Muscle Physiology

Anatomy of Motor Neurons and the Neuromuscular Junction

• Skeletal muscles are stimulated by somatic motor neurons.
• Axons (long, threadlike extensions of motor neurons) travel from the central nervous system to skeletal muscle.
• Each axon divides into many branches as it enters the muscle.
• Axon branches end on muscle fiber, forming the neuromuscular junction or motor end plate.
• Each muscle fiber has one neuromuscular junction with one motor neuron.

Overview of Skeletal Muscle Contraction

• Figure 9.7 provides an overview.

Background and Overview

• Axon terminal (end of axon) and muscle fiber are separated by a gel-filled space called the synaptic cleft.
• Stored within axon terminals are membrane-bound synaptic vesicles.
• Synaptic vesicles contain the neurotransmitter acetylcholine (ACh).
• Infoldings of the sarcolemma, called junctional folds, contain millions of ACh receptors.
• Neuromuscular junction (NMJ) consists of axon terminals, synaptic cleft, and junctional folds.

The Big Picture: Four Steps for Skeletal Muscle Contraction

1. Events at the neuromuscular junction
2. Muscle fiber excitation
3. Excitation-contraction coupling
4. Cross-bridge cycling

Events at the Neuromuscular Junction

1. Action potential (AP) arrives at the axon terminal.
2. Voltage-gated calcium channels open, allowing calcium to enter the motor neuron.
3. Calcium entry causes the release of ACh neurotransmitter into the synaptic cleft.
4. ACh diffuses across the synaptic cleft to ACh receptors (Na+ chemical gates) on the sarcolemma.
5. ACh binding to receptors opens gates, allowing Na+ to enter, resulting in end-plate potential.
6. Acetylcholinesterase degrades ACh.

When a Nerve Impulse Reaches a Neuromuscular Junction, Acetylcholine (ACh) is Released

• Focus Figure 9.1 illustrates the events at the neuromuscular junction.

Clinical Homeostatic Imbalance 9.2

• Many toxins, drugs, and diseases interfere with events at the neuromuscular junction.
• Myasthenia gravis is a disease characterized by drooping upper eyelids, difficulty swallowing and talking, and generalized muscle weakness.
• It involves a shortage of ACh receptors because the person’s ACh receptors are attacked by their own antibodies, suggesting it is an autoimmune disease.

Generation of an Action Potential Across the Sarcolemma

• Resting sarcolemma is polarized, meaning a voltage exists across the membrane; the inside of the cell is negative compared to the outside.
• Action potential is caused by changes in electrical charges and occurs in three steps:

1. Generation of end-plate potential
2. Depolarization
3. Repolarization

End Plate Potential

• ACh released from the motor neuron binds to ACh receptors on the sarcolemma.
• This causes chemically gated ion channels (ligands) on the sarcolemma to open.
• Na+ diffuses into the muscle fiber, and some K+ diffuses outward, but not much.
• Because Na+ diffuses in, the interior of the sarcolemma becomes less negative (more positive).
• This results in local depolarization called the end-plate potential.

Depolarization: Generation and Propagation of an Action Potential

• If the end-plate potential causes enough change in membrane voltage to reach a critical level called the threshold, voltage-gated Na+ channels in the membrane will open.
• A large influx of Na+ through the channels into the cell triggers an action potential (AP) that is unstoppable and will lead to muscle fiber contraction.
• The AP spreads across the sarcolemma from one voltage-gated Na+ channel to the next one in adjacent areas, causing that area to depolarize.

Repolarization: Restoration of Resting Conditions

• Na+ voltage-gated channels close, and voltage-gated K+ channels open.
• K+ efflux out of the cell rapidly brings the cell back to its initial resting membrane voltage.
• Refractory period: the muscle fiber cannot be stimulated for a specific amount of time until repolarization is complete.
• Ionic conditions of the resting state are restored by the $Na^+-K^+$ pump.
  • $Na^+$ that came into the cell is pumped back out, and $K^+$ that flowed outside is pumped back into the cell.

