*Conformational change of the foot causes a change of conformation in the ryanidine receptor, too, and thus opens the Ca+ channels.
*So, we say that at the junction of the T tubule and the cisternae, the AP coming down the T tube triggers the sarcoplasmic reticulum to open Ca+ channels and let Ca into the muscle cell.

====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.
*When troponin binds Ca, there is a conformational change.
*The change in conformation cause strain on tropomyosin such that it moves it's position on actin.
*Movement of tropomyosin 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+ 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 strength 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 '''twitch'''.
**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 tension 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 stretch again and stimulate again.
**This gives the active length tension curve.
*When you subtract the passive curve from the active curve, you get the total length tension 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.


*started here on 01/11/11 at 11AM.


*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) describes 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 and power are plotted as a function of force.
*Recall that power is force over time.
**Therefore, maximum power occurs where we can produce the most force in the shortest amount of time.
**Peak power occurs at 1/3 the maximum force.
**When force is zero, power output is zero.
*Think about the moving company example:
**Having all the men working at their maximum capacity would probably mean they move really slow.
**But having everyone work at about 1/3 their max means they can move quickly with that refrigerator, too.
*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 creatine 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.
***This can change the local pH (blood will become 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
**Oxygen debt is our body's demand for extra oxygen even after we stop running up the stairs.
**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 which is converted to lactic acid--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 z line attachment
*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.

=====Mechanisms for smooth muscle activation=====
*Can be stimulated by:
**neurogenic control 
***NTs from nerves
**hormones or locally produced substances 
***prostaglandins, leukotrienes, angiotensins
**changes in membrane potential 
***least common
**mechanical stimuli 
***pressure changes, stretching of cell membrane
**changes in environment
***ph, temp, local O2
***freezing fingers: smooth muscle of the vasculature has reacted to change in temperature.
*All non neurogenic stimulated smooth muscles are called myogenic.

=====Neurogenic smooth muscle activation=====
*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.

=====Smooth muscle contraction=====
*Once Ca concentrations are high in the muscle cell, calmodulin binds Ca.
*Calcium calmodulin complex activates myosin light chain kinase (MLCK).
*MLCK phosphorylates the 20 kd light chain.
*Myosin can now bind actin.
*Then cross-bridge cycle occurs, just like with skeletal cycle.
*Cross-briding will continue to occur until Ca levels drop low enough that Calmodulin no longer binds them and MLCK is dephosed.
*Note that this is a true activation, not a dis-inhibition.
**Myosin must be turned on in order to make a cross bridges.
*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.

=====Smooth muscle energy expenditure=====
*We use ATP to phos myosin light chain and to move the mysoin along the actin.
*But there is also a mode of operation that is very economical.
**This mode cycles cross-bridges very slowly.
*When we look at all the events taking place over the time of muscle contraction, we see that it is an efficient process.
**Dots are phos of myosin reg light chain
**Solid line is velocity of muscle shortening (cross-bridge cycling)
**Dashed is force production
**Hashed line is Ca concentration
**There is a dissociation of the force production maintenance from signaling.
**The point of this graph is that even after MLCK is off, there is still force being generated because it takes more time for the actin and myosin bridges to dissociate.

=====Velocity and Adaptation in Smooth Muscle=====
*The bladder provides a good example of adaptation of smooth muscle.
**Letting the bladder fill, adaptation makes stimulus of need to urinate go away as we hold it.
*The uterus provides a good example of when smooth muscle needs to be able to provide slow moving force:
**As the baby is growing the muscle is expanding, the cells are increasing in size, and we are moving up the expansion curve.
**Furthermore, there is more and more force on the uterine walls (tension in the smooth muscle cells).
**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.
**This is a good reminder that smooth muscle is unique in its ability to turn over cross-bridges very slowly.

=====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.
*started here on 01/12/11 at 11AM.


===Clarification===
*The finess of movement of muscle is determined in part by the number of motor units recruited.
**The more muscle units into which the muscle is divided the finor control.
*No motor end plates for smooth muscle.
**Done through autonomic nerves which release NT straight to muscle which has specific receptors.
**Also true in heart muscle.

===Cardiac muscle===
*Muscle can be under neurogenic control or myogenic.
**Skeletal muscle is always under neurogenic control.
**Cardiac muscle is always under myogenic control
***So contraction arises form spontaneous activity in the heart muscle and spread through gap jxn at intercalated disks.
***Nerves to cardiac muscle modifies activity of the heart.
**Smooth muslce is either.
***Some smooth muscles have gap jxns and others don't.
***Intestinal does, whcih allows for peristalsis like continuous activity.  This is the passing of the AP from one syncytial unit to the next.
*The heart has gap juxns, too.
*The cardiac muscle cells branch and are relatively small (20-30 microns).
**Skeleltal is 90 microns.
*Skeletal muscle has the elaborate t-tuble system because of the large diameter--diffusion wouldn't work as a method for moving Ca into a huge muscle cell.
*Cardiac muscle cells have a t tubule system but it is not as impt or elaborate.
**There is a well developed endoplasmic retic.
**There is a t tuble system.
*Sarcomeric arrangement of cardiac cells is the same as skeletal muscle.

====Spnteous cardiac activity====
*Comes from spontaneous depolarization of pacemaker cell sin the heart.
**This spreds through the heart.
*APs are very different, though, than smooth and skelletal muscl.
*The resting membrane potential is usually around -80 mV.
*We call phase 4 resting phase
*Na channels open, phase 0.
*AP is shorter than the AP of skeletal muscle, only to +40.
*Then Ca channel opens to give a long plateau.
**NA channels are closing
**K channels are opening.
*There is a long absolute refractory period (when na channels won't open again).
*The relative refractory periord occurs and is short.
*There is a periord of supranormal excitability:  when na channels are able to be open and the membrane potential isn't fully back to normal (such that it is less negative and easier to get to threshold).

