Sliding Filament Hypothesis and Muscle Contraction

Introduction

• Proposed by Hugh Huxley and Andrew Huxley (1954).
• Explains how muscles contract through the interaction of actin and myosin.

Overview of Muscle Structure

• Hierarchical Organization: Muscle → Fascicles → Muscle Fibers → Myofibrils → Sarcomeres.
• Sarcomere: The functional unit of muscle contraction, extending between two Z-discs.
  • A-band: Contains thick filaments (myosin).
  • I-band: Contains only thin filaments (actin).
  • H-zone: Central region of A-band with only thick filaments.

The Sliding Filament Hypothesis

• Core Principle: Muscle contraction occurs when thin filaments (actin) slide past thick filaments (myosin).
• Key Observation: Sarcomere shortens, but individual filaments maintain their original length.

Molecular Components

• Actin (Thin Filaments):
  • F-actin: Double helix of G-actin monomers.
  • Associated Proteins: Tropomyosin (blocks myosin-binding sites) and Troponin (binds calcium).
• Myosin (Thick Filaments):
  • Myosin Head: Contains actin-binding site and ATPase activity.

The Cross-Bridge Cycle

1. Cross-Bridge Formation: Myosin head (high-energy state) binds to actin (after Ca²⁺ exposes sites).
2. Power Stroke: ADP and Pi release, myosin head pivots, pulling actin filament.
3. ATP Binding & Detachment: New ATP binds to myosin, causing detachment from actin.
4. ATP Hydrolysis & Reset: ATP is hydrolyzed, re-cocking the myosin head for the next cycle.

Regulation of Muscle Contraction

• Calcium-Mediated Regulation (Excitation-Contraction Coupling):
  1. Action potential in sarcolemma and T-tubules.
  2. Sarcoplasmic reticulum releases Ca²⁺.
  3. Ca²⁺ binds to Troponin C, causing Tropomyosin to shift.
  4. Myosin-binding sites on actin are exposed, initiating cross-bridge cycling.
• Relaxation: Ca²⁺ is actively pumped back into the sarcoplasmic reticulum, and Tropomyosin re-blocks binding sites.

Energy Requirements

• ATP Functions:
  1. Cross-bridge cycling (myosin head movement).
  2. Calcium reuptake into sarcoplasmic reticulum.
  3. Maintaining membrane potential (Na⁺-K⁺ pump).
• Energy Sources: Phosphocreatine, Glycolysis, Oxidative Phosphorylation.

Clinical Significance

• Muscle Disorders: Muscular dystrophies (defects in structural proteins), Myosin myopathies, Actin myopathies.
• Rigor Mortis: Stiffening after death due to ATP depletion, preventing cross-bridge detachment.
• Pharmacological Targets: Calcium channel blockers, Troponin inhibitors, Myosin inhibitors.