Module 4: Molecular Basis of Skeletal Muscle Contraction (2)

What brings about a muscular contraction in skeletal muscles? How is this mechanism formed?

Sliding filament mechanism

• cross-bridge formation between a myosin head and actin form the basis of the sliding filament mechanism

What occurs during the sliding filament mechanism as a muscle contracts? How does the sarcomere change? Recall the sarcomere goes from z-line to z-line and has thick filaments in the middle and thin on the sides. What do we call the result of this whole muscle contraction?

During contraction, thin filaments move inwards over the thick filaments.

• this makes the z-lines move closer together (sarcomere shortens).

This occurs simultaneously across the whole muscle fibre and all the sarcomeres shorten to the same degree.

Length of thick and thin filaments does not change; just the degree of overlap (ex. A-bands and I-bands stay the same length)

Thus the whole muscle shortens, which is called concentric contraction

What is the power stroke? When does it occur?

interaction between myosin and actin that leads to a shortening of the sarcomere.

occurs when cross-bridge bends and pulls the thin myo-filament inwards towards the centre of thick filament.

Describe the process of a cross-bridge cycle. Hint: there are 4 steps.

1. Binding

   • myosin cross-bridge binds to actin molecule

2. Power stroke

   • myosin head bends, pulling thin myo-filament inwards

3. Detachment

   • cross-bridges detach at the end of a power stroke and returns to its original conformation

4. Binding

   • cross-bridge binds to distal actin molecule and the cycle repeats.

What is the result of the power stroke? What happens during/after each successive cross-bridge cycle?

actin molecules being pulled closer to the centre of myosin molecules.

After each successive cross-bridge cycle, the actin is pulled in even more.

Each myosin molecule is surrounded by 6 actin molecules on both ends; they are all pulled inward simultaneously at contraction

• at any given time, not all cross-bridges are actively pulling actin; some hold actin in position while others prepare for power stroke.

• myosin each have 2 heads but only one may be attached to actin at any given time.

How do power strokes get energy to shorten sarcomeres?

Excitation-Contraction Coupling → process of converting an electrical signal into an actual contraction.

Recall that at the motor end plate, ACh is released into the neuromuscular junction where it causes permeability changes and initiates an AP that’s conducted across the entire muscle membrane. Skeletal muscle cells have 2 membrane structures that help to transmit this signal to muscle fibres. What are they? Briefly describe each.

1. Sarcoplasmic Reticulum

   • membranous structure that runs parallel to the fibres.

   • At its end, the lateral sacs are in close proximity to the T-tubules.

   • STORAGE SITE FOR CALCIUM.

2. T-tubules

   • invaginations of plasma membrane.

   • At the junction of A and I bands, they dip into the fibres and run perpendicular to the fibres.

The sarcoplasmic reticulum and T-tubules work together. When the membrane depolarizes, this wave of depolarization also goes deeper into the cells by spreading down the T-tubules. Since the SR and TT are in close proximity, this electrical signal is transmitted from TT to SR. Go into greater detail as to how these two interact.

1. The sarcoplasmic reticulum runs longitudinally with segments that expand to form the lateral sacs (which lie beside the TT). The T-tubules dip deep into the muscle fibre at junctions between the A and I bands.

2. Dihydropyridine receptors on the surface of t-tubules are like voltage sensors that detect the wave of depolarization as it moves down the TT.

3. immediately opposite to the dihydropyridine receptors on the SR are the ryanodine receptors (form of calcium channel).

4. when the wave of excitation enters the TT, its sensed by dihydropyridine receptors which influence the ryanodine receptors to undergo conformational change.

5. When ryanodine receptors are activated, they open and calcium enters the cytoplasm.

Why is the release of calcium from the sarcoplasmic reticulum so important?

Calcium is the primary trigger to allow skeletal muscles to contract.

What does a relaxed skeletal muscle look like when contraction can’t occur? What does an excited skeletal muscle look like when a contraction can occur?

Relaxed muscle

• tropomyosin and troponin are positioned in such a way to prevent cross-bridge formation; blocks myosin binding site on actin.

Excited muscle

• calcium enters muscle and binds to troponin, causing conformational changes resulting in tropomyosin moving out of the way, exposing myosin binding sites on actin molecules.

What is the cause of muscle relaxation?

decreased nerve activity at neuromuscular junction.

• when ACh stops being released, acetylcholinesterase can remove the remaining ACh from the junction, stopping action potential generation in skeletal muscle fibres.

• action potentials are no longer causing the sarcoplasmic reticulum to release its stored calcium.

• The calcium -ATPase pumps on sarcoplasmic reticulum pump calcium back into the SR store for later use.

• without calcium, troponin-tropomyosin complex can cover actin molecules.

Therefore, muscle lengthens and relaxes.

Fill in the blanks time!!

1. Action potential generated in response to binding of ACh and subsequent end-plate potential is propagated across surface membrane and down _____ of muscle cell.

2. Action potential in t-tubule triggers ____ release from the sarcoplasmic reticulum.

3. Calcium ion released from lateral sacs binds to _____ on actin filaments; leading to ______ being physically moved aside to uncover cross-bridge binding sites on actin.

4. _____ cross-bridges attach to actin and bend, pulling actin filaments toward the centre of the sarcomere; powered by energy provided by ______.

5. Calcium is actively taken up by the ____ when there is no longer an action potential.

6. With _____ no longer bound to _____, _____ slips back to its blocking position over binding sites on actin; contraction ends and actin slides back to original resting position.

1. T-tubules

2. calcium

3. Troponin, Tropomyosin

4. Myosin

5. Sarcoplasmic reticulum

6. calcium, troponin, tropomyosin

Exposure of actin binding sites allows for ATP-powered cross-bridge cycle. Describe a cross-bridge cycle in the presence or absence of calcium.

For both, myosin heads have an actin binding site and an ATPase site which can bind to ATP. This splits ATP into ADP and Pi (inorganic phosphate). By removing Pi from ATP, stored energy is released and transferred to myosin cross-bridge meaning it’s now “cocked and ready to fire”.

• without calcium → cross-bridge remains “cocked” and contraction won’t occur.

• with calcium → troponin-tropomyosin complex exposes actin molecules and cross bridge can bind with actin. This “pulls trigger” and cross-bridge swings causing a power stroke.

Pi is released during power stroke. When power stroke is complete, ADP is released, leaving ATPase site empty. However the cross-bridge is still bound to actin.

Binding of new ATP molecule causes the cross-bridge to detach and then return to it’s “uncocked” shape.

What happens to cross-bridge cycling after death?

Rigor mortis kicks in. Calcium concentration increases in cells. Since cross-bridges were already “cocked”, muscles start contracting until they run out of ATP. They will then remain contracted.

• after a few days, sufficient muscle proteins decay and relaxation occurs again.

Describe the three part relationship between an action potential and the resulting muscle twitch. Recall when a muscle is activated and required to exert a force that is less than the maximum tension it can generate, the muscle begins to shorten.

(an AP in skeletal muscle = very short)

1) latent period

• delay before contraction starts

• generally the AP is completed during this time before contraction occurs.

• when cross-bridge cycling occurs

2) contraction time

• once cross-bridge cycling begins, it takes time for actin filaments to slide along myosin, creating increased tension.

• peak tension occurs between 40-120 ms.

• variability in peak tension due to type of muscle fibre (fast twitch vs. slow twitch) and location within body.

3) relaxation time

• contractile response doesn’t end until all calcium has been removed

• usually 50-200 ms from peak tension

What is peak tension?

greatest tension that can be reached while still creating force against an outside load.