Guyton and Hall - Chapters 6, 7 & 8: Muscle Physiology

CHAPTER 6 - Contraction of Skeletal Muscle

1. Physiological Anatomy of Skeletal Muscle

• Muscle fiber (cell): 10-80 micrometers in diameter, usually spanning the full length of the muscle. Each fiber is innervated by a single nerve ending located near its midpoint.
• Sarcolemma: The muscle cell membrane. It has a true plasma membrane plus an outer polysaccharide coat embedded with collagen fibrils. At each end the sarcolemma fuses with tendons, which connect to bone.
• Myofibrils: Each fiber contains hundreds to thousands of myofibrils. Each myofibril contains ~1,500 myosin (thick) filaments and ~3,000 actin (thin) filaments.
• Banding pattern: Where actin and myosin overlap, the filaments create alternating light (I) bands (actin only, isotropic) and dark (A) bands (myosin + overlapping actin ends, anisotropic). This gives skeletal and cardiac muscle their striated appearance.
• Z disk: Actin filaments attach at each end to a Z disk. The region between two successive Z disks is one sarcomere - the fundamental contractile unit, about 2 micrometers long at full contraction.
• M line: A protein disc at the center of each sarcomere that holds myosin filaments in place.
• Titin: Giant elastic filament running from Z disk to M line that holds myosin in position and gives the sarcomere passive spring-like properties, preventing overstretching.

2. Sliding Filament Mechanism

3. Molecular Mechanisms of Contraction

• Each myosin molecule (MW ~480,000) has two heavy chains (wound as a double helix forming the "tail") and four light chains. One end of each heavy chain folds into a globular myosin head (cross-bridge).
• The heads have ATPase activity - they cleave ATP to generate force.
• In the filament, heads project outward in a helical array, with bare zones in the center.

• Two strands of F-actin (polymerized G-actin monomers) wound in a double helix.
• On each actin strand, tropomyosin threads along the groove, and at every 7 actin monomers sits the troponin complex (troponin I, T, and C).
• At rest, tropomyosin physically blocks the active sites on actin, preventing cross-bridge binding.

1. At rest (no Ca²+): tropomyosin covers actin active sites. Myosin heads are cocked with ADP + Pi attached (energized state).
2. Ca²+ release: Ca²+ binds troponin C, causing a conformational change that shifts tropomyosin away from actin's active sites.
3. Cross-bridge attachment: Energized myosin heads bind to exposed actin sites.
4. Power stroke: The heads tilt ~45°, pulling the actin filament toward the M line. ADP + Pi are released.
5. ATP binding: New ATP binds to the myosin head, causing it to detach from actin.
6. Re-energizing: ATP is hydrolyzed back to ADP + Pi, re-cocking the head ready for the next cycle.
7. This cycle repeats as long as Ca²+ is present and ATP is available.

• Stored in the sarcoplasmic reticulum (SR), which wraps around every myofibril.
• Released upon action potential arrival. Ca²+ diffuses to troponin C, initiating contraction.
• After the signal stops, the SR actively pumps Ca²+ back via Ca²+-ATPase, relaxing the muscle.

4. Amount of Overlap Determines Force

• Optimal overlap (~2 µm sarcomere length): Maximum number of cross-bridges engaged - greatest force.
• Stretched beyond ~3.65 µm: No overlap - no force.
• Over-compressed (<1.65 µm): Actin filaments from both sides collide, reducing force. This produces the classic length-tension curve.

5. Velocity-Load Relationship

6. Energetics of Muscle Contraction

1. ATP (stored): ~4 mM in the fiber - sufficient for only 1-2 seconds of maximal contraction.
2. Phosphocreatine (PCr): Instantly reconstitutes ATP via creatine kinase. About 5× more abundant than ATP. Together, ATP + PCr sustain maximal contraction for 5-8 seconds.
3. Glycolysis: Rapid anaerobic breakdown of stored glycogen. Produces ATP quickly but generates lactic acid. Sustains high-intensity exercise for ~1 minute.
4. Oxidative phosphorylation: Aerobic metabolism via the citric acid cycle - the most efficient source, sustaining prolonged activity.

7. Characteristics of Whole Muscle Contraction

• Twitch: A single muscle fiber action potential causes a brief contraction-relaxation cycle.
• Summation: When a second stimulus arrives before relaxation is complete, contractions add - this is wave summation (temporal summation).
• Tetanus: At high stimulation frequencies, contractions fuse into a sustained, smooth contraction (complete tetanus). Force in tetanus is 3-4× that of a single twitch.
• Isotonic contraction: Muscle shortens while the load remains constant. The muscle develops tension equal to the load before shortening begins.
• Isometric contraction: Muscle develops tension without changing length (e.g., holding a weight in place). Tension is built in internal elastic components.

8. Motor Unit

• Muscle tension gradation: achieved by (1) recruiting more motor units or (2) increasing firing frequency of active units.
• Asynchronous recruitment of motor units prevents fatigue.