Action Potential Tracing

• Indicates changes in $Na^+$ and $K^+$ ion channels (Figure 9.9).

Excitation-Contraction (E-C) Coupling

• Excitation-contraction (E-C) coupling: events that transmit the AP along the sarcolemma (excitation) are coupled to the sliding of myofilaments (contraction).
• The AP is propagated along the sarcolemma and down into T tubules, where voltage-sensitive proteins in the tubules stimulate $Ca^{2+}$ release from the sarcoplasmic reticulum (SR).
• $Ca^{2+}$ release leads to contraction.
• The AP is brief and ends before contraction is seen.

Muscle Fiber Contraction: Cross-Bridge Cycling

• At low intracellular $Ca^{2+}$ concentration:
  • Tropomyosin blocks active sites on actin.
  • Myosin heads cannot attach to actin.
  • The muscle fiber remains relaxed.
• Voltage-sensitive proteins in T tubules change shape, causing the sarcoplasmic reticulum (SR) to release $Ca^{2+}$ to the cytosol.

Muscle Fiber Contraction

• At higher intracellular $Ca^{2+}$ concentrations, $Ca^{2+}$ binds to troponin.
• Troponin changes shape and moves tropomyosin away from myosin-binding sites.
• Myosin heads are then allowed to bind to actin, forming a cross-bridge.
• Cycling is initiated, causing sarcomere shortening and muscle contraction.
• When nervous stimulation ceases, $Ca^{2+}$ is pumped back into the SR, and contraction ends.

Four Steps of the Cross-Bridge Cycle

1. Cross-bridge formation: the high-energy myosin head attaches to an actin thin filament active site.
2. Working (power) stroke: the myosin head pivots and pulls the thin filament toward the M line.
3. Cross-bridge detachment: ATP attaches to the myosin head, causing the cross-bridge to detach.
4. Cocking of the myosin head: energy from the hydrolysis of ATP “cocks” the myosin head into a high-energy state, which will be used for the power stroke in the next cross-bridge cycle.

Clinical – Homeostatic Imbalance 9.3: Rigor Mortis

• 3–4 hours after death, muscles begin to stiffen; peak rigidity occurs about 12 hours postmortem.
• Intracellular calcium levels increase because ATP is no longer being synthesized, so calcium cannot be pumped back into the SR, resulting in cross-bridge formation.
• ATP is also needed for cross-bridge detachment, resulting in the myosin head staying bound to actin, causing a constant state of contraction.
• Muscles stay contracted until muscle proteins break down, causing myosin to release.

Whole Muscle Contraction

• Same principles apply to the contraction of both single fibers and whole muscles.
• Contraction produces muscle tension, the force exerted on a load or object to be moved.
• Contraction may or may not shorten the muscle.
  • Isometric contraction: no shortening; muscle tension increases but does not exceed the load.
  • Isotonic contraction: the muscle shortens because muscle tension exceeds the load.

Force and Duration of Contraction

• Vary in response to stimuli of different frequencies and intensities.
• Each muscle is served by at least one motor nerve.
  • A motor nerve contains axons of up to hundreds of motor neurons.
  • Axons branch into terminals, each of which forms a neuromuscular junction (NMJ) with a single muscle fiber.
• A motor unit is the nerve-muscle functional unit.

The Motor Unit

• Consists of the motor neuron and all muscle fibers (four to several hundred) it supplies.
  • Smaller the fiber number, the greater the fine control.
• Muscle fibers from a motor unit are spread throughout the whole muscle, so stimulation of a single motor unit causes only weak contraction of the entire muscle.

The Muscle Twitch

• Simplest contraction resulting from a muscle fiber’s response to a single action potential from a motor neuron.
  • The muscle fiber contracts quickly, then relaxes.
• A twitch can be observed and recorded as a myogram.
  • Tracing: a line recording contraction activity.

