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55 terms

Skeletal Muscle

1. Explain the sliding filament theory of contraction. 2. Describe thin and thick filaments and the function of the associated proteins. 3. Explain the role of ATP in muscle contraction. 4. Explain the role of the sarcoplasmic reticulum in muscle contraction and relaxation. 5. Describe excitation-contraction coupling. 6. Describe the all-or-none law of muscle fibers and explain how muscles can produce graded and sustained contractions. 7. Explain the differences between isometric and isotonic co…
What is a sarcomere?
During muscle contraction what does each band do? During muscle relaxation what does each band do?
Describe the thick filament
primarily composed of the protein mysoin.

Contains a tail region and globular head-looks like a golf club

connected together by a hinge.

Mammalian mysoin dimerizes through inter twining of their tails.
What two other proteins are associated with each myosin molecule?
1. Essential light chain-stabilizes the bolular head of the myosin

2. Regulatory light chain-regulates the ATPase activity of the myosin
How many proteins does the thick filament have once made
largest subunit-heavy chain-so myosin is the heavy chain, ELC and RLC are the light chains, the total complex is considered a hexamere-6 proteins, or 2 trimers

These hexameric myosin complex then further assemble into a much larger thick filament

the thick filament is a bi polar structure growing out form a core
Where is myosin's ATPase activity?
Located in myosin heads-globular part, by hydrolyzing ATP myosin can alter its conformation by pivoting around the hinge region of the molecule. So the energy supplied by the hydrolysis of the ATP causes a change in the 2 dimensional structure of the myosin molecule
What is the thin filament?
Made of multiple proteins

Actin, tropomyosin, troponin,
globular actin naturally polymerizes into fibers in the presence of Mg and ATP

the functional unit of the think filament is composed of two strand of F-actin that forms a double stranded alpha helix-looks like DNA but uses actin molecules instead of nucleotides bases.

elongated protein consisting of 2 alph helix chains which lie parallel to the actin chains within the groove formed by the 2 parallel actin strands

There is one unit of Tm for each 7 G actins

Tm functions to cover active sites on the corresponding actin chain to prevent bind of the thick filament to those sites of actin.
3 protein subunits Tn

Troponin T-TnT- binds to the other two troponin proteins and to Tm

Tropoinin-C-has binding sites for Ca2+ each molecule binds up to 4 calicum, causing a conformational change in the Tn complex which changes the relationship of Tm to actin.

Troponin I-functions as an inhibitory protein. When no Ca 2+ is present to bind the Tn-C, the troponin complex allows tropomyosin to cover the active binding site on the actin chain.

The binding of Ca causes a conformation change which causes Tn-I to change its position.

Tm is then rotated away from the actin binding sites it covers.

Tn and Tm are considered regulatory proteins.

The advantage of Tn-Tm arrangements is tha the change in conformation f the single Tn complex includes the rotation of the Tm out of the formed by the actin helix and permits the single Tm chain to expose the multiple binding sites on the actin chain that were covered by the single Tm chain.
Describe the Cross Bridge Cycle
What is the role of troponin and tropomyosin?
1. cross bridge-binding of actin and myosin

2. Roles are to regulate formation of cross bridges this regulation is done using Ca, in absence of Ca, tropomyosin blocks the actin myosin binding sites

3. When Ca is present it binds to TnC, causing a conformational change to the troponin complex that forces torpomyosin to move away from the actin myosin binding iste

thus allowing actin to bind to myosin and form the cross bridge.
What regulated the release of Calcium?
AP travels down the axon

ACh is released at nerve terminal, ACh binds to its receptor on the postynaptic cell muscle cell.

End plate potential develops depolarizing area above threshold for voltage gated Na channel rapid depolarization spread over entire muscle.

SP travels down the T tubes where the Dihydropyridine receptor is activated

DHP receptor then activates the Ryanodyne recpetor-found in the sacroplasmic reticulum

Ca exits the sarcoplasmic reticulum, down its concentration gradient

Immediately Ca pumps begin returning Ca back to the sarcoplasmic reticulum
Dihydropyridine receptor
activated via AP that travels down T tubes
Receptor foundi n the sarcoplasmic reticulm that is activated by DHP, helps release Ca from Sarcoplasmic reticulum down it concentration gradient.
What are the steps of excitation-contraction coupling?
1. Calcium diffuses throughout the muscle cell and binds to troponin
2. Troponin changes conformation, moving tropmyosin off the myosin binding site of actin
4. Myosin binds to actin-corss bridge formation
5. ADP and Pi are released and power stroke ensures
6. ATP binds to myosin
7. Myosin release from Actin
8. ATP is hydrolyzed
9. Myosin changes conformation rebinds to actin, ADP and Pi are released and power stroke.
11. Next DHP receptor closes, blocking the exit of Ca from the sarcoplasmic reticulum
12. Remaining calcium is pumped back into the SR by active transport
13. Troponin returns to its non calcium bound conformation, moving tropomyosin back on the actin myosin binding site
14. Muscle is now relaxed.
Isometric contraction
a contraction where the length of the muscle stays the same

we generate tension, not shortening
Isotonic contraction
when the muscle is stimulated it is capable of holding the weight, but also shortens as well.

