Lecture 7

Molecular Participants in Skeletal Muscle Contraction

• Molecular Participants:

  • Sliding Filament Theory: Describes how skeletal muscle contracts.

    • Involves 5 molecules and calcium.

      • Myosin: Forms thick filaments.

      • Actin: Primary protein in thin filaments.

      • Tropomyosin: Regulatory protein that binds to actin.

      • Troponin: Binds actin and tropomyosin; site of calcium binding.

      • ATP: Energy source for muscle contraction.

      • Calcium ions: Released from the sarcoplasmic reticulum.

Myosin

• Myofibrils are made of sarcomeres, which are composed of the myofilaments (thick and thin filaments).

• Sarcomeres extend between two adjacent Z-lines.

• In skeletal muscle cells, myosin molecules bundle to form thick filaments.

• Myosin molecules have a long tail with 2 globular heads.

  • Globular heads are cross-bridges.

  • Cross-bridges move back and forth.

  • The flexing movement of the head provides the power stroke.

• The cross-bridge has two binding sites:

  • One site binds ATP, the other binds Actin.

  • The actin binding site is on the top of the globular head, and the ATP binding site is at the base.

• Myosin exists in two states:

  • Low energy state: The head is bent, and myosin is bound to ATP.

  • High energy state: Myosin hydrolyzes ATP, becoming bound to ADP and inorganic phosphate. The head position changes to a flat position

Thin Filament

• Actin is the major component and has a binding site for myosin.

• Two other molecules associated with thin filaments:

  • Tropomyosin: A double helical strand that wraps around actin, covering myosin binding sites.

    • In unstimulated muscle, tropomyosin covers actin's binding sites, preventing myosin interaction.

  • Troponin: Attached to tropomyosin at regular intervals.

    • Troponin has a binding site for calcium.

    • Calcium binding to troponin moves tropomyosin, exposing myosin binding sites on actin.

    • Calcium is released from the sarcoplasmic reticulum after an action potential.

Cross-bridge Cycling

• Cross-bridge cycling is the process where myosin binds to actin, causing muscle contraction.

• Muscle action potential propagates through the T-tubule system, causing calcium release from the sarcoplasmic reticulum into the cytosol.

• Calcium is released due to the coupling of the dihydropyridine receptor (voltage-gated $Ca^{2+}$ channel) with the ryanodine receptor.

• Six Steps of Cross-bridge Cycling:

  • Exposure of binding sites: Action potential releases calcium from the sarcoplasmic reticulum

    • Calcium binds to troponin, causing a conformational change in the troponin-tropomyosin complex and exposing myosin binding sites on actin.

    • Myosin must be in its high-energy state to bind to actin; ATP is hydrolyzed into ADP and inorganic phosphate.

  • Myosin binds to actin: The energized myosin cross-bridge binds to the binding site on actin.

  • The power stroke: The myosin head pivots, shortening the H-zone and pushing the actin molecule toward the middle of the sarcomere.

    • ADP and inorganic phosphate are released from the myosin head.

  • Myosin releases from actin: ATP binds to its binding site on the myosin head, causing a conformational change that releases myosin from actin.

  • Re-energizing the cross-bridge: ATP is hydrolyzed into ADP and inorganic phosphate, tilting the myosin head back into its high-energy state, ready to bind to actin again.

    • ATP binding is essential for the release of the myosin cross-bridge from actin.

    • ATP hydrolysis is essential for re-energizing and re-positioning the myosin molecule.

  • Removal of calcium ions: Calcium ions are released from troponin and actively transported back into the sarcoplasmic reticulum via ion pumps.

    • When calcium ions are released from troponin, the troponin/tropomyosin complex covers the binding sites on actin again.

    • Muscle contraction stops due to the absence of calcium ions.

    • At the neuromuscular junction, only acetylcholine is released, which is always excitatory; there is no inhibitory neurotransmitter.

Multiple Cross-bridge Cycles

• Many myosin molecules are in the high-energy state and ready to bind to actin at any given time.

  • The number of myosin molecules participating in contraction can vary, affecting the intensity and duration of the muscle contraction.

    • More ATP results in more energized myosin molecules, leading to longer duration and larger amplitude contractions.

    • Less ATP results in fewer energized myosin molecules, leading to shorter duration and smaller amplitude contractions.

• During contraction, cross-bridges are not all bound or disconnected simultaneously.

Calcium Pumps

• Calcium moves back into the sarcoplasmic reticulum from the cytosol after muscle contraction is completed.

  • Calcium is taken back up via an active transport pump, which requires ATP.

Role of ATP

• ATP plays an important role in the muscle cell by:

  • Energizing the power stroke of the myosin cross-bridge.

  • Disconnecting the myosin cross-bridge from its binding site on actin at the conclusion of a power stroke.

  • Pumping $Ca^{2+}$ back into the sarcoplasmic reticulum.

Metabolic Variations of Muscle Fiber Types

• Two main types of muscle fibers: white muscle fibers and red muscle fibers.

  • Differ in size, coloration, and mechanisms for synthesizing ATP.

• Myoglobin: The primary oxygen-carrying protein of muscle tissues.

• Capillaries: Bring oxygen to the muscle cells.

• Mitochondria: Require oxygen brought by blood capillaries to make ATP.

• Glycogen: The storage form of glucose; broken down to release glucose.

• Glycolysis: Uses glucose to make ATP in the absence of oxygen (anaerobic).

• Muscle Fiber Type Characteristics:

  • Red Muscle Fibers:

    • Also called: Slow-twitch fibers

    • Used for: Long-lasting continuous contractions

    • Size: Half the diameter of white muscle fibers

    • Myoglobin: Large quantity of myoglobin

    • Blood supply: High blood supply (many capillaries)

    • Mitochondria: Numerous mitochondria

    • Glycogen Content: Low glycogen content (use aerobic processes)

    • Process used to make ATP: Krebs cycle and oxidative phosphorylation (aerobic processes)

    • Speed of cross-bridge cycling: Cross-bridge cycling occurs relatively slowly

    • Fatigue: Fatigue resistance and high endurance

  • White Muscle Fibers:

    • Also called: Fast-twitch fibers

    • Used for: Intense but short-lasting contractions

    • Size: Large diameter

    • Myoglobin: Reduced myoglobin

    • Blood supply: Poor blood supply (few capillaries)

    • Mitochondria: Few mitochondria

    • Glycogen Content: High glycogen content

    • Process used to make ATP: Glycolysis (anaerobic process)

    • Speed of cross-bridge cycling: Rapid cross-bridge cycling results in fast contractions

    • Fatigue: Fatigue rapidly due to the build-up of lactic acid and glycogen