Three Phases of the Muscle Twitch

1. Latent period: events of excitation-contraction coupling; no muscle tension is seen.
2. Period of contraction: cross-bridge formation; tension increases.
3. Period of relaxation: $Ca^{2+}$ reentry into the SR; tension declines to zero.

• Muscle contracts faster than it relaxes.

Differences in Twitch Strength and Duration

• Due to variations in metabolic properties and enzymes between muscles.
• Example: eye muscle contractions are rapid and brief, whereas larger, fleshy muscles (calf muscles) contract more slowly and hold it longer.

Graded Muscle Responses

• Normal muscle contraction is relatively smooth, and the strength varies with needs; a muscle twitch is seen only in a lab setting or with neuromuscular problems, but not in normal muscle.
• Graded muscle responses vary the strength of contraction for different demands and are required for proper control of skeletal movement.
• Responses are graded by:
  • Changing the frequency of stimulation.
  • Changing the strength of stimulation.

Muscle Response to Changes in Stimulus Frequency

• Single stimulus results in a single contractile response (i.e., muscle twitch).
• Wave (temporal) summation results if two stimuli are received by a muscle in rapid succession.
  • Muscle fibers do not have time to completely relax between stimuli, so twitches increase in force with each stimulus.
  • Additional $Ca^{2+}$ that is released with the second stimulus stimulates more shortening.

Muscle Response to Increased Stimuli Frequency

• If the frequency of stimuli increases, muscle tension reaches near maximum.
  • This produces smooth, continuous contractions that add up (summation).
• A further increase in stimulus frequency causes the muscle to progress to a sustained, quivering contraction referred to as unfused (incomplete) tetanus.

Muscle Response to Further Increase in Stimuli Frequency

• If the stimuli frequency further increases, muscle tension reaches maximum.
  • This is referred to as fused (complete) tetanus because contractions “fuse” into one smooth, sustained contraction plateau.
  • Prolonged muscle contractions lead to muscle fatigue.

Muscle Response to Changes in Stimulus Strength

• Recruitment (or multiple motor unit summation): a stimulus is sent to more muscle fibers, leading to more precise control.
• Types of stimulus involved in recruitment:
  • Subthreshold stimulus: a stimulus not strong enough, so no contractions are seen.
  • Threshold stimulus: a stimulus strong enough to cause the first observable contraction.
  • Maximal stimulus: the strongest stimulus that increases maximum contractile force all motor units have been recruited.

Recruitment Works on Size Principle

• Motor units with the smallest muscle fibers are recruited first.
• Motor units with larger and larger fibers are recruited as stimulus intensity increases.
• The largest motor units are activated only for the most powerful contractions.
• Motor units in a muscle usually contract asynchronously; some fibers contract while others rest, which helps prevent fatigue.

Muscle Tone

• A constant, slightly contracted state of all muscles.
• Due to spinal reflexes:
  • Groups of motor units are alternately activated in response to input from stretch receptors in muscles.
• Keeps muscles firm, healthy, and ready to respond.

Isotonic Contractions

• Muscle changes in length and moves a load.
  • Isotonic contractions can be either concentric or eccentric.
  • Concentric contractions: the muscle shortens and does work (Example: biceps contract to pick up a book).
  • Eccentric contractions: the muscle lengthens and generates force (Example: laying a book down causes biceps to lengthen while generating a force).

Isometric Contractions

• The load is greater than the maximum tension the muscle can generate, so the muscle neither shortens nor lengthens.

Electrochemical and Mechanical Events

• Are the same in isotonic or isometric contractions, but the results are different.
  • In isotonic contractions, actin filaments shorten and cause movement.
  • In isometric contractions, cross-bridges generate force, but actin filaments do not shorten (myosin heads “spin their wheels” on the same actin-binding site).

