The Mechanism of Muscle Contraction: Sarcomeres, Action Potential, and the Neuromuscular Junction

Skeletal Muscle Composition: Skeletal muscles are made up of fascicles, which are in turn made of muscle fibers (multinucleated muscle cells).
Myofibrils: Each muscle fiber contains myofibrils composed of myofilaments organized into contractile units called sarcomeres.
- Contractile proteins: Actin and myosin
- Regulatory proteins: Troponin (controls tropomyosin) and tropomyosin (blocks myosin binding to actin)
- Accessory proteins: Nebulin (aligns actin) and Titin (elasticity and stabilizes)

A Bands and I Bands:
- Dark A bands and light I bands contribute to the striated appearance of skeletal muscle.
- The A band contains an H zone split by the M line, which is made of myomesin.
- I bands are divided by Z discs, defining functional sarcomeres from one Z disc to the next.
Filament Arrangement:
- Thick filaments contain myosin and span the A band, connected at the M line.
- Thin filaments are composed of actin, extending across the I band into the A band.
- Elastic filaments, composed of titin, extend from Z discs to the thick filament.

Myosin Structure:
- Myosin consists of two globular heads and a long tail, with heads serving as the active sites.
- Active sites contain ATP binding sites as well as actin binding sites.
- Thick and thin filaments will interact at these sites by making cross bridges.
- No myosin heads are present in the center of the sarcomere, which helps define the H zone.
Actin Structure:
- Composed mainly of actin subunits that twist to form thin filaments.
  - G-actin —> F-Actin
- Active sites on actin are blocked by tropomyosin in a relaxed muscle fiber.
- Troponin complex binds to actin, tropomyosin, and calcium, regulating muscle contraction
- When calcium ions are released from the sarcoplasmic reticulum, they bind to troponin, causing a conformational change that moves tropomyosin away from the active sites, allowing myosin heads to attach to actin and initiate the sliding filament mechanism.

Sarcoplasmic Reticulum Function:
- Surrounds each myofibril regulating calcium levels essential for muscle contraction.
- Contains T tubules that help propagate signals throughout the muscle fiber.
  - T-tubules sit at each A-band and I-band junction

Mechanism:
- When stimulated by the nervous system, myosin heads form cross bridges with actin, pulling thin filaments towards the center of the sarcomere.
- This process shortens the I bands, eliminates the H zone, and brings the A bands closer together, leading to muscle contraction.

Neuromuscular Junction:
- Connection point between the nervous system and skeletal muscle, involving acetylcholine release from axon terminals into the synaptic cleft.
- Pathway —> Excitation-contraction coupling:
- Brain sends electrical signal through nerve to muscle (Start the race)
  1. ACh releases by synaptic cleft, binds to nicotinic cholenergic receptors
    - Nerve releases a ACh (Pass the baton)
  2. Binding of ACh opens the channels —> Na+/K+ moves across the membrane
    - ACh is removed by acetylcholinesterase
    - Na+ influx > K+ efflux = local depolarization occurs at synapse (EPP)
    - Ach tells muscle to create elec. sig. to muscle. (Spread the signal)
  3. Action potential occurs at EPP down the T-tubules
    - DHP on Ca2+
    - DHP detects depolarization
  4. DHP changes RyR = opening of Ca2+ at the sarcoplasmic reticulum
    - Signal reaches SR and calcium gates open (Open the gates)
  5. Ca2+ to troponin on thin filament —> tropomyosin “on”
    - Calcium binds to troponin, moves tropomyosin out of the way, exposes “grab-sites” on actin
    - Calcium says “go”
  6. Myosin to actin goes through cross bridge
    - muscle contracts
- Acetylcholine binds to receptors causing sodium influx, resulting in depolarization and action potential generation.

Cross Bridge Cycle:
- Active sit on actin is exposed when Ca2+ binds to troponin
  - calcium says go!
- Myosin head binds to actin at the actin binding site and forms a weak crossbridge
  - Mysoin grabs actin
- the inoragnaic phosphate releases from mysoin that causes the mysoin head to pivot toward the centre of the sarcomere
  - This pulls the thin filament toward the M line
  - Myosin pull actin (power stroke)
- Release of ADP from myosin after the power stroke
  - Myosin lets go
- myosin is now firmly bound to actin —> rigor state
- a new molecule of ATP attaches to the myosin head, causing the crossbridge to detach
  - ATP resets myosin
- The myosin head ATPase hydrolysis ATP—> ADP +Pi which returns myosin to the cocked position. Return to step 2 and continue the cycle if Ca2+ is bound to troponin.
  - Repeat as long as calcium is there

Action Potential Propagation:
- The action potential moves along the sarcolemma and down T tubules, resulting in calcium ion release from the sarcoplasmic reticulum.
- Repolarization occurs after action potential propagation when potassium channels open, restoring the negative charge inside the muscle fiber.

Calcium Role:
- Rising levels of calcium ions in the cytosol displace tropomyosin from myosin binding sites on actin, facilitating contraction.
- Myosin heads bind to actin, perform cross bridge cycling while hydrolyzing ATP, resulting in filament sliding that leads to muscle contraction.
Relaxation Phase:
- As calcium levels decrease, troponin reverts to its original shape, tropomyosin re-blocks binding sites, and the muscle fiber relaxes.

Muscle contraction begins at the neuromuscular junction with acetylcholine release.
Sodium and potassium ions create a voltage change, leading to action potential generation.
This action potential travels through T tubules, stimulating calcium release that enables myosin-actin interaction and muscle contraction.