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Detailed Muscle Physiology Notes

Muscle Physiology

Module 4 Overview

  • Module 4 explores how an action potential leads to muscle contraction.

Muscle Contraction

  • Muscle contraction involves the development of tension and the potential shortening of muscle fibers.
  • Skeletal muscle constitutes a significant portion of body mass, approximately 35-40%.

Myofibers

  • Myofibers, or muscle fibers, are formed by the fusion of undifferentiated, mononucleated cells called myoblasts.
  • These are single, cylindrical, multinucleated cells, relatively large and elongated.
  • Adult myofibers range from 20-100 µm in diameter and up to 20 cm in length.
  • Skeletal muscles exhibit striations, which are alternating light and dark bands perpendicular to the long axis when viewed under a microscope.
  • Cardiac and skeletal muscles are categorized as striated muscles.

Muscle Structure

  • Muscle structure is organized in a hierarchical manner:
    • Muscle: bound together by epimysium.
    • Muscle Fascicle: a group of muscle fibres/cells, bound together by perimysium.
    • Muscle Fiber (Myofiber): a single muscle cell, bound together by endomysium.
    • Myofibril: located inside muscle cells.
  • Connective tissue binds cells together to facilitate communication.
  • Tendons are composed of collagen fibres, connecting muscle to bone.

Striations

  • Striations in muscle tissue arise from the arrangement of thick and thin filaments.
  • These filaments are made up of the contractile proteins actin (thin filaments) and myosin (thick filaments).
  • Myofibrils, which constitute 80% of muscle volume, contain these filaments arranged in repeating patterns.
  • The sarcomere is the functional unit of muscle, representing one unit of this repeating pattern.

Sarcomere Structure

  • A band: The wide, dark band in the center of the sarcomere, where thick filaments (myosin) are located.
  • I band: The lighter band between the ends of the A bands, where thin filaments (actin) do not overlap the thick filaments. Thin filaments are anchored to the Z line.
  • Z line: A network of connecting proteins where thin filaments are anchored; defines the boundary of a sarcomere.
  • H zone: The center of the A band, where there is no overlap between thin and thick filaments.
  • The sarcomere is the smallest contractile component of a myofiber.

Filament Anchoring

  • Titin fibers anchor thick filaments (myosin).
  • Actin (thin) filaments are anchored to Z-lines, which consist of anchoring proteins.
  • Titin is the largest protein in the body, containing approximately 27,000 amino acids and having a molecular weight of 3 million daltons.

Regulatory Molecules

  • Tropomyosin and troponin are crucial regulatory molecules that bind to actin filaments.

Cross-Bridges

  • Cross-bridges are portions of myosin molecules that extend toward the thin actin filaments, facilitating muscle contraction.
  • During contraction, thin filaments move toward the center of the sarcomere via the sliding movement.
  • Myosin cross-bridges bind to actin and flex to facilitate sliding.

Actin-Myosin Interaction

  • Each myosin filament can interact with six actin filaments.
  • Each actin filament can interact with three myosin filaments.

Muscle Contraction Mechanism

  • Muscle contraction doesn't always result in muscle shortening.
  • Contraction is the activation of force-generating actin-myosin cross-bridge cycling within muscle fibres.
  • Relaxation occurs after contraction.
  • The sliding-filament mechanism is responsible for muscle contraction, driven by cross-bridge cycling.
  • Force generation shortens skeletal muscle fibres as overlapping thick (myosin) and thin (actin) filaments in each sarcomere move past each other due to cross-bridge movement.
  • The sliding filament mechanism is stimulated by an action potential in skeletal, smooth, and cardiac muscles.
  • Myosin and actin interactions are regulated by calcium ions in all three muscle types.
  • Changes in muscle membrane potential are linked to internal changes in calcium release and subsequent contraction.

