Muscle+Physiology

MUSCLE .....PHYSIOLOGY

__ SKELETAL MUSCLE CONTRACTION __

Stimulation of the muscle at neuromuscular junction



__ Generation of an ACTION POTENTIAL __ All cell membranes is in a polarized state. When the muscle fibre (cell) is relaxed, the membrane is at resting membrane potential. The outside is relatively positive in comparison to the inner surface of the membrane. Stimulus —> spread of wave of depolarization local membrane ---> Voltage gated channels in cell membrane opens —> Na+ enters cells —> wave of depolarization spreads —>

Na+ enters newly depolarized sections —> Repolarization —> K+ voltage gates open and K+ exits cell —> Refractory period —> ?

__ Excitation-Contraction Coupling __ 1. Action potential - along sarcolemma —> T-tubules

2. Action potential reach triad —> SR release Ca+ into sarcoplasm

3. Some Ca+ binds to troponin —> moves tropomyosin —> exposes binding site on actin

No activity visible yet

__ Role of Calcium in Muscles __ Ca+ in sarcoplasm must be kept sufficiently low not to form hydroxyapatite, the hard crystal salt found in bone matrix. Ca+ + PO4= in watery matrix —> hydroxyapatite PO4= —> generated when ATP —> ADP + Pi

Intracellular levels of Ca+ carefully regulated by proteins s.a. calsequestrin and calmodulin.
 * triggers neurotransmitter secretion
 * helps in sliding action of the myosin filaments
 * promotes breakdown of glycogen —> more fuel for action
 * promotes synthesis of ATP


 * Calcium Pumps**

Two calcium ions enter the pump (transport protein embedded in the membrane of the SR). ATP to the pump and is hydrolyzed into ADP and Pi. The energy released from ATP hydrolysis is used to change the conformation of the pump, allowing the calcium ions to move into the lumen of the SR. ADP and Pi fall off the pump, allowing it to return to it's original conformation.

• In a relaxed muscle cell, the concentration of calcium ions about 10,000 lower in the cytosol than in the SR. During a muscle contraction, the concentration of calcium in the cytosol increases, but it is still higher inside the SR. To move the calcium against the gradient, from the lower concentration in the cytosol to the higher concentration inside the SR, Active transport is needed.

__**Role of Calcium in Muscle Contraction:**__

Action Potential Occurs Calcium Ions are Released from the Terminal Cisternae. Calcium Ions then Bind to Troponin Tropomyosin Moves Away from the Myosin Binding Sites on Actin

__ CONTRACTION OF THE MUSCLE FIBRE __

__ THE SLIDING FILAMENT THEORY __

When a muscle cell contracts, the thin filaments slide past the thick filaments towards each other, and the sarcomere shortens. If many sarcomeres shorten, the muscle fibre will shorten as a result.

__The chemical players in muscle contraction are: __

1. myosin (protein) ......... a protein molecule found in the thick filaments.

2. actin (protein)

3. tropomyosin (protein)

4. troponin (protein)

5. ATP (nucleotide)

6. calcium ions


 * Myosin is a protein molecule found in the thick filaments.**

Myosin Molecule with Hinged Head Myosin has a tail and two heads (called cross bridges) which will move back and forth, providing the power stroke for muscle contraction.

The tail of myosin has a hinge which allows vertical movement so that the cross-bridge can bind to actin.

The cross bridge (head) of myosin has a binding site for ATP. Myosin is in its low energy conformation when the cross bridge is in this position:


 * Note: The term "conformation" is often used to indicate the shape of a protein. Proteins often change their shape or conformation as they function.

ATP is a molecule with a high chemical energy. ATP binds to myosin heads when they are tilted back in their low energy position. When ATP is hydrolyzed into ADP and phosphate, the energy is released and transferred to the myosin head.

After the ATP has been hydrolyzed to ADP and phosphate, the energy is transferred to the myosin head. Now the head is glowing to show that it's high energy. When the myosin head is pointing up, it is in a high energy state.

__**Thin filaments are made of these three protein molecules:**__

1. actin 2. tropomyosin 3. troponin

The **major component of the thin filament, actin** is composed of a double strand of actin subunits each of which contain myosin binding sites.


 * The regulatory protein, tropomyosin,** is also part of the thin filament. Tropomyosin twists around the actin. When the sarcomere is not shortening, the position of the tropomyosin covers the binding sites on the actin subunits and prevents myosin cross bridge binding.


 * Troponin, which is found periodically along the tropomyosin strand**, functions to move the tropomyosin aside, exposing the myosin binding sites.



As myosin functions within muscle cells, it undergoes the following four steps:

1. ATP binds to myosin head in low energy state 2. ATP hydrolysed to ADP + Pi .... Released energy transferred to myosin head. 3. Myosin head in high energy state....tail hinge bends.... myosin head makes contact with actin .... bond stabilized by Ca+ 4. ADP and Pi released from myosin head ... heads thrusts forward, pulling actin filament.


