ME

Muscle Physiology Quick Reference (NMJ, Skeletal, Cardiac, Smooth)

Neuromuscular Junction (NMJ)

  • Definition: Synapse between a motor neuron and a skeletal muscle fiber. Key components: presynaptic terminal (contains ACh vesicles), synaptic cleft, postsynaptic membrane (motor end plate with nicotinic ACh receptors).

NMJ Signaling Cascade

  • 1. Action potential arrives at the axon terminal.
  • 2. Voltage-gated Ca^{2+} channels open.
  • 3. Acetylcholine (ACh) released into synaptic cleft by exocytosis.
  • 4. ACh binds nicotinic receptors → Na^{+} influx and K^{+} efflux → depolarization.
  • 5. End plate potential leads to muscle action potential.
  • 6. ACh degraded by acetylcholinesterase to choline and acetate; ~50% choline returned to presynapse via Na+-choline cotransporter.

Myasthenia Gravis

  • Autoimmune disease with antibodies against ACh receptors at the NMJ.
  • Mechanism: receptor internalization and destruction → reduced receptor availability → muscle weakness.
  • Diagnosis: Repetitive nerve stimulation (decreased CMAP amplitude); Tensilon test (short-acting acetylcholinesterase inhibitor).
  • Treatments: IV immunoglobulin therapy; plasma exchange; thymus removal.

Botulinum Toxin and Curare (NMJ Agents)

  • Botulinum toxin: protease that cleaves SNARE proteins, blocking exocytosis and ACh release; causes skeletal muscle paralysis; treatment with horse-derived antitoxin in early exposure.
  • Curare: competitive antagonist at nicotinic ACh receptors; prevents ACh binding; causes paralysis.
  • D-tubocurarine: used to induce skeletal muscle relaxation during anesthesia.
  • AChE inhibitors: prolong ACh action (used in myasthenia gravis).
  • Hemicholinium: blocks choline reuptake, depleting ACh synthesis.

Agents that Alter Neuromuscular Junction Function

  • Botulinus toxin: blocks Ach release → paralysis, respiratory failure.
  • Curare: competes with Ach at nicotinic receptors → paralysis.
  • D-tubocurarine: therapeutic muscle relaxation during anesthesia.
  • AChE inhibitors: prevent Ach degradation to enhance NMJ signaling (MG treatment).
  • Hemicholinium: reduces Ach synthesis by blocking choline reuptake.

Skeletal Muscle: Structure and Hierarchy

  • Muscle hierarchy: Organ (whole muscle) → Fascicle (bundle) → Muscle fiber (cell) → Myofibril (subcellular) → Sarcomere (contractile unit).
  • Connective tissue:
    • Epimysium surrounds the whole muscle.
    • Perimysium surrounds a fascicle.
    • Endomysium surrounds a single muscle fiber.
  • Innervation and perfusion are essential for function.

Skeletal Muscle Structure: Key Components

  • Sarcolemma: plasma membrane of a muscle fiber.
  • Sarcoplasm: cytoplasm rich in glycogen and myoglobin.
  • Sarcoplasmic reticulum (SR): stores Ca^{2+}.
  • T-tubules: transmit action potentials into the cell.

Myofibrils and Sarcomeres

  • Myofibrils contain repeating sarcomeres; sarcomere is the functional unit of contraction.

Sarcomere Architecture

  • Delineated by Z disks; contain A-band (thick filaments in center) and I-band (thin filaments).
  • H-zone: center region with no thin filaments; M-line: center of sarcomere anchoring thick filaments.
  • Z-disks define sacromere boundaries.

Myofilaments (Molecular Level)

  • Thin filaments: Actin, Tropomyosin, Troponin (TnT binds tropomyosin; TnC binds Ca^{2+}; TnI inhibits actin-myosin binding).
  • Thick filaments: Myosin with heads that bind actin and hydrolyze ATP; heads have actin-binding and ATPase sites.

Excitation-Contraction Coupling (ECC) - Skeletal

  1. Action potential propagates along the sarcolemma and into T-tubules.
  2. Depolarization activates DHP receptor, opening RyR on SR.
  3. Ca^{2+} released into cytoplasm.
  4. Ca^{2+} binds troponin C, shifting tropomyosin to expose actin-binding sites.
  5. Myosin binds actin → power stroke.
  6. ATP required for cross-bridge detachment and re-cocking of the myosin head.
  7. Ca^{2+} re-sequestered by SERCA pump back into SR.