Muscle Twitch
contraction/relaxation of muscle fiber in response to a single action potential (stimulus)
All or None Response
all action potentials are all or none

the response of an excitable cell to stimulation.

It either happens or it doesn't

Individual muscle cells are all or none

Muscle as a whole is a graded response.
Graded response
an intermediate response not all or none

ability to lift something smoothly regardless of weight.
Isometeric twitch
1st we start off giving an action potential to the muscle, sticking electrodes in it.

AP happen really quickly. Only one AP so it goes back to normal.

In response to the action potential, a large amount of Calcium is released into the cell. Ca binds to Troponin C, tropomyosin moves, power strokes move, a few cross bridge periods becasue there is some slack. After the latent period, we see tension is created.

Over time Calcium get pumped back into SR. now we start to get relaxation. The Twitch force depends of Calcium concentration. Classic twitch in isometeric contraction
What happens to the tension of a muscle during an isometeric twitch when you vary the frequency of APs?
Isometeric contraction, trying to lift something but can't. You contract but muscle does not shorten. Then you give up and relax. Sorta what we are seeing here.

If you hit it with an AP, you get at twitch, hit it with another one get a twitch.

If you hit it twice with 2 APs, you will see. The first part is exactly like the twitch you have seen, but when we hit it again it goes up higher. If we hit it with a bunch of forces then we see maximal contractability and it is Tetanized.

Treppe-a rockier road going up, until you get tetanuization. At this point either fatigue sets in or we stop stimulating and and it goes back into relaxation.
How does summation occur? Why is the second peak higher than the first peak when two AP are stimulated close to one another?

What is tetanized muscle?
The slack is out of the system, so the second action potential doesn't have to waste any energy and can get a larger force for APs.

Also bc the two APs were so close to one and another, more Ca channels were opened, stimulating more muscle contraction.

At tetanus-either we have released as much Ca as we possible could or that all the cross bridges are used up, either way it is the maximum amount of tension a muscle can generate.

A tetanized muscle is often 3-4 times more tension than a single twitch.
What is a motor unit? Why are they important?
What percent you decide to use to get a graded response.

Motor unit is a single alpha motor neuron and all the muscle fibers that it innervates.

don't have to contract all, they can passively contract not due to a AP due to another motor unit contracting

It is important bc a single tetanized muscle fiber only increases tension 3 fold due to APs. Using the motor unit, now the body has the ability to increase tension by a lot.

Size can vary from very small to large ones

size correlates with precision of control need for a particular muscle-smaller units are for fine, precise movements or adjustments like eyeball, large motor units are not very precise -gastronemius for example.

works in an all or nothing fashion

smaller motor units are activated first, as more tension is need to be generated then more motor units are added-motor units are progressively bigger and produce much more tension per motor unit than the initial ones activated
Describe the Latent period and Refractory period of a Muscle Twitch
How is the motor unit appear in a muscle?
Motor units are spread out a little bit in the muscle fiber.
How do you produce smooth contractions at different tensions?
A combination of motor units recruited and stimulation rate provide for smooth contractions at different tensions..
What is the Length-Tension Relationship in Muscle Isometerically? Describe it in a graph length vs tension.
Skeletal muscle->is ideally at the top of the curve. When completely extended it is at the descending part D, When in the curl it is in the Ascending part B.

This is most important for the heart. It you fill it too much you will be on the descending part of curve, if you fill too little it will be on the ascending..

Tension developed depends on the length of the muscle.

The more you stretch the muscle fiber and increase the length, the greater the tension until a certain point where there is no substantially tension bc the sacromere has been pushed too far.
How do we get the graph?
Isometric tension developed depends on the
length of the muscle. If a muscle or muscle fiber was clamped between two fixed ends,
stimulated electrically to contract and the
resulting tension measure and this was repeated as the distance between the fixed
clamps (note: affects muscle length) was
progressively increased (i.e., the muscle is stretched) in small increments, then the
relationship between muscle (sarcomere) length and isometric developed tension
could be plotted.
Explain the relationship between muscle length and tension via the Sliding Filament Theory
The degree of passive stretch (length) of the muscle determines the relationship between the thick and thin filaments.

The amount of OVERLAP determines the number of potential cross bridges that may be formed.