Actin Molecule Structure

  • Actin is a globular molecule composed of a single polypeptide chain of amino acids.
  • Actin molecules polymerize to form long actin filaments composed of two intertwined helical chains.
  • Each actin molecule has a binding site for myosin.
  • Regulatory molecules include troponin and tropomyosin.

Troponin

  • In relaxed skeletal muscle, tropomyosin blocks the myosin cross-bridge binding site on actin.
  • Each tropomyosin molecule is held in an inhibitory binding position by the troponin molecule, covering about 7 actin molecules.
  • Troponin consists of three subunits:
    1. T: Interacts with tropomyosin.
    2. I: Inhibitory grip that prevents tropomyosin movement along actin.
    3. C: Binding site for calcium.
  • Tropomyosin and troponin block myosin-actin interaction in resting myofibers.

Myosin Molecule Structure

  • Myosin consists of two large polypeptide heavy chains and four smaller light chains.
  • These chains combine to form a molecule with two globular heads and a long tail.
  • The globular heads form cross-bridges with actin.
  • Each globular head has two binding sites:
    1. One for actin.
    2. One for ATP.
  • The ATP binding site exhibits ATPase activity, providing energy for contraction.
  • Myosin molecules at each end of the thick filament are oriented in opposite directions, allowing cross-bridges to move thin filaments toward the sarcomere center.

Cross-Bridge Cycle Steps

  • Molecular basis of skeletal muscle contraction involves a sequence of events known as the cross-bridge cycle:
    1. Binding between the myosin head and the thin filament.
    2. Movement of the cross-bridge (power stroke).
    3. Detachment of the cross-bridge.
    4. Re-energizing the myosin head for re-attachment.

Sarcomere Changes During Contraction

  • During the transition from a relaxed to a contracted sarcomere:
    • I band: Shortens.
    • H zone: Shortens.
    • A band: Remains the same width.
    • Overall sarcomere length (Z line to Z line): Shortens.

Excitation-Contraction Coupling

  • Calcium initiates cross-bridge cycling following its entry into the cytoplasm; this process is called excitation-contraction coupling.
  • Action potentials trigger cross-bridge cycling through several steps.
  • The transverse tubule (T-tubule) directly links the plasma membrane and lateral sacs.
  • T-tubules run perpendicularly from the muscle cell membrane into the central portion of the muscle fibre.

Role of Calcium

  • Cytosolic calcium concentration is low in relaxed muscle.
  • Action potentials lead to a rapid increase in cytosolic calcium concentration.
  • Calcium is released from the sarcoplasmic reticulum, which is similar to the endoplasmic reticulum and forms sleeve-like segments around each myofibril.
  • Lateral sacs at the end of these segments are connected via smaller tubular elements.
  • A triad consists of a single T-tubule and two lateral sacs, which is essential for excitation-contraction coupling.

T-Tubules and Calcium Release

  • Transverse tubules carry action potentials into the skeletal muscle fibres, passing close to the sarcoplasmic reticulum.
  • T-tubule membrane contains voltage-sensitive Dihydropyridine receptors (DHPR), which activate in response to action potentials.
  • The sarcoplasmic reticulum's meshwork ensures calcium readily diffuses to all troponin sites.
  • Steps:
    1. Action potential reaches the T-tubule from the sarcoplasmic reticulum, opening calcium channels.
    2. Cytosolic calcium concentration increases.
    3. Calcium binds to subunit C, inducing a conformational change in troponin.
    4. The inhibitory grip on tropomyosin is released.
  • DHPR are coupled to ryanodine receptors (Ca2+ release channels) on the sarcoplasmic reticulum, leading to calcium release.

Calcium and Cross-Bridge Binding

  • Opening of voltage-gated calcium channels (ryanodine receptors) on the sarcoplasmic reticulum releases calcium ions into the cytosol, which then bind to troponin.
  • The calcium-troponin complex pulls tropomyosin off the myosin-binding site of actin, allowing cross-bridge binding and subsequent filament sliding.
  • Calcium re-uptake into the SR occurs through SERCA (SarcoEndoplasmic Reticulum Calcium ATPase).