9. Muscle Fiber Types

10. Muscle Hypertrophy, Atrophy, and Repair

• Hypertrophy: Occurs in response to heavy loading. Myofibrils split and new myofibrils are formed within each fiber. Glycolytic enzymes increase. Sarcomeres are added in series when muscles are stretched (length adaptation) and removed when muscles are held shortened.
• Atrophy: Occurs with disuse or denervation. The ubiquitin-proteasome pathway degrades contractile proteins. After ~2 months of denervation, degenerative changes appear; after 1-2 years, recovery is impossible.
• Satellite cells: Adult stem cells residing beneath the basal lamina that are normally quiescent. Muscle injury activates them - they proliferate, differentiate, and fuse to repair damaged fibers. Exercise activates satellite cells; reduced satellite cell function contributes to sarcopenia (age-related muscle loss).

CHAPTER 7 - Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling

1. The Neuromuscular Junction (Motor End Plate)

• The myelinated motor nerve fiber branches near the muscle, with each branch ending in a nerve terminal that invaginates into the muscle fiber surface (but remains outside the plasma membrane).
• The entire structure is called the motor end plate, covered by Schwann cells.
• The invaginated muscle membrane forms the synaptic gutter (trough); the gap between nerve terminal and muscle membrane is the synaptic cleft (20-30 nm wide).
• At the bottom of the synaptic gutter are subneural clefts - numerous smaller membrane folds that greatly increase the surface area for neurotransmitter action.

2. Acetylcholine Synthesis and Storage

• Acetylcholine (ACh) is synthesized in the cytoplasm of the nerve terminal and packaged into synaptic vesicles (~300,000 vesicles per end plate).
• Each vesicle contains several thousand ACh molecules.
• Acetylcholinesterase in the synaptic cleft destroys ACh within milliseconds of release, ensuring a brief, controlled response.

3. ACh Release: Mechanism of Exocytosis

1. Voltage-gated Ca²+ channels in the presynaptic membrane open.
2. Ca²+ flows into the terminal from the synaptic cleft.
3. Ca²+ activates Ca²+-calmodulin-dependent protein kinase, which phosphorylates synapsin proteins anchoring vesicles to the cytoskeleton.
4. Freed vesicles move to active zones adjacent to dense bars on the inner presynaptic membrane.
5. Vesicles dock, fuse with the membrane, and release ACh by exocytosis - approximately 125 vesicles per action potential.

4. ACh Action on the Muscle Membrane

• ACh binds to nicotinic ACh receptors (ligand-gated ion channels) located at the mouths of the subneural clefts.
• Each receptor is a pentameric ion channel; binding of 2 ACh molecules opens the channel.
• The channel is non-selective for cations - both Na⁺ and K⁺ flow, but net Na⁺ inflow dominates, causing a local end-plate potential (EPP).
• The EPP is large enough (typically 50-75 mV depolarization) to far exceed the threshold for firing a muscle action potential (~-55 mV).
• This initiates an action potential that propagates along the entire muscle fiber in both directions.

5. Safety Factor of Neuromuscular Transmission

• Myasthenia gravis: Autoantibodies against nicotinic ACh receptors - reduced EPP amplitude, muscle weakness and fatigue.
• Lambert-Eaton syndrome: Autoantibodies against presynaptic Ca²+ channels - reduced ACh release.
• Botulinum toxin: Blocks ACh vesicle exocytosis.
• Curare (d-tubocurarine): Competes with ACh for receptor binding.
• Organophosphates (nerve agents, insecticides): Inhibit acetylcholinesterase, causing sustained depolarization and paralysis.
• Neostigmine: Anticholinesterase used therapeutically in myasthenia gravis.

6. Excitation-Contraction (E-C) Coupling

• The muscle fiber membrane sends deep invaginations into the fiber called transverse tubules (T-tubules), which run perpendicular to the myofibrils.
• T-tubules carry the action potential deep into the fiber, reaching every sarcomere simultaneously.
• Where T-tubules contact the sarcoplasmic reticulum (SR), they form triads (one T-tubule flanked by two SR terminal cisternae).

• The T-tubule membrane contains dihydropyridine (DHP) receptors (voltage sensors/L-type Ca²+ channels).
• When depolarization reaches the T-tubule, DHP receptors change conformation and mechanically activate ryanodine receptors (RyR1) on the SR membrane.
• RyR1 opens, releasing a massive burst of Ca²+ from the SR terminal cisternae into the sarcoplasm.
• Ca²+ diffuses to the myofibrils within 1-2 milliseconds and binds troponin C, triggering contraction (see Chapter 6 mechanism).

• After the action potential ends, DHP receptors close, RyR1 closes.
• The SR membrane contains Ca²+-ATPase (SERCA) pumps that actively pump Ca²+ back into the SR against its concentration gradient.
• When sarcoplasmic Ca²+ falls below ~10⁻⁷ M, troponin C releases Ca²+, tropomyosin re-covers actin, and cross-bridge cycling stops - the muscle relaxes.