 * There are two binding sites on each myosin head, one for ATP and one for actin.

Cross bridge cycling is broken down into six steps



.
 * Step 1**: Exposure of Binding Sites on Actin

Presence of an action potential in the muscle cell membrane. Release of calcium ions from the terminal cisternae. Calcium ions rush into the cytosol and bind to the troponin. There is a change in the conformation of the troponin-tropomyosin complex. This tropomyosin slides over, exposing the binding sites on actin.


 * Step 2**: Binding of Myosin to Actin
 * Note during this entire step, the myosin head is in its high energy, upright position. If it was tilted backward, in its low energy position, the actin binding site would not be in the proper position to bind the actin.


 * Step 3**: Power Stroke of the Cross Bridge

The ADP and Pi are released from the actin. The myosin head (cross bridge) tilts backward. The power stroke occurs as the thin filament is pulled inward toward the center of the sarcomere. There has been a transfer of energy from the myosin head to the movement of the thin filament.


 * Step 4**: Disconnecting the Cross Bridge

ATP binding to the cross bridge, allowing the cross bridge to disconnect from the actin.


 * Note that even though the ATP has bound, the energy has not yet been transferred from the ATP to the cross bridge since the head is still tilted backward.


 * Step 5**: Re-energizing the Cross Bridge

ATP is hydrolyzed into ADP and phosphate. The energy (yellow glow) is transferred from the ATP to the myosin cross bridge, which points upward.


 * Step 6** Removal of Calcium Ions

Calcium ions fall off the troponin. Calcium is taken back up into the sarcoplasmic reticulum. Tropomyosin covers the binding sites on actin.


 * Note: Since the terminal cisternae and the sarcoplasmic reticulum are continuous, the pumping of calcium ions back into the sarcoplasmic reticulum causes an increase in calcium ions within the terminal cisternae as well. This animation shows the calcium ions being pumped back into the terminal cisternae, but they are really pumped back in along the length of the sarcoplasmic reticulum.
 * If these six steps occurred exactly as shown, the sarcomere would not move very far - it would only shorten about 1%. In the contraction of a typical sarcomere, step 1 occurs then steps 2-5 repeat themselves over and over again, before step 6 occurs. This allows the thin filament to slide all the way inward. Steps 2-5 repeat themselves over and over as long as both ATP and calcium ions are present.
 * If these six steps occurred exactly as shown, the sarcomere would not move very far - it would only shorten about 1%. In the contraction of a typical sarcomere, step 1 occurs then steps 2-5 repeat themselves over and over again, before step 6 occurs. This allows the thin filament to slide all the way inward. Steps 2-5 repeat themselves over and over as long as both ATP and calcium ions are present.

__ Shortening of the sarcomere __



• Many power strokes occur to bring the Z lines of the sarcomere closer together during the contraction of a muscle cell. During relaxation, the myosin heads detach from the actin and the thin filaments slide back to their resting position.

• The width of the H zone decreases during a contraction and increases during relaxation.

• The length of the sarcomere shortens during a contraction, but the thin and thick filaments do not shorten, they just slide by each other.


 * This is an important animation. View it several times to make sure to understand the theory here.

Remember as long as calcium ions and ATP are present, the thin filaments slide toward the center of the sarcomere. When the calcium is taken back up into the SR, then all the cross bridges let go and the thin filaments passively slide back to their resting position.

. Review of the Role of ATP

• Summary of the role that ATP plays in the contraction of muscle:

1. ATP transfers its energy to the myosin cross bridge, which in turn energizes the power stroke.

2. ATP disconnects the myosin cross bridge from the binding site on actin.

3. ATP fuels the pump that actively transports calcium ions back into the sarcoplasmic reticulum.

__ MACRO-VIEWS: THE ACTIVITY OF THE WHOLE MUSCLE __

__ EFFECT of above action ON WHOLE MUSCLE __


 * Muscle tension against muscle load **

__ The MOTOR UNIT __ An axon, with all its terminal branches, that makes contact with parts of a muscle through a neuromuscular junction = a motor unit. The fibres innervated in such a unit need not be close to one another, but spread throughout the muscle. If only one unit is stimulated, these parts will contract throughout the muscle, causing a weak response of the muscle as a whole. Thus, the more units that are stimulated at the same time, the stronger the action of the muscle.

__The MUSCLE TWITCH__ Recorded on a myogram. The action of a muscle after stimulation produces a twitch.

This twitch is characterized by 3 phases 1. Latent period: Stimulus has taken effect, excitation-contraction coupling occurs - No visible effect yet.

