24-25 Muscle Physiology

Functional Morphology of Skeletal Muscle

• Muscle → Fascicles (bundles) → Muscle Fiber (cell) → Myofibrils → Myofilaments (actin/myosin).

• Muscle: Composed of fascicles (bundles of muscle fibers).

• Muscle Fiber (Cell): Long, cylindrical cell with multiple nuclei. Contains:

  • Myofibrils: Thread-like structures packed with actin (thin filaments) and myosin (thick filaments).

  • Sarcolemma: Cell membrane with an outer polysaccharide layer; connects to tendons.

  • Sarcoplasmic Reticulum (SR): Calcium storage network surrounding myofibrils.

  • T-Tubules: Invaginations of the sarcolemma that transmit action potentials to the SR.

• Sarcomere: Functional unit of contraction, bounded by Z-discs (anchor actin). Contains:

  • A-band: Dark region with overlapping actin and myosin.

  • I-band: Light region with actin only.

  • H-zone: Central region of A-band with myosin only (shortens during contraction).

• Titin: Giant elastic protein connecting myosin to Z-discs, maintaining sarcomere structure.

Mechanism of Contraction of Skeletal Muscle: Sliding Filament Theory

1. Excitation-Contraction Coupling:

   • Neuromuscular Junction: Motor neuron releases acetylcholine (ACh), triggering muscle membrane depolarization.

   • Action Potential Propagation: Travels along sarcolemma and T-tubules → signals SR to release Ca²⁺.

   • Calcium Role: Binds troponin on actin filaments → shifts tropomyosin to expose myosin-binding sites.

2. Cross-Bridge Cycling:

   • Attachment: Myosin heads (energized by ATP hydrolysis) bind actin.

   • Power Stroke: Myosin heads pivot, pulling actin toward sarcomere center (ADP + Pi released).

   • Detachment: ATP binds myosin → head releases actin.

   • Reset: ATP split to ADP + Pi by myosin ATPase → head re-cocks for next cycle.

   • "Walk-Along" Mechanism: Repeated cycles cause filaments to slide, shortening sarcomeres (I-bands narrow; H-zone disappears).

3. Relaxation:

   • Ca²⁺ Reuptake: SR’s Ca²⁺-ATPase pumps Ca²⁺ back into SR.

   • Tropomyosin re-blocks actin sites → muscle returns to resting length (passive process)

Energetics of Contraction of Skeletal Muscle

• ATP Roles:

  • Powers myosin detachment and resetting.

  • Fuels Ca²⁺ pumps in SR.

  • Immediate: Creatine phosphate (regenerates ATP in 5–10 sec).

  • Short-Term: Glycolysis (2–3 min, produces lactate).

  • Long-Term: Oxidative phosphorylation (mitochondria, requires O₂).

• Creatine Phosphate: Rapidly regenerates ATP during short bursts.

• Fatigue: Caused by ATP depletion, lactic acid buildup, or ion imbalances (K⁺, Ca²⁺).

• Oxygen Debt: Excess post-exercise O₂ consumption to replenish ATP, clear lactate, and restore ions.

Length-Tension Relationship

• Optimal Sarcomere Length (~2.0–2.2 µm):

  • Maximal force due to optimal actin-myosin overlap (all cross-bridges engage).

• Overstretched Sarcomeres (>2.2 µm):

  • Reduced overlap → fewer cross-bridges → weaker contraction.

• Overly Short Sarcomeres (<2.0 µm):

  • Actin filaments crumple → cross-bridge interference → reduced force.

Types of Skeletal Muscle Contractions

• Isotonic: Muscle shortens against constant load (e.g., lifting weights).

• Isometric: Muscle tension without shortening (e.g., holding a plank).

• Twitch: Single contraction-relaxation cycle (latent period → contraction → relaxation).

• Summation/Tetanus: Rapid stimuli → fused, sustained contraction (no relaxation).

Muscle Fiber Types

Motor Units and Recruitment

• Motor Unit: One motor neuron + all innervated muscle fibers.

  • Size Principle: Small units (slow fibers) recruited first; large units (fast fibers) added for greater force.

• Summation: Increased force via multiple fiber recruitment or frequency (tetanus).

Skeletal Muscle Work & Fatigue

• Work = Force × Distance.

• Power = Work/Time.

• Fatigue Mechanisms:

  • Peripheral: ATP depletion, lactic acid buildup, ionic imbalances (K⁺, Ca²⁺), glycogen loss.

  • Central: CNS inhibition (protective mechanism).

• Recovery: Requires O₂ to restore ATP, clear lactate, and normalize ions.

Electromyography (EMG)

• Principle: Records electrical activity of muscle fibers during contraction.

  • Motor Unit Action Potentials (MUAPs): Summed depolarization of fibers in a motor unit.

• Clinical Uses:

  • Diagnose neuromuscular disorders (e.g., myasthenia gravis, ALS).

  • Assess muscle recruitment patterns in sports science.

Skeletal Muscle Disorders

• Hypertrophy: Resistance training → increased myofibrils (not cell number).

• Atrophy: Disuse → proteolysis (e.g., bed rest, denervation).