Excitation-Contraction Coupling: Cardiac and Smooth Differences

  • Smooth muscle uses calmodulin-MLCK system; skeletal/cardiac use troponin-tropomyosin.
  • Cardiac: Ca^{2+}-induced Ca^{2+} release via RyR2; extracellular Ca^{2+} entry contributes; plateau phase helps prevent tetany.
  • Smooth: Ca^{2+} binds calmodulin → MLCK → phosphorylation of myosin light chains → contraction; slower, longer-lasting.

Sliding Filament Theory

  • Mechanism of muscle contraction via cross-bridge cycling between actin and myosin.
    Steps:
  1. Myosin head with ADP+Pi binds exposed actin.
  2. Power stroke; actin moves; sarcomere shortens.
  3. ADP+Pi released.
  4. ATP binds to myosin; cross-bridge detaches.
  5. ATP hydrolysis re-cocks the myosin head.
  • Note: ATP is required for detachment; no ATP leads to rigor mortis.

Skeletal Muscle Relaxation

  • ACh breakdown by AChE terminates stimulation.
  • Cessation of action potential and Ca^{2+} reuptake terminate contraction.
  • Ca^{2+} unbinds from troponin C; tropomyosin blocks myosin-binding sites.
  • Cross-bridge cycling stops; SR Ca^{2+} reuptake by SERCA uses ATP.
  • Important: ATP is needed for relaxation (SERCA and detachment). Failure to reuptake Ca^{2+} can cause sustained contraction/cramps.

Skeletal Muscle Metabolism

  • ATP is required for cross-bridge cycling and Ca^{2+} reuptake via SERCA.
  • Creatine phosphate provides rapid ATP replenishment; stores near-resting muscle.
  • Anaerobic glycolysis (glucose → 2 ATP + 2 pyruvate) yields lactate; used during high-intensity activity when O_{2} delivery is limited.
  • Oxygen debt: post-exercise O_{2} consumption; aerobic respiration provides most resting/moderate ATP needs.

Skeletal Muscle Fiber Types

  • Type I (Slow twitch): high mitochondria, high myoglobin, oxidative metabolism, fatigue-resistant; endurance uses (e.g., marathon).
  • Type IIa (Fast oxidative): intermediate mitochondrial density; mixed metabolism; moderate fatigue resistance.
  • Type IIb/x (Fast glycolytic): low mitochondria, low myoglobin; anaerobic glycolysis; fatigues quickly; sprint/weightlifting.

Skeletal Muscle Contraction Types

  • Isotonic: muscle changes length.
    • Concentric: shortens.
    • Eccentric: lengthens while contracting.
  • Isometric: tension without length change.

Malignant Hyperthermia

  • Autosomal dominant.
  • Hypermetabolic response to volatile anesthetics or succinylcholine.
  • Mutations in DHP receptors (sense AP in T-tubules) or RYR1 (Ca^{2+} release from SR).
  • Consequences: ↑ metabolism, ↓ ATP, ↑ O{2} consumption and CO{2} production, lactic acidosis, heat, muscle rigidity, potential organ failure.

Duchenne Muscular Dystrophy

  • X-linked recessive; dystrophin gene mutation.
  • ↓ Functional dystrophin leads to sarcolemma injury during contraction, triggering inflammation and fibrofatty replacement of muscle tissue.
  • Dystrophin transfers force from the cytoskeleton to the cell membrane and acts as a scaffold for membrane-associated proteins.

Cardiac Muscle Structure and Physiology

  • Striated like skeletal muscle but involuntary; branched fibers; 1–2 central nuclei.
  • Intercalated discs contain desmosomes (mechanical) and gap junctions (electrical connectivity) → syncytium.
  • Rich in mitochondria; fatigue-resistant.
  • No motor neuron input; intrinsic pacemaker activity present.

Cardiac Action Potential (Contractile Cell AP)

  • Phase 0: Na^{+} influx (depolarization).
  • Phase 1: Brief K^{+} efflux (notch).
  • Phase 2: Plateau; Ca^{2+} influx via L-type channels + K^{+} efflux.
  • Phase 3: Repolarization (K^{+} efflux).
  • Phase 4: Resting potential.
  • Note: Plateau phase prolongs contraction to prevent tetany.

Cardiac Pacemaker Activity

  • SA node is the natural pacemaker and has the highest rate of spontaneous depolarization.
  • AP in pacemaker cells: Phase 4 spontaneous depolarization via funny current (If) → Na^{+} leak; Phase 0 Ca^{2+} influx (not Na); Phase 3 K^{+} efflux → repolarization.

