Topic 10

Skeletal Muscle Characteristics and Functions

• Muscle Characteristics:

  • Excitable: Muscles respond to stimuli by producing action potentials (APs).

  • Contractile: Muscles have the ability to shorten and thicken.

  • Extensible: Muscles can stretch when pulled.

  • Elastic: Muscles return to their original shape after contraction or extension.

• Muscle Functions:

  • Movement: Facilitates activities such as walking and breathing.

  • Posture and Facial Expression: Maintains body alignment and enables communication through facial movement.

  • Heat Production: Assists in maintaining a core body temperature of approximately $37\,^{\circ}\text{C}$.

  • Protection of Viscera: Provides a protective barrier for internal organs within the body wall.

The Neuromuscular Junction (NMJ)

• Innervation Patterns:

  • Each individual muscle fibre (cell) is innervated by only one neuron.

  • The axon of a motor neuron branches out to innervate several muscle fibres. Typically, one neuron innervates approximately $150$ fibres within the same whole muscle.

  • Motor Unit: Defined as a single motor neuron plus all the muscle fibres it innervates.

• Structure of the NMJ:

  • Presynaptic Cell: The neuron containing Acetylcholine (ACh) stored in neurotransmitter vesicles.

  • Postsynaptic Cell: The muscle membrane, specifically the sarcolemma. It contains a specialized region known as the motor end plate which is densely packed with ACh receptors.

  • Synaptic Cleft: The physical space separating the two membranes.

• Functional Steps of the NMJ:

  1. An action potential (AP) reaches the axon terminal and the synaptic end bulb of the neuron.

  2. $Ca^{2+}$ enters the neuron via voltage-gated channels, which triggers the exocytosis of ACh.

  3. ACh binds to the ACh receptors located on the motor end plate.

  4. Chemical gates open and $Na^+$ enters the muscle cell, resulting in an End Plate Potential (EPP). The EPP is a depolarizing graded potential (GP).

  5. The EPP causes the opening of $Na^+$ voltage gates on the adjacent sarcolemma, triggering an AP. This AP has the same properties and uses the same types of channels as an AP on a neuron; it propagates along the sarcolemma.

• Critical Stimulus Principle:

  • One AP in a neuron leads to one EPP, which always leads to one AP in the muscle (1 AP neuron $\rightarrow$ 1 EPP $\rightarrow$ 1 AP).

  • This occurs because a large amount of ACh is released and the motor end plate contains many receptors.

  • To inhibit skeletal muscle, one must inhibit the motor neuron itself.

Molecular Basis of Skeletal Muscle Contraction

• Condition of Relaxed Muscle:

  • Tropomyosin covers the myosin binding sites on the actin filament.

  • The myosin head is already activated.

• Myosin Head Activation:

  • Activation involves the breakdown of ATP: $\text{ATP} \rightarrow \text{ADP} + P_i \rightarrow \text{Energy}$.

  • The ADP and $P_i$ remain on the myosin head, and the energy is stored within the head, rendering it "activated."

  • Once binding sites on actin are exposed, the activated myosin binds to them.

• Detailed Steps of Muscle Contraction:

  1. Excitation of the muscle fibre (Electrical Event):

  • The sarcolemma is depolarized (EPP $\rightarrow$ AP).

  • The AP propagates down the T-tubules to reach deep within the fibre.

  1. Excitation-contraction coupling (Electrical to Mechanical Event):

  • The AP in the T-tubules causes the release of $Ca^{2+}$ (the coupling agent) from the terminal cisternae of the sarcoplasmic reticulum (SR) via mechanically gated channels.

  • $Ca^{2+}$ binds to troponin.

  • The troponin-tropomyosin complex moves, exposing the myosin binding sites on the actin filament.

  1. Contraction (Mechanical Event - Sliding Filament Mechanism):

  • Activated myosin heads attach to the binding sites on actin, forming a cross bridge.

  • Energy stored in the myosin head is released, causing the head to pivot in what is known as the POWER STROKE. During this, ADP and $P_i$ are released.

  • Actin slides over the myosin toward the centre of the sarcomere (M line).

  • ATP attaches to the myosin head, causing it to release from the actin and "unpivot" in a RECOVERY STROKE.

  • The myosin head reactivates through the hydrolysis of ATP ($\text{ATP} \rightarrow \text{ADP} + P_i$).

