Skeletal Muscle Contraction Lecture Flashcards

Clinical Context and Neuromuscular Integration

  • Link to Multiple Sclerosis (MS):

    • MS is characterized by degeneration in the Central Nervous System (CNS), which disrupts the control of muscle function.

    • Understanding the link between a CNS disorder and peripheral signs/symptoms requires a deep knowledge of the muscle contraction process.

  • Coordination of Movement:

    • Movement depends on coordinated muscle activity, specifically the reciprocal action of flexors and extensors.

    • Smooth Movement Example: Flexors contract while Extensors relax.

    • Neural to Peripheral Pathway: CNS (neural) $\rightarrow$ Muscle (peripheral) $\rightarrow$ Muscle contracts.

    • Consequences of Disruption: Disruption in neural output leads to muscle weakness and spasms (common in MS).

  • Higher Center Involvement:

    • The cerebellum and cerebral cortex act in conjugation to regulate coordination.

    • Failure of these systems results in complete incoordination, lack of balance, and trouble walking, clinically referred to as Ataxia.

Macroscopic Structure of Skeletal Muscle

  • Hierarchical Organization:

    • Muscle Belly: Contains the bulk of the muscle cells/fibers.

    • Epimysium: The outermost fibrous covering of the entire muscle.

    • Fascicle: A bundle of muscle fibers.

    • Perimysium: The connective tissue layer that surrounds each fascicle.

    • Muscle Fiber (Cell): Individual multinucleated cells within the fascicle.

    • Endomysium: The connective tissue layer surrounding individual muscle fibers.

    • Sarcolemma: The plasma membrane of the muscle fiber.

    • Tendon Attachment: Point where the muscle attaches to the bone.

  • Internal Components:

    • Nuclei: Located peripherally in the fiber.

    • Capillaries: Supply blood for oxygen and nutrients.

    • Myofibrils: Long chains of sarcomeres within the muscle fiber.

    • Myofilaments: The individual contractile proteins (Actin and Myosin).

Microscopic Structure: The Sarcomere

  • Definition: The sarcomere is the basic functional and contractile unit of the myofibril.

  • Structural Landmarks (E-M Appearance):

    • Z-line (Z-disk): Boundaries of a single sarcomere; contains Desmin and $\alpha$-Actinin.

    • M-line: The center point of the sarcomere; contains Myomesin.

    • A-band (Anisotrophic): The dark band containing the full length of the thick filaments (Myosin). Length remains constant during contraction.

    • I-band (Isotrophic): The light band containing only thin filaments (Actin). Length decreases during contraction.

    • H-zone: The central part of the A-band containing only thick filaments (no actin overlap). Length decreases during contraction.

  • Structural Proteins and Anchoring:

    • Desmin: Scaffolds and supports the Z-line.

    • Titin: A large elastic protein that anchors Myosin to the Z-line.

    • $\alpha$-Actinin: Specifically anchors Actin filaments to the Z-line.

    • Myomesin: Anchors the tail of Myosin to form the M-line.

  • Contraction Summary (Sliding Filament Theory):

    • The distance between Z-lines decreases.

    • The H-zone and I-band shorten.

    • The A-band length stays the same.

Molecular Composition of Myofilaments

  • Thin Filament (Actin Complex):

    • G-actin: Globular actin molecules, each possessing one myosin-binding site.

    • F-actin: Fibrous actin strands formed by the polymerization of G-actin molecules. Two F-actin strands wind together in a double helix.

    • Tropomyosin: Long filaments that wind around the F-actin double helix, blocking the myosin-binding sites on actin during rest.

    • Troponin Complex: Works in concert with tropomyosin and consists of three subunits:

      1. Troponin T (Tp-T): Binds to tropomyosin.

      2. Troponin I (Tp-I): Binds to actin and inhibits the actin-myosin interaction.

      3. Troponin C (Tp-C): Provides a binding site for Calcium ions (Ca2+Ca^{2+}).

  • Thick Filament (Myosin Complex):

    • Myosin II: The specific protein subtype in skeletal muscle.

    • Heavy Chains (Two): Form the rod-like tail, the hinge region, and the globular head.

      • The head contains the ATPase activity and the actin-binding site.

    • Light Chains (Four):

      1. Alkaline Light Chains: Responsbile for stabilizing the myosin head.

      2. Regulatory Light Chains: Regulate ATPase activity.

    • Bipolar Arrangement: Myosin molecules are arranged tail-to-tail in the center, which is critical for drawing Z-lines toward the M-line during contraction.