ATP-Powered Cross-Bridging Cycling

  • Resting myofibre exhibits low calcium concentration, precluding actin-myosin interaction.
  • Myosin filament heads (M) are in an energized state due to ATP hydrolysis, with ADP and Pi bound to the cross-bridge.
  • M + ATP => M-ADP-Pi
  • Calcium release allows myosin-binding site on actin to become available, allowing energized myosin heads to bind and form a cross-bridge.
  • M + ATP => M-ADP-Pi => Able to interact with Actin (if tropomyosin removed)

Power Stroke

  • M + ATP => M-ADP-Pi Binding
  • A-M.ADP.Pi
  • Power stroke involves movement of the cross-bridge.
  • Release of ADP+Pi
  • Full hydrolysis and departure of ADP + Pi causes the flexing of the bound cross-bridge.
  • Binding of a “new” ATP to the cross- bridge uncouples it.
  • Hydrolysis of the bound ATP energizes or re-cocks the bridge.

Role of ATP in Muscle Contraction

  • ATP plays a critical role for skeletal muscle contraction
    1. Hydrolysis of ATP by myosin energizes cross-bridges, providing energy for force generation.
    2. Binding of ATP to myosin dissociates cross-bridges bound to actin, allowing cycle repetition.
    3. Hydrolysis of ATP by the Ca^{2+}-ATPase in the sarcoplasmic reticulum actively transports calcium ions into the reticulum, lowering cytosolic calcium, which ends contraction and allows muscle fibre relaxation.
  • Rigor mortis occurs if no ATP is available post-mortem, leading to permanent actin-myosin binding

Skeletal Muscle Activity and Tension

  • An action potential lasts 1-2 msec in a myofiber; mechanical activity is not observable before it ends.
  • The latent period between excitation and tension development includes time for: calcium release from the sarcoplasmic reticulum, tropomyosin movement, and cross-bridge cycling.
  • Mechanical activity lasts about 100 ms.

Muscle Contraction at the Whole-Muscle Level

  • A single action potential in a muscle fibre results in a brief, weak contraction (twitch).
  • Muscle fibres cooperate to produce variable strength contractions via:
    1. Changing the number of contracting fibres (recruitment).
    2. Affecting the tension developed by each contracting fibre (activation rate).
  • Motor unit recruitment activates all muscle fibres within a motor unit.
  • Upon reaching a muscle, the axon branches to form connections with individual fibres at the neuromuscular junction.
  • A motor unit comprises one motor neuron and all the myofibres it innervates.
  • More motor units recruited results in greater total muscle tension.

Asynchronous Recruitment and Fatigue Prevention

  • Muscles contain different fibre types with varying resistance to fatigue.
  • Weak or moderate exercise recruits fatigue-resistant motor units (Type I) first.
  • Different muscles have different numbers and sizes of motor units to vary movement precision.
  • Fingers: fewer fibres per motor unit = greater fine movement control.
  • Back muscles: more fibres per motor unit = less fine movement control.

Motor Unit Recruitment

  • Orderly recruitment of motor units:
    • Minimizes fatigue by activating fatigue-resistant (Type I) muscle fibres first.
    • Larger units are recruited as needed for greater force.
    • Finer control of muscle forces due to weaker units allowing smaller gradation of force.
    • Simplified control of force by the central nervous system (automatic recruitment).
  • Henneman’s size principle: motor units are recruited according to their force output, from smallest to largest.

Frequency of Activation and Muscle Tension

  • Whole muscle tension depends on the number of contracting fibres (i.e., motor unit recruitment) and tension developed by each fibre (frequency of motor unit activation).
  • Factors influencing tension development:
    • Frequency of stimulation.
    • Fibre length at the onset of contraction.
    • Extent of fatigue.
    • Fibre thickness (number of myofibrils/sarcomeres).
  • One action potential results in a twitch.
  • Repetitive stimulation causes temporal summation (similar to EPSP summation).

