20110107 Lecture 6 7 8 9 notes.txt

From Iusmphysiology

• started here on 01/07/11 at 11AM.

Contents 1 Organization of a muscle 2 Skeletal muscle 2.1 Voluntary versus involuntary 3 Cardiac muscle 4 Smooth muscle 5 Skeletal muscles 6 Contractile apparatus 7 A closer look at the contractile apparatus 8 A molecular look at the contractile apparatus 9 A full picture of the mechanism 10 Activating skeletal muscle 10.1 Getting the signal from the neuron 10.2 Distributing the AP through the myofiber to the contractile apparatus 10.3 Activation of the contractile apparatus by Ca+ 10.4 The cross-bridge cycle 10.5 Clearing the AP, stopping the contractile apparatus

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.