CHAPTER 8 - Excitation and Contraction of Smooth Muscle

1. Basic Properties of Smooth Muscle

2. Types of Smooth Muscle

• Individual fibers operate independently, each innervated by its own nerve ending.
• Surrounded by basement membrane-like material that electrically insulates fibers from each other.
• Control is predominantly neural.
• Examples: ciliary muscle of the eye, iris, piloerector muscles.

• Hundreds to thousands of fibers contract as a single unit.
• Adjacent cells are connected by gap junctions (connexins), allowing free flow of ions and action potentials from cell to cell - behaves as a syncytium.
• Cells are also adherent to each other so mechanical force is transmitted.
• Control involves neural, hormonal, and local chemical inputs.
• Found in: GI tract walls, bile ducts, ureters, uterus, most blood vessels.

3. Contractile Mechanism in Smooth Muscle

• Actin and myosin filaments are not organized into regular sarcomeres. Instead, they are arranged obliquely, attaching to dense bodies distributed throughout the cell and on the inner cell membrane. Dense bodies are equivalent to Z disks.
• When smooth muscle contracts, the dense bodies are pulled together, causing the cell to shorten and bulge.

1. Ca²+ enters the cell from the extracellular fluid through voltage-gated or receptor-operated Ca²+ channels, and/or is released from the SR.
2. Ca²+ binds calmodulin (4 Ca²+ per calmodulin).
3. The Ca²+-calmodulin complex activates myosin light chain kinase (MLCK).
4. MLCK phosphorylates the myosin light chains on the myosin head.
5. Phosphorylated myosin can now bind actin and undergo cross-bridge cycling - contraction begins.

• When Ca²+ falls, calmodulin dissociates from MLCK, MLCK becomes inactive.
• Myosin light chain phosphatase dephosphorylates the myosin light chains, stopping cross-bridge cycling.

• A unique feature of smooth muscle: once contracted, myosin cross-bridges can enter a "latch state" - they remain attached to actin with very slow cycling, maintaining force with minimal ATP consumption.
• This is why smooth muscle is ideal for sustained, low-energy contractions (e.g., maintaining vascular tone, holding sphincters closed).

4. Electrical Properties and Action Potentials

• In some smooth muscle, the upstroke is primarily due to Ca²+ influx through voltage-gated Ca²+ channels (not Na⁺ as in skeletal/cardiac muscle). This makes smooth muscle action potentials slower.
• Some smooth muscle (e.g., ureter, uterus) has spike potentials with plateau - the plateau is maintained by slow Ca²+ influx.

• Characteristic of visceral smooth muscle.
• Cyclical, spontaneous oscillations of membrane potential (not action potentials themselves).
• Caused by rhythmic changes in ion pump activity and/or ion channel conductances.
• When slow wave peaks reach threshold (~-35 mV), they trigger action potentials, which cause rhythmic contractions.
• This is the basis of the basic electrical rhythm (BER) of the GI tract, controlling peristalsis.

• Stretching visceral smooth muscle generates action potentials - the combination of slow wave potentials plus membrane depolarization from stretch triggers firing.
• This allows the gut, when overfilled, to automatically contract and push contents forward.

5. Excitation Without Action Potentials

• Multi-unit smooth muscle is too small to generate propagating action potentials. Instead, nerve transmitter (ACh or norepinephrine) causes local depolarization (junctional potential) that spreads electrotonically over the whole fiber - sufficient to trigger contraction.
• ~50% of all smooth muscle contraction is initiated by local chemical factors or hormones acting directly on the contractile machinery without action potentials.

6. Neural, Hormonal, and Local Control of Smooth Muscle

• Smooth muscle is innervated by both sympathetic and parasympathetic nerves.
• Nerve terminals form varicosities that release transmitter en passant along the muscle sheet (not discrete end plates as in skeletal muscle).
• Sympathetic: releases norepinephrine - acts on α or β adrenergic receptors. α₁ generally causes contraction; β₂ causes relaxation.
• Parasympathetic: releases ACh - muscarinic receptors. Generally causes contraction of viscera, relaxation of sphincters.

• Many hormones cause smooth muscle contraction or relaxation by acting on G-protein coupled receptors:
  • Epinephrine (β₂ activation) → relaxes bronchial smooth muscle.
  • Oxytocin → contracts uterine smooth muscle.
  • Angiotensin II → contracts vascular smooth muscle.
  • Histamine → contracts bronchial smooth muscle.

• Hypoxia, increased CO₂, decreased pH, increased K⁺, and adenosine cause vasodilation (relaxation of vascular smooth muscle).
• Local metabolic needs can override neural/hormonal signals to regulate blood flow.

• Produced by endothelial cells. Diffuses into smooth muscle → activates guanylyl cyclase → increases cGMP → activates protein kinase G → dephosphorylates myosin → relaxation.
• Major mechanism of vasodilation.

Key Comparisons Across All Three Chapters