Physiology Chapter on Neuromuscular Transmission

Neuromuscular Transmission

• Neuromuscular transmission is the process of transmitting nerve impulses from alpha motor neurons (αMNs) to skeletal muscle fibers.
• It is a crucial process for voluntary muscle movement.

Physiology of Skeletal Muscles

• Skeletal muscles are attached to bones and are responsible for voluntary movement.
• Human bodies contain over 400 skeletal muscles.
• Skeletal muscle functions include:
  • Static force production for maintaining posture and stabilizing joints.
  • Kinetic force production for locomotion and breathing.
  • Heat production.
  • Help venous drainage.

Muscle Proteins

• Myosin protein:

  • Contains an actin-binding site, ATP binding site, and a catalytic site for ATP hydrolysis (myosin ATPase).
  • The head of the myosin protein extends to the side to form an arm.
  • Arms and heads together are called cross-bridges.
  • Cross-bridges are flexible at two points called hinges.

• Thin filament proteins:

  • Each thin filament contains 300-400 actin molecules.
  • Actin molecules have specific myosin cross-bridge binding sites (active sites), an ATP binding site, and a catalytic site for ATP hydrolysis (actomyosin ATPase).
  • Tropomyosin molecules cover the active sites on actin under resting conditions, preventing contraction.
  • Troponin is a complex of three globular protein molecules:
    • Troponin-I binds actin to inhibit actomyosin ATPase activity.
    • Troponin-T binds to tropomyosin.
    • Troponin-C binds Ca2+.

Tubular System

• Transverse (T) Tubules:

  • Invaginations of the sarcolemma.
  • Located at the junction of A and I bands in mammalian skeletal muscle.
  • Propagate action potentials from the sarcolemma into the T tubule network.
  • Contain extracellular fluid (ECF).

• Sarcoplasmic Reticulum (SR):

  • ER of the muscle fiber that surrounds each myofibril.
  • Contains high levels of calcium ions (Ca2+) used to initiate muscle contraction.
  • Expanded ends form terminal cisternae (TC), which make contact with T tubules on either side of the sarcomere at the A and I band junction (triad).
  • Foot processes span the space between T tubule and SR membranes.
  • The SR membrane contains the ryanodine receptor, which is a Ca2+ release channel.
  • The T-tubule membrane contains the dihydropyridine (DHP) receptor, which opens the ryanodine Ca2+ release channel on the SR.

Neuromuscular Junction

• The neuromuscular junction (NMJ) is the site where a motor neuron communicates with a muscle fiber.
• Action potentials in the motor neuron cause the release of acetylcholine (ACh) at the NMJ, triggering muscle contraction.
• Physiologic anatomy of the NMJ:
  • Alpha motor neurons (αMNs) branch to innervate multiple muscle fibers.
  • Each muscle fiber receives only one axon terminal containing ACh vesicles.
  • The nerve ending fits into a depression in the muscle membrane called the motor end plate (MEP).
  • MEP is rich in Ach receptors and contains junctional folds.
  • The synaptic cleft is the extracellular space between the nerve terminal and muscle membrane, containing basal lamina and the enzyme acetylcholinesterase (AChE).

Neuromuscular Transmission

• The sequence of events during neuromuscular transmission includes:
  • Action potential reaches the nerve ending, opening voltage-gated Ca2+ channels.
  • Ca2+ influx into the nerve terminal binds to calmodulin and activates CaM kinases.
  • ACh vesicles fuse with the membrane and release their contents by exocytosis.
  • ACh diffuses across the synaptic cleft and binds to receptors on the MEP, opening ion channels.
  • Na+ influx and K+ efflux depolarize the muscle membrane, creating an end-plate potential (EPP).
  • EPP triggers action potentials on either side of the MEP, which propagate along the muscle fiber and initiate contraction.
  • Acetylcholinesterase (AChE) rapidly degrades ACh in the synaptic cleft to prevent continuous stimulation of the muscle fiber.

Properties of Neuromuscular Transmission

• Unidirectional: transmission occurs from neuron to muscle fiber.
• Delay: a short delay (0.5 msec) between nerve stimulation and muscle contraction.
• Fatiguability: prolonged stimulation leads to fatigue as ACh vesicles become depleted.
• Ionic influences: ion concentrations affect neuromuscular transmission.
• Drug effects: drugs can stimulate or block neuromuscular transmission.

Myasthenia Gravis (MG)

• A serious autoimmune disease characterized by muscle weakness and fatigue.
• Caused by antibodies against ACh receptors, leading to decreased receptor numbers at the NMJ.
• Symptoms worsen with repeated stimulation due to decreased ACh release.
• Can be ocular, bulbar, or generalized.
• Patients may have a family history of autoimmune disorders, and thymic abnormalities are frequently observed.

Treatment of Myasthenia Gravis

• Chest CT scan is indicated to rule out thymoma.
• Anticholinesterase drugs such as physostigmine and neostigmine can ameliorate symptoms by increasing ACh levels.
• Thymectomy is considered, especially when thymoma is suspected.