Neuromuscular Junction & Anatomy

• The neuromuscular junction is a key area to understand, including the processes and chemicals involved in muscle contraction.

Proprio- and Entero-

• "Proprio-" means "sense of," relating to body position, movement, and awareness.
• Proprioceptors are sensory receptors providing feedback on body position and movement.
• "Entero-" means "gut," relating to the gastrointestinal system's nervous control.
• The Enteric Nervous System (ENS) is a division of the autonomic nervous system that controls digestion.

Anterior and Posterior

• Anterior refers to the front.
• Posterior refers to the back.

Action Potential Movement into Muscle

• A motor neuron releases acetylcholine (ACh) at the synapse, which binds to receptors on the sarcolemma (muscle cell membrane), starting an action potential in the muscle.
• The action potential spreads across the sarcolemma, traveling along the muscle fiber; more positive ions are inside, and the outside becomes negative.
• The action potential moves into the T-tubules (transverse tubules), carrying the electrical signal deep into the muscle cell.
• The action potential in the T-tubules stimulates the sarcoplasmic reticulum (SR), which then releases calcium ions (Ca²⁺) into the cytoplasm.
• The released calcium binds to troponin, shifting tropomyosin and allowing myosin to bind to actin, leading to muscle contraction.

Depolarization Process in the Nerve

• At rest, the inside of the neuron is negatively charged (-70 mV) compared to the outside.
• This is due to the Na⁺/K⁺ pump, which keeps sodium (Na⁺) outside and potassium (K⁺) inside.
• A stimulus causes some Na⁺ channels to open, allowing sodium ions to enter the neuron.
• If the membrane potential reaches -55 mV (threshold), an action potential occurs.
• Voltage-gated Na⁺ channels open, and Na⁺ rushes into the cell, making the inside more positive (+30 mV).
• This rapid change in charge is depolarization.
• The positive charge spreads along the neuron, triggering depolarization in the next membrane section, continuing the signal down the axon.

All or None Principle

• A threshold of -55 mV must be reached for an action potential to occur; it either happens fully or not at all.

Alpha Motor Neuron

• Alpha motor neurons are large nerve cells that directly stimulate skeletal muscle fibers to produce movement.
• They are part of the somatic nervous system.
• They are located in the ventral horn of the spinal cord.
• They work with gamma motor neurons, which regulate muscle spindle sensitivity.
• Efferent neurons carry signals from the central nervous system to the muscles.
• The cell body (soma), located in the spinal cord, processes signals and starts action potentials.
• Dendrites are branch-like structures that receive signals from the brain, spinal cord, or sensory neurons.
• The axon is a long fiber that transmits the electrical signal from the cell body to the muscle.
• The myelin sheath is a fatty layer (produced by Schwann cells) that insulates the axon and speeds up signal transmission.
• Nodes of Ranvier are gaps in the myelin sheath where the action potential jumps, increasing conduction speed (saltatory conduction).
• Axon terminals (synaptic boutons) are the ends of the axon that release acetylcholine (ACh) at the neuromuscular junction, triggering muscle contraction.
• The neuromuscular junction is the connection between the alpha motor neuron and the muscle fiber, where neurotransmission leads to muscle activation.

Muscle Spindle

• Found within the muscle belly between muscle fibers
• Detects muscle stretch and length changes.
• When a muscle is stretched, the muscle spindle sends signals to the spinal cord, starting a stretch reflex (causing the muscle to contract and resist excessive stretching).
• An example is the knee-jerk reflex.

Golgi Tendon Organ (GTO)

• Found in the tendons near where the muscle attaches to the bone.
• Detects muscle tension and force.
• If the muscle generates too much force, the GTO sends signals to the spinal cord to inhibit contraction, causing the muscle to relax and prevent injury.
• An example is when lifting a heavy weight, the GTO helps prevent excessive force that could tear the muscle/tendon.

Muscle Spindle vs. GTO

• Muscle spindle detects stretch and causes contraction.
• GTO detects tension and causes relaxation.

Pulmonary System

• Lung volumes should be understood.
• Tidal Volume (TV) is the amount of air inhaled or exhaled during normal, relaxed breathing (quiet breathing).
• Inspiratory Reserve Volume (IRV) is the amount of air that can be inhaled after a normal tidal inhalation (deep inhalation e.g. during exercise or heavy breathing).
• Expiratory Reserve Volume (ERV) is the amount of air that can be exhaled after a normal tidal exhalation (forced expiration e.g. blowing out candles).
• Residual Volume (RV) is the amount of air remaining in the lungs after a forceful exhalation.
• RV prevents alveolar collapse and ensures continuous gas exchange.
• Inspiratory Capacity (IC) is the maximum amount of air that can be inhaled after a normal exhalation: IC = TV + IRV.
• Functional Residual Capacity (FRC) is the amount of air remaining in the lungs after a normal exhalation.
• FRC ensures ongoing gas exchange between breaths; FRC = ERV + RV.
• Vital Capacity (VC) is the maximum amount of air that can be exhaled after a maximal inhalation (forced breathing: deep inhalation then complete exhalation); VC = TV + IRV + ERV.
• Total Lung Capacity (TLC) is the total volume of air the lungs can hold (full expansion after maximal inhalation); TLC = TV + IRV + ERV + RV.

