Neuromuscular Junction and Muscle Physiology

Muscle Types

• Skeletal Muscle
  • Voluntary, striated, multinucleated
  • Works with bones, tendons, ligaments to support body weight and generate movement
• Cardiac Muscle
  • Involuntary, striated, contains intercalated discs, autorhythmic
  • Contracts rhythmically to pump blood through the cardiovascular system
• Smooth Muscle
  • Involuntary, non-striated, spindle-shaped, located in walls of hollow organs
  • Generates motility and maintains tonic tension (e.g., intestinal peristalsis, airway caliber during breathing)

Excitation–Contraction Coupling (General Sequence)

• 1. Action potential (AP) travels down T-tubules
• 2. Activates dihydropyridine (DHP) receptor → opens ryanodine receptor on sarcoplasmic reticulum (SR)
• 3. \text{Ca^{2+}} released into cytoplasm
• 4. \text{Ca^{2+}} binds troponin → tropomyosin shifts → exposes actin sites
• 5. Myosin binds actin → power stroke
• 6. ATP binds, detaches crossbridge, re-cocks myosin head (ATP required for both detachment and re-energizing)
• 7. \text{Ca^{2+}} resequestered via SERCA pumps → relaxation

Muscle-Specific E–C Coupling Mechanisms

• Skeletal Muscle
  • Mechanical link between DHP and ryanodine receptor
  • No extracellular \text{Ca^{2+}} required once SR stores are filled
• Cardiac Muscle
  • AP opens L-type \text{Ca^{2+}} channels → Ca-induced Ca-release from SR
  • Repolarization: \text{K^{+}} efflux
• Smooth Muscle
  • Stimuli (neural, hormonal, stretch) allow \text{Ca^{2+}} entry or SR release
  • \text{Ca^{2+}} + calmodulin → MLCK activation → myosin light-chain phosphorylation → contraction
  • Contractions slower but sustained

Sliding Filament Theory (Mechanical Shortening)

• 1. Myosin head (loaded with ADP + \text{P_i}) binds exposed actin site
• 2. Power stroke pulls actin → sarcomere shortens
• 3. ADP + \text{P_i} released
• 4. New ATP binds → myosin detaches
• 5. ATP hydrolyzed → myosin re-cocked
• Band Changes: H zone & I band shorten, A band remains constant

Muscle Fiber Types

• Type I (Slow-twitch)
  • High mitochondrial density & myoglobin (red)
  • ATP via oxidative phosphorylation
  • Fatigue-resistant; e.g., posture, marathon
• Type IIa (Fast-twitch, intermediate)
  • Moderate mitochondria/myoglobin; mix of oxidative & glycolytic ATP production
  • Moderate fatigue resistance; e.g., middle-distance running, cycling
• Type IIb/x (Fast-twitch, glycolytic)
  • Low mitochondria/myoglobin (white)
  • ATP via anaerobic glycolysis; fatigues quickly; e.g., sprinting, weightlifting

Muscle Contraction Types

• Isotonic: muscle changes length
  • Concentric: shortens
  • Eccentric: lengthens while generating force
• Isometric: tension generated with no length change

Neuromuscular Junction (NMJ) Structure

• Presynaptic terminal of motor neuron (ACh-containing vesicles)
• Synaptic cleft (contains acetylcholinesterase)
• Postsynaptic membrane (motor end plate) with nicotinic ACh receptors (nAChRs)

NMJ Signaling Cascade

• 1. Neuronal AP arrives at axon terminal
• 2. Voltage-gated \text{Ca^{2+}} channels open
• 3. Vesicular ACh released into cleft (SNARE-dependent exocytosis)
• 4. ACh binds nAChRs → Na⁺ influx → depolarization (end-plate potential)
• 5. If threshold reached, muscle AP propagates along sarcolemma & into T-tubules
• 6. ACh degraded by acetylcholinesterase → terminates signal

Clinical Relevance

Malignant Hyperthermia (MH)

• Autosomal dominant mutation in RYR1 or DHP receptor genes
• Trigger: volatile anesthetics or succinylcholine
• Pathophysiology: uncontrolled \text{Ca^{2+}} release → sustained contraction & hypermetabolism
  • ↑ \text{O2} consumption, ↑ \text{CO2} production
  • ↓ ATP, lactic acidosis, heat generation, rhabdomyolysis, myoglobinuria
• Presents with fever, muscle rigidity, pulmonary/cerebral edema

Duchenne Muscular Dystrophy (DMD)

• X-linked recessive dystrophin mutation → absence of functional dystrophin
• Dystrophin roles
  • Transfers contractile force to sarcolemma & extracellular matrix
  • Acts as scaffold anchoring signaling complexes
• Lack of dystrophin → membrane fragility → injury during contraction → inflammation → replacement with fibrofatty tissue → progressive weakness

Myasthenia Gravis (MG)

• Autoimmune; antibodies against nAChRs → receptor internalization & degradation
• Fewer functional receptors → rapid fatigability & muscle weakness

Botulinum Toxin (BoNT, "BOTOX")

• Clostridium botulinum protease cleaves SNARE proteins
• Prevents ACh vesicle fusion → inhibits ACh release
• Results in flaccid paralysis, diaphragmatic/respiratory failure
• Treatment: horse-derived antitoxin (passive immunity) if early

Curare

• Plant-derived neuromuscular blocker; competitive antagonist at nAChRs
• Prevents ACh binding → no depolarization → paralysis
• Historically used for hunting and therapeutically (e.g., tetanus, surgical paralysis)

Functional & Regulatory Differences (Clinical Spotlight)

• Skeletal Muscle
  • MG: autoimmune nAChR loss → weakness
  • Botulinum toxin: prevents ACh release → flaccid paralysis
• Cardiac Muscle
  • \beta-blockers (e.g., metoprolol) ↓ HR/BP by blocking \beta_1 receptors
  • Digoxin: ↑ intracellular \text{Ca^{2+}} → ↑ contractility in heart failure
• Smooth Muscle
  • Asthma: \beta_2-agonists (e.g., albuterol) relax bronchial smooth muscle
  • Pre-term labor: tocolytics (e.g., \beta_2-agonists) inhibit uterine contractions
  • Nitrates ↑ NO → vascular smooth muscle relaxation → ↓ preload

Integrative & Ethical Considerations

• Understanding E–C coupling is foundational for anesthesia safety (MH), neuromuscular blocking use (curare, BoNT), and autoimmune diagnostics (MG)
• Genetic screening/ counseling for DMD & MH mutations crucial for patient/family well-being
• Pharmacologic modulation of muscle systems (e.g., \beta-agonists/blockers) demonstrates translational physiology bridging bench to bedside