2. Contraction: Cross bridges established, movement occurs - peak tension developed > *. Enough Ca+ in sarcoplasm —> myosin heads attach —> pulls actin filament > > *. Ca+ released rapidly —> returns to SR for later use > > > 3. Relaxation: No more tension in muscle, muscle assumes original shape, size >
 * *. Low Ca+ in sarcoplasm —> troponin return to normal state —> binding sites blocked as tropomyosin moves back into place —> muscle relaxes

__ GRADED MUSCLE RESPONSES __ In vivo, muscles responds to the demands made on them. These responses :


 * to the frequency of the stimulation


 * to the demands / loads placed on the muscle - stimulus strength

see Graphs: Marieb p. 297

1. Single twitch

2. Summation - repeated stimuli, with time for slight relaxation in between.

3. Incomplete Tetanus - frequency higher than in 2, very little recovery of fibres

4. Complete Tetanus - continuous stimulus - no evidence of any relaxation of muscle.

__ THRESHOLD STIMULUS __

The minimum stimulus required to elicit an observable reaction from the muscle.

__ MAXIMAL STIMULUS __

The strongest stimulus that results in an increase in muscle contraction. At this point all the muscle’s motor units have been recruited (roped in - put to work). Any stronger stimulus will not have an effect on the muscle action and may cause damage to the muscle, particularly if the stimulus is artificial.

__ TREPPE __ [The Staircase Effect] Marieb p. 299

Consider a muscle stimulated and gives a mild response. The same stimulus follows, a contraction almost twice the strength of the first response is obtained. A third stimulus of same strength provides even greater response from muscle.... and it can continue.... Muscle “warming up”, More Ca ++ becomes available, more ATP available etc. Check me lifting a 10kg weight. First time,,,, 10cm from ground, 2nd time 20 cm etc etc.

Muscle keeps doing more as it becomes ‘accustomed’ to the load

__ MUSCLE TONE __

No active movement of muscle, but a certain amount of tension in the muscle keeps the body firm. Not like an earthworm trying to walk vertically. This tone of the muscle is important in helping to stabilize joints when walking or working and maintaining good POSTURE.

Thus, lifting the feet when walking (these days there is a fashion of dragging the feet with shoes making a noise - HOW PROFESSIONAL! )

__ ISOTONIC AND ISOMETRIC CONTRACTIONS __

Isotonic - tension remains the same = shape / size will have to change
 * Concentric= muscle shortens and does work ( biceps picking up something)


 * Eccentric = muscle lengthens as it does work (gastrocnemius as you walk uphill)

Isometric - the size / length remains the same, tension increases

__ FORCE OF MUSCLE CONTRACTION __ 1. The number of muscle fibres stimulated (motor units)

2. The size of the stimulated fibres

3. Frequency of stimulation

4. Degree of muscle stretch

__ MUSCLE FATIGUE __ Muscle unable to contract due to lack of requirements. Physiologically tired. Muscle may receive stimuli, but is unable to respond. Lack of ATP - results in conctractures - state of continuous contraction - maintained contraction due to cross bridges stuck (cramps in hands and feet often for no apparent reason)

Ca++ enhances ATP formation and mobilization — thus lack of Ca ++ can be the culprit Other ionic imbalances such as Na+ K + that are involved in nerve conduction can also play a role in this regard.

__ OXYGEN DEBT __ Muscle contraction requires oxygen for energy production. A lack of oxygen results in anaerobic respiration... production of ATP in the absence of oxygen. Less ATP is produced during anaerobic respiration and activity slows down. The muscle then “owes” itself oxygen to restore the muscle to its ‘normal’ state. It is therefore advisable that exercise starts off slowly to adapt the breathing pattern accordingly. Suddenly increase in activity may result in too little oxygen reaching the muscles in time. Cooling down exercises are as important as warming up. This helps to maintain muscle ‘sanity’.

__ HEAT GENERATION DURING MUSCLE CONTRACTION __ Aerobic respiration provides much ATP. Some of the energy provided by aerobic respiration is liberated in the form of heat, thus the increase in body temperature during exercise. Because more of the energy is converted to heat than ATP, the body needs to guard against overheating — perspiration during exercise.

When we are cold, muscles go into action (shivering) to produce heat.

__ EFFECT OF EXERCISE ON MUSCLES __ Aerobic activities = physiological benefits less physical benefits (endurance training)

Anaerobic activities = physical benefits - less physiological benefits (weight lifting)

Hypertrophic muscles Lack of exercise = hypotrophy /atrophy (Not lean muscles but weak muscles)

SMOOTH MUSCLE CONTRACTION Involuntary, controlled by MO and other ‘subconscious’ centres. Slow, synchronised contractions. Filaments contain dense bodies that can be compared to the Z-lines in a skeletal muscle fibre. Marieb p.311