• Denervation: Muscle fibers atrophy; replaced by fibrous tissue (contractures if untreated).

• Rigor Mortis: Post-mortem ATP depletion → permanent cross-bridge attachment (stiffness).

• Muscular Dystrophy: Genetic defects in dystrophin → sarcolemma instability.

• Myasthenia Gravis: Autoimmune attack on ACh receptors → muscle weakness.

Neuromuscular Junction (NMJ): Structure & Function

• Motor End Plate: Specialized region of the muscle fiber membrane where the axon terminal synapses.

  • Synaptic Gutter: Invagination of the muscle membrane where the nerve terminal sits.

  • Subneural Clefts: Folds in the muscle membrane (increase surface area for ACh receptors).

• Axon Terminal: Contains vesicles with acetylcholine (ACh) and mitochondria (ATP for ACh synthesis).

• Synaptic Cleft: 20–30 nm space between nerve and muscle membranes.

• Voltage-Gated Ca²⁺ Channels (nerve terminal): Open during depolarization → Ca²⁺ influx triggers ACh release.

• ACh Receptors (muscle end plate): Ligand-gated Na⁺/K⁺ channels.

Acetylcholine (ACh) Release & Signal Transmission

1. Action Potential Arrival:

   • Nerve depolarization opens voltage-gated Ca²⁺ channels in the axon terminal.

   • Ca²⁺ influx triggers exocytosis of ACh vesicles (~125 vesicles per impulse).

2. ACh Binding:

   • ACh diffuses across the synaptic cleft → binds to nicotinic ACh receptors on the muscle end plate.

   • Each receptor is a pentamer (2α, β, δ, γ subunits). Binding opens the channel.

3. End Plate Potential (EPP):

   • Na⁺ influx > K⁺ efflux → local depolarization (~50–75 mV).

   • EPP is always suprathreshold (triggers muscle action potential).

4. Termination of Signal:

   • Acetylcholinesterase (on synaptic cleft matrix) breaks ACh into acetate + choline.

   • Choline is reabsorbed into the nerve terminal for ACh resynthesis.

Muscle Action Potential & T-Tubule System

Muscle Fiber Depolarization:

• EPP → voltage-gated Na⁺ channels open → action potential propagates along sarcolemma.

• T-Tubules: Invaginations of the sarcolemma that carry the action potential deep into the muscle fiber.

  • Triad: T-tubule flanked by terminal cisternae of the sarcoplasmic reticulum (SR).

Excitation-Contraction Coupling

1. Calcium Release:

   • T-tubule depolarization opens voltage-sensitive dihydropyridine (DHP) receptors → mechanically linked to ryanodine receptors (RyR) on SR.

   • RyR channels open → Ca²⁺ floods sarcoplasm from SR stores.

2. Calcium’s Role:

   • Binds troponin C → tropomyosin shifts → exposes myosin-binding sites on actin.

3. Contraction:

   • Cross-bridge cycling begins

4. Relaxation:

   • Ca²⁺-ATPase (SERCA) pumps Ca²⁺ back into SR.

   • Tropomyosin re-blocks actin → muscle relaxes.

Drugs/Toxins of the NMJ

• Curare: Blocks ACh receptors → flaccid paralysis.

• Botulinum Toxin: Prevents ACh vesicle fusion → paralysis (used in Botox).

• Neostigmine: Inhibits acetylcholinesterase → prolongs ACh action (treats myasthenia gravis).

• Lambert-Eaton Syndrome: Autoantibodies target voltage-gated Ca²⁺ channels → reduced ACh release → muscle weakness (improves with repeated use).

• Organophosphate Poisoning: Inhibits acetylcholinesterase → ACh overload → muscle spasms, respiratory arrest.

Molecular Mechanisms of ACh Synthesis & Recycling

• ACh Synthesis:

  • Choline + acetyl-CoA → ACh (via choline acetyltransferase in axon terminal).

  • Packaged into vesicles by vesicular ACh transporter.

• Vesicle Recycling:

  • After exocytosis, vesicle membranes are retrieved via clathrin-coated pits → reformed into new vesicles.

Functional Morphology of Smooth Muscles

• Structure:

  • No Sarcomeres: Actin/myosin arranged in lattice (attached to dense bodies).

  • Caveolae: Membrane invaginations (store Ca²⁺, similar to T-tubules).

  • Gap Junctions: Allow electrical coupling in unitary smooth muscle (e.g., gut).

• Types:

  • Unitary (Visceral): Sheets with gap junctions (self-excitatory).

  • Multi-Unit: Independent fibers (neurogenic, e.g., iris).

Types of Smooth Muscle

Multi-Unit Smooth Muscle:

• Structure: Discrete, independent fibers (no gap junctions).

• Control: Primarily by autonomic nerves (e.g., iris muscles, piloerector muscles).

• Example: Adjusts pupil size or causes hair erection.

Unitary (Single-Unit) Smooth Muscle:

• Structure: Sheets of fibers connected by gap junctions (electrical syncytium).

• Control: Self-excitatory (pacemaker cells), hormones, stretch, or neurotransmitters.