  • If $Ca^{2+}$ levels in the cytosol remain high, the cycle repeats many times to shorten the sarcomere.

The Sliding Filament Mechanism

• Sarcomere Changes:

  • Sarcomeres shorten as a whole.

  • The H zone and I band shorten during contraction.

  • The A band remains the same length.

• Overall Physical Changes:

  • Myofibrils shorten, leading to the shortening of the entire muscle.

  • The thin (actin) and thick (myosin) myofilaments themselves remain the same length.

Muscle Fibre Relaxation

• Steps of Relaxation:

  1. Acetylcholine (ACh) is broken down by the enzyme Acetylcholinesterase (AChE) located on the motor end plate facing the cleft. The breakdown products are: $\text{ACh} \xrightarrow{\text{AChE}} \text{acetic acid} + \text{choline}$. Acetic acid enters the Krebs Cycle as Acetyl CoA, and choline is recycled.

  2. The Sarcoplasmic Reticulum (SR) actively takes up $Ca^{2+}$ via the $Ca^{2+}\text{-ATPase}$ pump (active transport).

  3. ATP binds to the myosin heads to release them from the actin, allowing for the deconstricting of the muscle.

  4. Tropomyosin moves back to cover the myosin binding sites on actin once the myosin heads are released.

• Essential Roles of ATP:

  1. Cross bridge release (ATP binds but is not immediately broken down for this step).

  2. Activation of myosin heads ($\text{ATP} \rightarrow \text{ADP} + P_i$) and the power stroke.

  3. Pumping $Ca^{2+}$ back into the SR.

  4. Support of fibre $Na^+/K^+\text{-ATPase}$ pump activity.

Clinical Applications and Pathophysiology

• Rigor Mortis ("Stiffness of Death"):

  • Myosin heads remain activated even after death and can bind to actin.

  • ATP production gradually stops because of a lack of $O_2$.

  • Intracellular $Ca^{2+}$ increases due to leakage from the ECF and SR. This exposes binding sites and forms cross bridges.

  • Because no new ATP is produced, myosin heads cannot release from actin, causing the muscle to remain contracted.

  • Onset begins approximately $3\,\text{hours}$ after death, reaching maximum stiffness at $12\,\text{hours}$, and subsides over several days as cells break down. There is enough ATP for cross bridge formation but not enough for release.

• Extracellular $Ca^{2+}$ Levels:

  • Low ECF $Ca^{2+}$ (associated with pregnancy or lactation) destabilizes $Na^+$ voltage gates, causing them to open spontaneously.

  • This leads to $Na^+$ entering the fibre, resulting in depolarization and muscle cramps (contractions).

• Flaccid Paralysis Conditions:

  • Myasthenia Gravis: An autoimmune reduction in ACh receptors. Treatment involves AChE inhibitors to increase ACh binding to the remaining receptors.

  • Curare Poisoning: Prevents ACh from binding to its receptors; it was historically used in surgery.

  • Botulism: Caused by Clostridium botulinum (improper canning). It prevents the exocytosis of ACh. Medical uses include treating uncontrolled blinking or crossed eyes; cosmetic use is known as Botox (for wrinkles and sweating).

• Substances Causing Muscle Contraction:

  • Nicotine: Binds to receptors and mimics the effect of ACh, causing muscle spasms.

  • Black Widow Spider Venom: Causes a massive release of ACh, which could lead to respiratory arrest.

Factors Affecting Muscle Tension

• Muscle Tension: The force exerted by a muscle or muscle fibre, determined by the number of cross bridges formed.

• Frequency of Stimulation:

  • Twitch: A weak contraction and relaxation produced by a single stimulus ($1\,\text{AP}$ lasting $1-2\,\text{msec}$). Includes a latent period ($\sim 2\,\text{msec}$), a contraction period ($10-100\,\text{msec}$), and a relaxation period. Maximum tension is not reached in a twitch because $Ca^{2+}$ is taken back too rapidly by the SR.

  • Wave Summation: A second stimulus arrives before complete relaxation. Since the muscle AP is over but $Ca^{2+}$ uptake is incomplete, more $Ca^{2+}$ is released, allowing more myosin heads to attach. Contraction has no refractory period.

  • Incomplete Tetanus: Rapid sequence of stimuli causing partial relaxation and quivering between contractions.

