Neuromuscular Junction and Muscle Contraction

Neuromuscular Junction and Skeletal Muscle Excitation-Contraction Coupling

• The neuromuscular junction (NMJ) is one of the fastest and most efficient synapses in the human body.
• It transmits signals from nerves to muscles with incredible precision and speed.
• Within milliseconds of receiving an electrical signal, the NMJ releases acetylcholine (ACh), initiating a cascade of events leading to muscle contraction.
• This rapid process, called excitation-contraction coupling, enables muscles to respond almost instantaneously to stimuli.
• This enables complex motor functions, such as typing and sprinting.

Learning Outcomes

• Students should be able to describe the connection between motor neurons and muscles (Neuromuscular junction).
• Explain neurotransmitter release and binding at the NMJ and the generation of a post-synaptic electrical signal.
• Explain the process of excitation-contraction coupling.
• Describe clinical disorders associated with NMJ dysfunction (e.g., Myasthenia Gravis, Lambert-Eaton Syndrome) and the use of neuromuscular blockers.

Neuromuscular Junction

• The synapse between motor neurons and muscle fibers is called the neuromuscular junction.
• Motor neurons innervate muscle fibers.
• A motor unit consists of a single motor neuron and the muscle fibers it innervates.
• Larger muscles (e.g., hip or knee flexors) have more muscle fibers per motor unit (e.g., 1200+).
• Smaller muscles (e.g., intrinsic hand muscles) have fewer muscle fibers per motor unit (e.g., 12 or less).

Skeletal Muscle Fiber Types

• Skeletal muscle fibers are categorized based on contraction speed and metabolic profile.
• Type I (Slow-twitch, oxidative): Small, rich in mitochondria, and blood capillaries (red). Fatigue-resistant, suited for sustained activities like standing.
• Type IIa (Intermediate, fast, oxidative-glycolytic (FOG)): Properties intermediate between Type I and Type IIx.
• Type IIx (Fast, glycolytic (FG)): Large, mitochondria-poor, and capillary-poor (white). Produce brief, powerful contractions, like sprinting.

Skeletal Muscle Structure

• A skeletal muscle is a collection of muscle cells (muscle fibers) with multiple nuclei near the surface.
• Each muscle fiber contains myofibrils, the contractile structures within the muscle fiber.
• Myofibrils are surrounded by sarcolemma (the cell membrane) with transverse tubules (T-tubules) for deep invaginations.
• Sarcoplasmic reticulum (SR) wraps around myofibrils, consisting of longitudinal tubules for storage and release of calcium ions.

Sarcomere Structure

• The sarcomere is the functional unit of a myofibril.
• Composed of light bands (I bands) and dark bands (A bands), containing thin (actin) and thick (myosin) filaments.
• The H zone is the part of the A band that contains only myosin filaments.
• The Z lines delineate the boundaries of each sarcomere.
• The M line (in the middle of each sarcomere) provides attachment for myosin filaments.

Excitation-Contraction Coupling

• Action potentials in motor neurons cause the release of acetylcholine (ACh) into the neuromuscular junction.
• ACh binds to receptors on the muscle cell membrane, generating an end-plate potential (EPP).
• EPP depolarizes the muscle cell membrane, initiating an action potential that spreads into the T-tubules.
• Release of calcium ions (Ca2+) from the sarcoplasmic reticulum (SR).
• Ca2+ binds to troponin, exposing myosin-binding sites on actin filaments; resulting in cross-bridge formation then myosin heads produce a power stroke, pulling actin filaments toward the center of the sarcomere; shortening the muscle fiber.
• Relaxation occurs when Ca2+ levels decrease, causing tropomyosin to block myosin-binding sites; preventing cross-bridge cycling.

Neuromuscular Blockade

• Used in anesthesia to paralyze patients.
• Depolarizing: Succinylcholine mimics ACh; causing prolonged stimulation, depolarization, and desensitization of receptors.
• Non-depolarizing: Rocuronium blocks ACh receptors; preventing EPP and muscle contraction.

Myasthenia Gravis

• An autoimmune disease causing extreme muscle weakness.
• Autoantibodies are produced that target and block acetylcholine receptors (AChR) at the neuromuscular junction.
• This causes the muscles to have a reduced response to signals, resulting in weakness.
• Symptoms include drooping eyelids, difficulty swallowing, and generalized muscle weakness.

Lambert-Eaton Myasthenic Syndrome (LEMS)

• A rare autoimmune disease affecting the nerve ending, specifically the calcium channels.
• Autoantibodies target voltage-gated calcium channels preventing the release of acetylcholine (ACh); thereby weakening the muscle contraction.
• Symptoms include muscle weakness, especially in proximal muscles, and diminished reflexes.