Neurotransmission and Excitation-Contraction (E-C) Coupling

  • Recap of NMJ Transmission:

    1. An Action Potential (AP) invades the motor axon terminal.

    2. Depolarization triggers voltage-gated Ca2+Ca^{2+} channels.

    3. Ca2+Ca^{2+} influx causes exocytosis of Acetylcholine (ACh).

    4. ACh binds to nicotinic receptors on the motor end plate, opening Na+Na^+ channels.

    5. End Plate Potential (EPP) is generated.

    6. The EPP triggers a muscle AP via voltage-gated Na+Na^+ channels near junctional folds.

  • The T-Tubule and Sarcoplasmic Reticulum (SR) System:

    • T-tubules: Deep invaginations of the muscle membrane (sarcolemma) that penetrate into the fiber to deliver the AP to each myofibril.

    • Sarcoplasmic Reticulum (SR): Internal membrane system surrounding myofibrils that stores high concentrations of Ca2+Ca^{2+}.

    • Terminal Cisternae (TC): Enlarged regions of the SR near the T-tubules.

  • The Triad:

    • Consists of one T-tubule flanked by two Terminal Cisternae.

    • Located at the A-I Junction in skeletal muscle (two triads per sarcomere).

  • Calcium Release Mechanism:

    • Electromechanical Coupling: The linkage between the T-tubule membrane and the SR is mechanical in skeletal muscle.

    • Voltage-sensitive channel: Located on the T-tubule sarcolemma (L-type/DHPR).

    • SR Calcium channel: Known as the Ryanodine Receptor (RyR) or Ca2+Ca^{2+}-release channel.

    • CICR (Calcium Induced Calcium Release): A process where small amounts of calcium trigger the release of larger amounts (though skeletal muscle relies heavily on the mechanical linkage).

The Cross Bridge Cycle (Mechanism of Contraction)

  • The Role of Calcium (Ca2+Ca^{2+}):

    • Normal intracellular [Ca^{2+}] < 0.01\,\mu m.

    • Following AP, [Ca^{2+}] > 0.01\,\mu m.

    • Ca2+Ca^{2+} binds to the Tp-C subunit, causing a conformational change in the Troponin-Tropomyosin complex.

    • Tp-I weakens its bind to actin, and Tropomyosin moves laterally to uncover the active myosin-binding sites on actin.

  • Step-by-Step Cycle:

    1. Pre-binding/Cocked State: ATP is cleaved (hydrolyzed) to ADP and Inorganic Phosphate (PiP_i) by myosin ATPase. The energy is stored; the head is extended (90∘90^\circ) but not attached because tropomyosin still blocks the sites.

    2. Cross Bridge Formation: Elevated Ca2+Ca^{2+} uncovers active sites. Myosin head binds to actin. The hinge region allows the head to pull upward.

    3. Power Stroke: A conformational change occurs where the myosin head tilts from 90∘90^\circ to 45∘45^\circ. This pulls the actin filament toward the M-line. PiP_i is released first, followed by ADP.

    4. Detachment: A new ATP molecule binds to the myosin head. Because of the strong repelling nature of the ATP-bound state, the myosin head detaches from actin.

    5. Recycling: If Ca2+Ca^{2+} and ATP remain available, the cycle repeats as ATP is hydrolyzed again to return the head to the cocked state.

  • Rigor State: A state where myosin is tightly bound to actin in the absence of ATP (as seen in rigor mortis).

Muscle Relaxation and Bioenergetics

  • Mechanism of Relaxation:

    • Calcium must be removed from the sarcoplasm for contraction to end.

    • SERCA (Sarcoplasmic Reticulum Calcium ATPase): A pump that actively transports Ca2+Ca^{2+} back into the SR.

    • Other mechanisms: Calcium is also extruded from the cell via the Sodium-Calcium exchanger (Na+Na^+/Ca2+Ca^{2+}) or a plasma membrane calcium pump.

    • This process is active and requires a significant amount of ATP.

  • Maintaining ATP Pools (The CP-CPK System):

    • Contraction depletes the reserve of high-energy phosphate bonds.

    • Creatine Phosphate (CP) and Creatine Phosphokinase (CPK): CPK helps transfer a phosphate group from CP to ADP to rapidly regenerate ATP.

    • Creatinine: A byproduct of this reaction which serves as a clinical marker for renal function.

Summary of Key Physiological Steps

  • AP travels down T-tubules $\rightarrow$ triggers Ca2+Ca^{2+} release from SR.

  • Ca2+Ca^{2+} binds Troponin C $\rightarrow$ Tropomyosin shifts $\rightarrow$ Actin sites exposed.

  • Myosin heads (hydrolyzed ATP) bind Actin $\rightarrow$ Power stroke (PiP_i/ADP release).

  • New ATP binds $\rightarrow$ Myosin detaches $\rightarrow$ ATP hydrolysis resets the head.

  • Relaxation requires ATPase (SERCA) to return Ca2+Ca^{2+} to the SR.