• Example: Gut, uterus, blood vessels (visceral organs).

Excitation & Electrophysiology of Smooth Muscle

• Depolarization Mechanisms:

  • Autonomic Nerves: Release ACh/norepinephrine → activate receptors.

  • Pacemaker Cells: Generate slow waves (e.g., gut interstitial cells of Cajal).

  • Stretch: Opens mechanosensitive channels → depolarization.

• Action Potentials:

  • Spike Potentials: Brief (10–50 ms) → phasic contractions (e.g., peristalsis).

  • Plateau Potentials: Sustained depolarization → tonic contractions (e.g., blood vessels).

Smooth Muscle - Mechanism of Contraction

• Calmodulin-Dependent:

  1. Ca²⁺ binds calmodulin → activates myosin light-chain kinase (MLCK).

  2. MLCK phosphorylates myosin → cross-bridge cycling.

  3. Latch State: Myosin phosphatase dephosphorylates myosin → slow detachment → sustained tension.

• Calcium Sources:

  • Extracellular: Via voltage-gated (L-type) or receptor-operated channels

  • Sarcoplasmic Reticulum: IP₃ or Ca²⁺-induced Ca²⁺ release

• Latch Mechanism:

  • Sustained contraction with minimal ATP use.

  • Myosin remains attached to actin even after dephosphorylation (via myosin phosphatase).

• Slow Cycling:

  • Cross-bridge cycling is slower than in skeletal muscle → energy-efficient, prolonged contractions.

Smooth Muscle Contraction - Regulation of Contraction

1. Nervous Control:

   • Autonomic Nerves: Release ACh (excitatory or inhibitory) or norepinephrine (varies by tissue).

   • Varicosities: Swellings along nerve fibers that release neurotransmitters diffusely (no structured NMJ).

2. Hormonal/Chemical Control:

   • Excitatory: Norepinephrine (α-receptors), endothelin, serotonin.

   • Inhibitory: Nitric oxide (NO), epinephrine (β-receptors), prostacyclin.

3. Local Factors:

   • Stretch: Mechanically opens ion channels → depolarization (e.g., bladder, gut).

   • Metabolic Changes: Low O₂, high CO₂, or H⁺ → vasodilation (e.g., in blood vessels).

4. Action Potentials:

   • Spike Potentials: Brief (10–50 ms), triggered by depolarization (e.g., gut peristalsis).

   • Plateau Potentials: Prolonged depolarization (100–1000 ms) → sustained contraction (e.g., uterus, ureter).

   • Slow Waves: Rhythmic depolarizations (pacemaker activity) in visceral smooth muscle (e.g., intestinal motility).

Calcium Signaling in Smooth Muscle

• Sources of Ca²⁺:

  • Extracellular Ca²⁺: Enters via voltage-gated Ca²⁺ channels (L-type) or receptor-operated channels (e.g., IP₃-linked).

  • Sarcoplasmic Reticulum (SR): Releases Ca²⁺ via IP₃ receptors or ryanodine receptors (Ca²⁺-induced Ca²⁺ release).

• Calcium Removal:

  • Ca²⁺-ATPase pumps Ca²⁺ back into SR or extracellular fluid.

  • Na⁺/Ca²⁺ exchanger (secondary active transport).

Smooth Muscle Contraction - Unique Features

• Stress-Relaxation/Reverse Stress-Relaxation

  • Adjusts tension in hollow organs (e.g., bladder, stomach) to maintain pressure despite volume changes.

  • Example: Bladder fills → smooth muscle stretches → contracts briefly, then relaxes to accommodate more urine.

• Plasticity: Adapts to length changes without changing tension (critical for organs like the uterus during pregnancy).

• Energy Efficiency: Uses 1/10 to 1/300 the ATP of skeletal muscle (due to slow cycling and latch state).

• Pharmacomechanical Coupling: Hormones (e.g., adrenaline) modulate contraction without depolarization.

Smooth Muscle Contraction - Excitation Pathways

1. Depolarization-Driven:

   • Action potentials → open voltage-gated Ca²⁺ channels → Ca²⁺ influx → contraction.

2. Pharmacomechanical Coupling:

   • Hormones/neurotransmitters → activate G-protein-coupled receptors (GPCRs) →

     • IP₃ pathway: Releases Ca²⁺ from SR.

     • Rho-kinase pathway: Inhibits myosin phosphatase → prolongs contraction.

3. Stretch Activation:

   • Mechanical stretch → opens stretch-activated channels → depolarization → Ca²⁺ entry.

Key Differences: Skeletal vs. Smooth Muscle

Smooth Muscle Disorders

• Hypertension: Overactivation of vascular smooth muscle (e.g., angiotensin II, endothelin).

• Asthma: Bronchial smooth muscle contraction (treated with β₂-agonists like albuterol).

• Erectile Dysfunction: Smooth muscle relaxation in penile arteries mediated by NO (treated with PDE5 inhibitors like sildenafil).

• Tocolytics: Drugs that relax uterine smooth muscle (e.g., magnesium sulfate to delay preterm labor).