====Ventricular myocyte====
*The phases are important to fthe fxn of the cell.
**Because cell is small and diffusion distance (the radius of the cell), diffusion causes:
***stretching of the AP (the plateau)
***the ca can actually be used by the contractile apparatus to contract (makes it a second messenger)
*Cardiac muscle also has another mech for release of ca from sarcoplasmic retic: ca induced ca release:
**As Ca comes in, Ca channels actually open to let Ca from SR into the cytoplasm.
*So Ca channel influx has multiple fxns.
*There is both electrostatic and chemical gradients running influx / efflux.

====Automaticity of the cells====
*The primary pacemaking cells have intrinsic electrical properties distinct from toher cardiomyocytes.
*Normally the SA nodal cells are the pace-maker cells.
*If they fail, the atrioventricular node (AV node) takes over (it is in the ventricle).
 She skipped some of the notes and just went to the summary.
*Electrophysiology is hard because:
**hard to get human heart
**electrode placemnt is so difficult and so variable.
*The mechanism of pacemaker cells:
**There is a slow drift toward the threshold for firing.
**This occurs in part because the cells are more permeable to Na which keeps their potential less negative and therefore closer to threshold.
**These cells are tight against K+ leak which ais int he above.
**There is also time dependent decrease in K+ which is probably the major reason for depolarization.
 Missed two points here.

====APs of cardiac cells====
*Pace maker cells lack the plalteau region.
**Phase 1 and 2 are missing.
**Phase 4 is the drift in the SA node cells.
*Atrial AP:
**Has 5 phases but a shorter duration and little phase 2.

====Four phases of the pacemaker cell AP====
*Phase 0:
*PHase 2: innactivation of Na channels, efflux of K to match Ca influx
*Phase 3: K efflux
*Phase 4: slow increase in Na influx and a decrease in K efflux (?)

====Heart has three physiological properties====
*Autorythmicity
**Assures that the heart will beat on its own.
*Conductivity
**There is a preferential conductance pathway through the heart.
**FRom SA to AV to bundle of HIs trhough septum, to perkinje fibers, then back up to the rest of the ventricle myocytes.
**It is a fnction of the location of the cells, the timing, and the path the AP takes that makes the ventricles myocytes contract after the atrial mycotyes.
**The conducting material is composed of modified muscle tissue; there is some debate as to whether they are neural or muscle cells.

====Neuro input to the heart====
*The autonomic nervous system provides this neuro signaling.
*There are cardiac accelatory and cardiac inhibitory centers in the ?
*Most of these neural cell openings end around the SA node and AV node, but they do go to much of the wall of the heart.
*The acceratory is sympathetic:
**Short preganglionic, long post ganglionic.
**increases heart rate and increases contraction strength.
**Uses NE.
*The inhibitory is parasympathetic.
**Slows's heart and decreases contraction
**Long preganglionic, short post ganglionic.
**Ganglion is in the heart tissue.
**Uses Ach
*We always have parasympathetic stimulation keeping our heart from overworking when at rest.
*When activity increases, parasympathetic signaling is decreased (Ach) and sympathetic signaling is increased (NE).

*Looking at AP and force of contraction:
**Because the ap is so long in duration, you cannot get mechanical summation.
**you cannot get another AP generated before the first muscle contraction has started to relax.
**This is important; our hearts can only act in twitch fassion.

====Muscle mechanics====
*Similar relationships (f-t, f-v, power output optimum) are all similar as with skeletal muscle.
*However, like smooth muscle and unlike the skeletal muscle, the muscle sarcomeres are not set at a specific length.
**So cardiac tissue, like smooth muscle, can operate over a large range of overlap.
**The blood volume in the heart helps set the cardiomyocytes at their starting position.
*Relative to smooth muscle, however, cardiac muscle has a smaller area of stretch in which it can work.
**This means that it is weak in its contraction once positioned past its optimal length.
**This means that a weak contraction will not expulse all the blood and this will increase the stretch, making it weaker, etc.
**This is a bad cycle: congestive heart failure.
*Normally, blood coming in places the myocytes at their optimal length.
**This is called the '''frank-starling law of the heart'''.

====Energetics====
*The difference between skeletal and cardiac muscle:
**skeletal musc prefers glucose and then fatty acids
**heart prefers lactic acid and then ?

====Mechanics====
*Force produced by heart muscle than skeletal when normalized for xsectional area.
*So is velocity.

*But the absolute force is greater than in smooth muscle and velocity is faster than smooth muscle.
*So cardiac lies somewhere in between skeletal and smooth muscle.

*Veleocity of shortening is affected by anything that affects isoforms of myosin
**Thyrotoxic heart (hyperthyroidism) has a change in isoform which causes lower function which causes increase in heart rate.
**familial hypertrophic cardiomyopathies: genetic defect, myosin can't make cross-bridges or can't go through cycle, or troponin defect; hypertrophy of the heart occurs.  MI occurs then death.
***With weak cross-bridging the hear tthinks it is working against a greater load, so hypertrophy factors are generated and hypertrophy occurs.
***A weak load causes weaker cross-bridges but more myosin and actin.
***Also, with hypertrophy, more oxygen is necessary.  This can cause MI because of too little oxygen.


*stopped here on 01/12/2011 at 12PM.