At short L, there is overlap of the thin filament into the region of the thick filament center with no mysoin heads or cross bridges.

As the length increases to Lo, more and more possible cross bridges may be formed.

When Lo is is exceeded, then there will be myosin heads in the center of the sacromere that can't bind to actin sites and the number of the potential cross bridges are reduced.
What are the various types of Tension?
Almost all this resting tension, is due to titan. Range of motion after ligaments and bone problems are eliminated, has to do with titan.
1. Developed or active tension (formed by cross-bridge formation).
2. Passive or resting tension - This is affected by the elasticity of the muscle tissue and connective tissue that are in parallel and series with the contractile elements (thick and thin filaments). When the maximum resting tension is exceeded, then the muscle will rupture or pull loose from the tendon or bone.
3. Total tension = Active + passive tension
What is Titan?
Responsible for the resting tension. As you keep stretching the muscle, Titan want to resist that stretch. The primary thing for range of motion after ligament and bone problems is probably going to be do to Titan. The amount of expression of titan can cause pathologies.

Largest protein attaches to Z line and goes out to H band.
When do we use isometric twitch? Compare and Contrast Isotonic vs Isometric?
1. Mechanical work is performed only during an isotonic contraction. Work =Force x distance

2. No shortening of the contractile elements in isometric contractions-no sliding between thick and thin filaments. Cross bridges are formed and broken but no net change in the relationship between actin and mysoin occurs. No external work is done. Energy consumed results in production of heat.

3. Isotonic muscle contraction must overcome the inertia of the object it is attempting to move by acceleration until a certain velocity is reached. Generally persist longer that isometric.

4. When muscle contracts isotonically and begins to shorten, the relationship between thick and thin filaments is continually changing.

The net effect is change the number of potential cross bridges. This explains why a muscle at one position may nor be able to sustain further contractions or maintain isometric tension but may be able to do so at a different position.
What are the four phases of Isotonic contractions?
1. Generating the tension, can't move the object
2. Shortening muscle-keeping the same amount of force generated.
3. Isotonic relaxation
4. Isometric relaxation.
What is the relationship with velocity of shortening vs. load for isotonic contraction?
the rate of muscle shortening is inversely related to the load of the muscle. A muscle with no laod wil shorten at its max velocity. As the load increases the velocity of shortening decreases.

At max load there is no shortening.
...How does the maximum load relate to the number of cross bridges?
As you increase the weight, velocity decrease of that contraction. More cross bridges need to be formed to create the initial tension, and what is left in cross bridges allows for the speed. Like a centipede carrying a weight.

If you have the same weight that you can lift all three points of the length tension relationship, let's say 5 lbs. It is gives you the same max velocity because, you will eventually get enough cross bridges.
What are come causes of Muscle Atrophy?
Myasthenia gravis
In this disease, which is fairly common especially among young women, polyclonal antibodies attack the acetylcholine receptor (a-bungarotoxin binding site) of the post-synaptic membrane of the neuromuscular junction. This is unwholesome, since binding of acetylcholine is blocked, and receptors are degraded too rapidly.
Interestingly, about 30% of these patients have a thymoma, and most of the rest have thymic hyperplasia (i.e., germinal follicles in the thymus gland).
Duchenne's Muscular Dystrophy
This is a common (one male in 3500), sex-linked recessive trait. One third of cases are new mutations, and no population group is without these people. The fundamental lesion is a lack of dystrophin, an inner-sarcolemmal cytoskeletal component homologous to spectrin and actin, which appears to strengthen muscle cells and keep them from popping when overworked (Nature 349: 69 & 243, 1991; Proc. Nat. Acad. Sci. 90: 3710, 1993). The gene's on Xp21.
Although the children appear normal at birth, the muscle is already abnormal, and the problem becomes obvious in early childhood. These boys have symmetric weakness, and must resort to unusual methods to stand up ("Gower's sign"). Fatty growth produces the characteristic "pseudohypertrophy of the calves". Boys become wheelchair-bound by their early teens
Becker's Muscular Dystrophy
Another sex-linked muscular dystrophy, caused by milder abnormal alleles at the Duchenne's locus. "Becker's" is defined to be "Duchenne's" in which patients can still walk by their 16th birthday. It's less common than Duchenne's: Lancet 337: 1022, 1991; Am. Heart J. 132: 642, 1996.
The problem in most cases is that dystrophin, though present, is mutated into a less-effective form. Dystrophin has several domains which do different things, and Becker's is very heterogeneous. For a recent review, see Brain 125: 4, 2002
Myotonic Dystrophy
This is an autosomal dominant (* chromosome 19: q13.2-13.3, cloned: Science 255: 1253 & 1256, 1992; protein is "myotonin" Science 260: 235, 1993), variably expressed because of other genes, affecting several systems. In some communities, it is as common as Duchenne's.
Patients have:
weakness, starting in the facial muscles (tiny chins and temples, etc.), eventually atrophy of most muscle groups
grip myotonia, with difficulty letting go of keys, handshakes, etc.
percussion myotonia (muscles tighten when you rub then)
frontal baldness and testicular atrophy (men)
a distinctive face ("carp mouth")
heart disease
early dementia (sometimes)
Facioscapulohumeral Dystrophy
An autosomal dominant (* locus 4q35: Am. J. Hum. Genet. Aug. 1992) with varying expressivity, and not lethal. Patients' shoulders and upper arms waste away, beginning in their teens or twenties.
Staining muscle with NADH reveals "moth-eaten" or "mottled" myofibers. Other changes are not usually striking.
What is tatanus and how can it generate muscle fatigue? What is Treppe
Tetanus is a sustained maxium contracton of muscle fiber that results from stimulation of a muscle fiber at a high rate.