Twitch Summation and Tetanus

  • Twitch summation is possible because the action potential duration (1-2 msec) is shorter than the twitch duration (100 msec).
  • Fibres can be re-stimulated while still in contraction.
  • Repeated stimulations without relaxation time lead to tetanus.

Muscle Length and Force Development

  • At optimal muscle length, maximum tension can be developed due to optimal thick and thin filament overlap.
  • Greater than optimal length reduces tension linearly by pulling thin filaments out from between thick filaments, decreasing crossbridge formation sites.
  • Less than optimal length decreases tension by overlapping thin filaments, limiting available active sites for crossbridge formation.

Isotonic and Isometric Contractions

  • Muscle tension is the force exerted by a muscle contraction on an object.
  • Muscle load is the force exerted on a muscle by an object.
  • Muscle length changes depend on the balance between tension and load.
  • Tension > load = Shortening.
  • Tension < load = Lengthening.
  • Isometric contraction: Muscle contracts without shortening (constant length).
  • Isotonic contraction: Contraction with constant load/tension.
    • Lengthening (eccentric contraction): Increase in muscle length.
    • Shortening (concentric contraction): Decrease in muscle length.
  • iso = same
  • tonic = tension
  • metric = length

Force-Velocity Relationship

  • The greater the load, the lower the velocity of shortening.
  • Maximal force is produced when velocity is zero (isometric contraction).
  • Maximal power is produced when the optimal load and velocity relationship is determined.
  • Isometric contraction
  • Unloaded shortening velocity (Vmax)
  • Ideal combination of force and velocity which produces maximal power (force x velocity) output

Skeletal Muscle Fiber Types

  • Three fibre types in human skeletal muscle:
    • Type I
    • Type IIA
    • Type IIX
  • These fibre types exhibit significant structural, functional, and metabolic differences.

Muscle Fibre Properties

  • Structural Properties:
    • Muscle fibre diameter: Small (Type I), Large (Type IIA, Type IIX).
    • Motor units per muscle: More, smaller (Type I); Fewer, larger (Type IIA, Type IIX).
    • SR development: Poor (Type I), Intermediate (Type IIA), High (Type IIX).
  • Functional Properties:
    • Twitch (contraction) time: Slow (Type I), Fast (Type IIA, Type IIX).
    • Relaxation time: Slow (Type I), Intermediate (Type IIA), Fast (Type IIX).
    • Force production: Low (Type I), Intermediate (Type IIA), High (Type IIX).
    • Fatigability: Fatigue-resistant (Type I), Fatigable (Type IIA, Type IIX).
    • Sensitivity to recruitment: High (Type I), Intermediate (Type IIA), low (Type IIX).
  • Metabolic Properties:
    • Red colour: Dark (Type I), Dark (Type IIA), Pale (Type IIX).
    • Myosin-ATPase activity: Low (Type I), Intermediate (Type IIA), High (Type IIX).

Determinants of Whole-Muscle Tension

  • Number of Fibres Contracting
    • Factors controlled to accomplish gradation of contraction.
    • Number of motor units recruited
    • Number of muscle fibres per motor unit
    • Number of muscle fibres available to contract
    • Size of muscle (number of muscle fibres in muscle)
    • Presence of disease (e.g., muscular dystrophy)
    • Extent of recovery from traumatic losses
  • Tension Developed by Each Contracting Fibre
    • Frequency of stimulation (twitch summation and tetanus)
    • Length of fibre at the onset of contraction (length-tension relationship)
    • Extent of fatigue
    • Duration of activity
    • Amount of asynchronous recruitment of motor units
    • Type of fibre (fatigue-resistant oxidative or fatigue-prone glycolytic)
    • Thickness of fibre
    • Pattern of neural activity (hypertrophy, atrophy)
    • Amount of testosterone (larger fibres in males than females)