Energy for Contraction and ATP

• ATP supplies the energy needed for the muscle fiber to:
  • Move and detach cross-bridges.
  • Pump calcium back into the SR.
  • Pump $Na^+$ out of and $K^+$ back into the cell after excitation-contraction coupling.
• Available stores of ATP are depleted in 4–6 seconds.
• ATP is the only source of energy for contractile activities; therefore, it must be regenerated quickly.

ATP Regeneration

• ATP is regenerated quickly by three mechanisms:

1. Direct phosphorylation of ADP by creatine phosphate (CP).
2. Anaerobic pathway: glycolysis and lactic acid formation.
3. Aerobic pathway.

Direct Phosphorylation of ADP by Creatine Phosphate (CP)

• Creatine phosphate is a unique molecule located in muscle fibers that donates a phosphate to ADP to instantly form ATP.
  • Creatine kinase is the enzyme that carries out the transfer of phosphate.
  • Muscle fibers have enough ATP and CP reserves to power the cell for about 15 seconds.
• Creatine phosphate + ADP → creatine + ATP

Anaerobic Pathway: Glycolysis and Lactic Acid Formation

• ATP can also be generated by breaking down and using energy stored in glucose.
  • Glycolysis: the first step in glucose breakdown does not require oxygen.
  • Glucose is broken into 2 pyruvic acid molecules, and 2 ATPs are generated for each glucose broken down.
  • Low oxygen levels prevent pyruvic acid from entering the aerobic respiration phase.

Anaerobic Glycolysis

• Normally, pyruvic acid enters the mitochondria to start the aerobic respiration phase; however, at high-intensity activity, oxygen is not available (bulging muscles compress blood vessels, impairing oxygen delivery).
  • In the absence of oxygen, referred to as anaerobic glycolysis, pyruvic acid is converted to lactic acid.

Lactic Acid

• Diffuses into the bloodstream and is used as fuel by the liver, kidneys, and heart, or converted back into pyruvic acid or glucose by the liver.
• Anaerobic respiration yields only 5% as much ATP as aerobic respiration but produces ATP 2½ times faster.

Aerobic Respiration

• Produces 95% of ATP during rest and light-to-moderate exercise and is slower than the anaerobic pathway.
• Consists of a series of chemical reactions that occur in the mitochondria and require oxygen.
  • Breaks glucose into $CO<em>2$, $H</em>2O$, and a large amount of ATP (32 can be produced).
• Fuels used include glucose from glycogen stored in the muscle fiber, then bloodborne glucose, and free fatty acids.
  • Fatty acids are the main fuel after 30 minutes of exercise.

Energy Systems Used During Sports

• Aerobic endurance: the length of time a muscle contracts using aerobic pathways this light-to-moderate activity, which can continue for hours.
• Anaerobic threshold: the point at which muscle metabolism converts to the anaerobic pathway.

Muscle Fatigue

• Fatigue is the physiological inability to contract despite continued stimulation.
• Possible causes include:
  • Ionic imbalances can cause fatigue; levels of $K^+$, $Na^+$, and $Ca^{2+}$ can change, disrupting the membrane potential of the muscle cell.
  • Increased inorganic phosphate (Pi) from CP and ATP breakdown may interfere with calcium release from the SR or hamper the power stroke.
  • Decreased ATP and increased magnesium (as ATP levels drop, magnesium levels increase, and this can interfere with voltage-sensitive T tubule proteins).
  • Decreased glycogen.
• Lack of ATP is rarely a reason for fatigue, except in severely stressed muscles.

Excess Postexercise Oxygen Consumption (EPOC)

• For a muscle to return to its pre-exercise state:
  • Oxygen reserves are replenished.
  • Lactic acid is reconverted to pyruvic acid.
  • Glycogen stores are replaced.
  • ATP and creatine phosphate reserves are resynthesized.
• All replenishing steps require extra oxygen, so this is referred to as excess postexercise oxygen consumption (EPOC), formerly referred to as “oxygen debt.”