  • Complete Tetanus: Sustained contraction with no relaxation between stimuli. This provides the highest tension ($3-4\times$ a twitch). All troponin is saturated with $Ca^{2+}$. Fibre heat (from ATP synthesis) allows the process to work faster.

• Fibre Length:

  • Resting length is optimal for maximum tension (maximum cross bridge formation).

  • Shorter Fibre: Thin filaments overlap and interfere with cross bridge formation ($\text{minimum length} = 70\% \text{ of optimal}$).

  • Stretched Fibre: Not all myosin heads are near actin binding sites ($\text{maximum length} = 130\% \text{ of optimal}$).

• Fibre Size:

  • Thicker fibres contain more myofibrils and generate more tension. Size increases with exercise and testosterone. Comparisons like a "brode of sticks" illustrate strength in numbers.

• Fatigue: Results in poor contraction and reduced maximum tension.

Muscle Fibre Types and Whole Muscle Dynamics

• Individual Fibre Types:

  • Fast (White): Contract and relax rapidly; contain little myoglobin.

  • Slow (Red): Contract and relax slowly; contain more myoglobin (similar to hemoglobin but for transport/storage). Examples include postural muscles.

• Whole Muscle Tension Factors:

  • Number of Fibres Contracting: Increasing active motor units increases tension (recruitment of small units first, then larger ones).

  • Number of Fibres per Motor Unit: More fibres per unit equal more tension (e.g., $1\text{ neuron} \rightarrow 10\text{ fibres}$ is weak; $1\text{ neuron} \rightarrow 1000\text{ fibres}$ is strong).

  • Muscle Size: Larger muscles (e.g., biceps brachii) have more fibres and myofibrils than smaller muscles (e.g., risorius).

Muscle Tone and Contraction Types

• Muscle Tone: A low level of tension in a few fibres developing as different groups of motor units are alternately stimulated over time, providing firmness.

• Types of Whole Muscle Contraction:

  • Isotonic: Muscle changes length; tension (relatively constant) exceeds the load resistance (e.g., elbow flexion to lift a book). Uses ATP.

  • Isometric: Muscle length remains constant; tension is less than required to move the load. Cross bridges form but no shortening occurs (e.g., holding a book steady). Uses ATP.

Muscle Metabolism and Energy Sources

• Resting Conditions:

  • Primarily uses fatty acids to produce ATP (aerobic).

  • Stores glycogen, creatine phosphate ($C\sim P$), and a small amount of ATP ($\text{ATP} + \text{Creatine} \Rightarrow \text{ADP} + C\sim P$).

• Short-term Exercise (< 1\,\text{minute}):

  • Primarily anaerobic. Uses available ATP and then Creatine Phosphate ($C\sim P + \text{ADP} \Rightarrow \text{ATP} + \text{creatine}$), which lasts about $15\,\text{seconds}$.

  • Muscle glycogen converts to glucose, then pyruvic acid, then lactic acid via an anaerobic pathway (lasts $30\,\text{seconds}$ to $2\,\text{minutes}$).

• Long-term Exercise ($1\,\text{minute}$ to hours):

  • Uses the aerobic pathway. Source for ATP is glucose (from the liver) and fatty acids (used increasingly as exercise continues).

  • $O_2$ sources include blood hemoglobin and muscle myoglobin.

Muscle Fatigue and EPOC

• Physiological Fatigue:

  • The inability to maintain tension. It is a protective mechanism; if ATP were completely depleted, cross bridges could not release.

  • Energy Depletion: Low glycogen levels.

  • End Product Build-up: $H^+$ from lactic acid (causes the "burn" and messes up protein function/pH); $P_i$ from ATP breakdown binds to $Ca^{2+}$, reducing its availability for troponin and slowing $P_i$ release from myosin.

  • Failure of APs: $K^+$ buildup in T-tubules disturbs membrane potential; long-term depletion of ACh (rare in healthy people).

• Psychological Fatigue:

  • The CNS fails to send commands to muscles, likely due to lactic acid and subjective feeling of exhaustion.

• EPOC (Excess Post-exercise $O_2$ Consumption):

  • Also known as recovery $O_2$ consumption (manifested as deep, rapid breathing).

  • $O_2$ is used to replenish glycogen, $C\sim P$, and $O_2$ on hemoglobin/myoglobin.

  • Converts lactic acid back to pyruvic acid (for Krebs) or glucose (in the liver).

  • Increased body temperature from exercise increases $O_2$ demand due to faster chemical reactions.