If the frequency of stimulation incresaes, the more and more calcium accumulates within the cell.

This permits contraction to continue without relaxation until the maximum number of cross bridges are formed. Tension remains at a plateau.

Treppe-observed at high but some what lower rates of stimulation, a rise and small fall in tension may be observed which produces what looks like a staircase phenomenon.

Max tension is mantained until the supply of ATP is impaired and the muscle then begins to fatigue. Muscle fatigue results in decrease in the strength of contraction, despite a high stimulation rate due to decrease in concentration of ATP.

ATP supply depends on availability of substrates. Different types of muscle fibers vary in their susceptibility to fatigue.
What do asynchronous alternate firing and relaxation of different motor units cause vs simultaneous firing ?
asynchronous alternate firing and relaxation of different motor units which result in a smooth contraction.

Simultaneous firing tends to produce jerky motion
What are multiunit summation or recruitment?
increasing the number of motor units contracting at the same time.

Generally, the samller motor units which are more sensitive are activated first, followed by progressively larger motor units.

Activation of more motor units will increase the greater the number of cross bridges formed and therefore produce more tension.
What are spatial or temporal wave summations?
increasing the number of stimuli delivered to a given motor unit per time.

Results in increased Ca concentration which then causes more tension/shortening.

Activation of more cross bridges per period of time will generate more tension per time.
Using what you know about motor units. Lets say you have two different ones A and B. A is size 3 and B is size 9. If you wanted to lift a heavy object what would you use? If you wanted to lift a light object what you do?
If you wanted to lift a heavy object you would use B. If you wanted to lift and EVEN heavier object you could use both A and B.

Light objects you would use A.

For a smooth muscle contraction you would want a higher frequency. But based on how you want the muscle to move, depends on how much and what size motor unit you use. This is a learned response.
What is responsible for a graded response?
The combination of motor units and the frequency of APs generated.
Slow oxidative muscle fibers
contract slower but very hard to fatigue

smaller axons bind to the muscle fibers but they are slower
Fast oxidative/glycolytic
quick contracting, a little resistant to fatigue but fatigue

in bigger motor neuron coming to it
Fast glycolytic
quick contracting-fatigue easily

in biggest motor neuron
Describe the Isometric Length Tension Relationship at each key point.
a. A muscle at its passive length (i.e., not stretched at all) develops very little tension.
b. As a muscle is stretched (i.e., its length progressively increased) up to some point (Point B on the graph), there is a corresponding increase in the developed tension. When there is perfect overlap between thin and thick filaments, we now can generate the maximum amount of tension.
c. There is a optimal length (Lo) where the peak developed tension occurs (Po). That length occurs when the sarcomere length is between 2-2.2 .
d. When the muscle length exceeds the Lo, then the developed tension begins to progressively decline (e.g., at Points C and D)

steric hinderence can between protein in the thin filament can cause them not to overlap well. seen A

If we stretch the sacromere too much, Ca no long stimulate the contraction, bc the thin and thick filaments don't even overlap, no contraction.
Describe the Sliding Filament Theory
The length of muscle determines the relationship between the thick and thin filaments.

The amount of overlap determines the number of potential cross bridges that may be formed

A short L, there is overlap of thin filament into the region of the thick filament with no myosin head or cross bridges.

As the length is increased towards Lo more and more possible cross bridges may be formed , when Lo is exceed then there will be mysoin heads in the center of the sarcomere that can't bind to actin sites and the number of potential cross bridges are reduced.
What happens to a muscle when it is significantly stretched both in vitro and invovo beyond the normal length?
Damage occurs to the structure of the muscle and the muscle may never again be capable of the maximum number of cross bridges. This is a typical hyperextension injuries to athletes.