Cardiac Regulation by Autonomic Nervous System

  • Sympathetic: β1 receptors ↑ cAMP → ↑ Ca^{2+} influx → ↑ heart rate and contractility; β-blockers (e.g., metoprolol) reduce HR/contractility.
  • Parasympathetic: M receptors (ACh) → opens K^{+} channels → ↓ heart rate via hyperpolarization of SA node.
  • Hormones: Epinephrine increases HR and contractility; thyroid hormone ↑ β1 receptor density.

Excitation-Contraction Coupling in Cardiac Muscle

  1. Action potential reaches cardiac myocyte.
  2. L-type Ca^{2+} channels open → Ca^{2+} influx from ECF.
  3. Calcium-induced Ca^{2+} release (from SR via RyR2).
  4. Ca^{2+} binds troponin C → exposes actin binding sites → cross-bridge cycling begins.
  5. Relaxation: Ca^{2+} removed by SERCA (into SR), NCX (Na^{+}/Ca^{2+} exchanger) into ECF, and PMCA (minor role).
  • Note: Cardiac muscle requires extracellular Ca^{2+} for contraction.

Cardiac Relaxation

  • Repolarization ends the AP (Phase 3).
  • Cytosolic Ca^{2+} must be removed to end contraction: SERCA, NCX, PMCA.
  • Troponin-tropomyosin blocks binding sites as Ca^{2+} detaches; cross-bridges detach with ATP.
  • Beta-adrenergic stimulation enhances relaxation by increasing phospholamban phosphorylation, relieving SERCA inhibition.

Clinical Relevance: Heart Failure, Arrhythmias, Ischemia

  • Heart Failure: impaired contractility → ↓ cardiac output; Digoxin increases intracellular Ca^{2+} by inhibiting Na/K ATPase to boost contractility.
  • Arrhythmias: abnormal pacemaker/conduction; treated with Ca^{2+} or K^{+} channel blockers.
  • Ischemia: ↓ O_{2} → ↓ ATP → impaired ion pumps → arrhythmias and cell death.

Smooth Muscle

  • Found in walls of hollow organs: GI tract, bladder, blood vessels, airways, eyes, uterine, etc.
  • Functional characteristics: slow, tonic contractions or rhythmic (phasic); latch state allows sustained contraction with low energy; highly plastic; fatigue-resistant; can be activated by neural, hormonal, stretch stimuli.

Smooth Muscle Structure and Hierarchy

  • Non-striated, uninucleated, involuntary.
  • Located in walls of hollow organs; no sarcomeres; actin and myosin arranged in crisscross pattern.
  • Gap junctions prominent in unitary (single-unit) smooth muscle; multi-unit smooth muscle fibers act more independently.

Smooth Muscle: Unit Timing and Contraction Types

  • Single-Unit (Unitary): coordinated, synchronous contraction; abundant gap junctions; examples: GI tract, uterus, bladder, small vessels.
  • Multi-Unit: independent fibers; little/no gap junctions; examples: iris, ciliary muscle, piloerector muscles.
  • Stimulus: spontaneous pacemaker activity or stretch; neural/hormonal cues.

Smooth Muscle Excitation-Contraction Coupling

  • Stimuli raise intracellular Ca^{2+}.
  • Ca^{2+} binds calmodulin.
  • Ca^{2+}-calmodulin activates myosin light-chain kinase (MLCK).
  • MLCK phosphorylates myosin → cross-bridge cycling.
  • Relaxation via myosin light-chain phosphatase (MLCP) dephosphorylation; Ca^{2+} removal via pumps/exchangers.
  • Key difference: regulation via MLCK/MLCP rather than troponin/tropomyosin.

Regulation of Smooth Muscle

  • Autonomic Nervous System: sympathetic NE via α1 → vasoconstriction; β2→ bronchodilation and uterine relaxation; parasympathetic via ACh mainly contracts in gut (M receptors).
  • Hormonal: oxytocin → uterine contraction; vasopressin/angiotensin II → vascular constriction.
  • Local factors: decreased O2, increased CO2, decreased pH → vasodilation; NO → NO/cGMP → relaxation.
  • Mechanical stretch also affects tone (myogenic response).

Clinical Relevance: Smooth Muscle

  • Asthma: bronchodilation via β2 agonists (e.g., albuterol).
  • Preterm labor: tocolytics inhibit uterine smooth muscle contraction.
  • Hypertension: vascular smooth muscle tone; treated with Ca^{2+} channel blockers or NO donors.
  • GI motility disorders: smooth muscle dysregulation (e.g., IBS, achalasia).

Practice Questions

  • (Practice questions provided in material)