How Lung Volumes Change in Different Conditions

• During exercise, Tidal Volume (TV) increases to meet higher oxygen demand.
• IRV and ERV may decrease as more of the lung’s capacity is used for each breath during exercise.
• RV remains unchanged during exercise.
• In Obstructive Lung Diseases (e.g., COPD, asthma), Residual Volume (RV) increases due to air trapping.
• Vital Capacity (VC) decreases as airflow is restricted in obstructive lung diseases.
• In Restrictive Lung Diseases (e.g., pulmonary fibrosis), TLC, VC, and IC decrease due to lung stiffness.
• RV may be normal or slightly reduced in restrictive lung diseases.
• Atmospheric pressure at rest: 760mmHg at sea level.
• Shortness of breathing is termed dyspnea.
• Obstructive dyspnea is due to blocked or narrowed airways, as seen in asthma, COPD, or bronchitis.
• Restrictive dyspnea is due to limited lung expansion, as seen in pulmonary fibrosis or obesity-related breathing issues.
• Expiration is passive during rest but active during exercise.
• The double-walled sac surrounding the lungs demonstrates that "structure enables function."
• Pleural Sac: allows for gas exchange between avolie and capillaries.

Factors Critical to Pulmonary Diffusion

• Partial Pressure Gradient: A higher difference in oxygen (O₂) and carbon dioxide (CO₂) pressures between the alveoli and blood drives diffusion.
• Membrane Thickness: A thinner alveolar-capillary membrane allows for faster gas exchange.
• Surface Area: A larger alveolar surface area increases diffusion capacity.
• Diffusion Coefficient: CO₂ diffuses faster than O₂ due to its higher solubility in blood.
• Gas Partial pressure is the most critical factor.

The Bohr Effect

• During exercise, increased carbon dioxide and decreased blood pH decrease hemoglobin's affinity for oxygen at the tissue, promoting its movement from blood to muscle fiber.
• The Bohr Effect creates more efficient unloading of oxygen.

Chemoreceptors During Exercise

• During exercise, chemoreceptors stimulate an increase in breathing rate and depth, primarily in response to increased CO₂ levels and decreased pH (increased H⁺ concentration) in the blood.
• Central Chemoreceptors (Medulla Oblongata) primarily detect elevated CO₂ (forms carbonic acid and lowers pH in cerebrospinal fluid).
• They are the main drivers of increased ventilation during exercise.
• Peripheral Chemoreceptors (Carotid and Aortic Bodies) respond to low O₂ levels (hypoxia), increased CO₂, and decreased pH.
• During exercise, CO₂ and H⁺ buildup is the primary trigger for increased respiration, with central chemoreceptors playing the dominant role.

Lung Volume and Pressure During the Inspiration Phase

• During the inspiration phase of pulmonary ventilation, expansion of the rib cage results in increased lung volume and decreased pressure.
• Expansion creates more volume and thus a lower pressure within the lungs than that of the atmosphere, causing air to be drawn into the lungs.

Decreased Hemoglobin Affinity for O₂ During Exercise

• During exercise, hemoglobin’s affinity for O₂ decreases, promoting oxygen unloading to active muscles, mainly due to the Bohr effect.
• Increased CO₂ Levels: More carbon dioxide is produced by working muscles, which forms carbonic acid (H₂CO₃) and lowers blood pH.
• Decreased pH (Increased H⁺ Ions): A more acidic environment reduces hemoglobin’s ability to hold onto oxygen, enhancing oxygen release to tissues.
• Increased Temperature: Exercising muscles generate heat, further reducing hemoglobin’s oxygen-binding affinity.
• Increased 2,3-BPG (Bisphosphoglycerate): This metabolite, produced by red blood cells during anaerobic metabolism, binds to hemoglobin and facilitates oxygen unloading.

Trigger of Ventilation Increase at Exercise Onset:

• The immediate increase in ventilation that occurs as exercise first begins is triggered or stimulated by the motor cortex, proprioceptor feedback, and anticipatory responses.
• Motor Cortex Activation (Central Command Theory): The brain’s motor cortex sends simultaneous signals to both muscles and the respiratory centers in the medulla, increasing breathing rate and depth before chemical changes occur.
• Proprioceptor Feedback (Muscle and Joint Receptors): Mechanoreceptors in muscles, tendons, and joints detect movement and send signals to the respiratory centers to increase ventilation immediately.
• Anticipatory Response (Sympathetic Nervous System): Before movement even begins, the autonomic nervous system prepares the body for exercise by increasing breathing rate, heart rate, and blood pressure.
• The initial rise in ventilation is driven mainly by neural mechanisms to meet oxygen needs.

Anatomy of Airflow Through the Pulmonary System

• Air enters through the nose or mouth where the nasal cavity filters, warms, and humidifies air.
• Air then travels through the pharynx (throat), a passageway shared by the respiratory and digestive systems.
• Next, air passes through the larynx (voice box), which contains the vocal cords and prevents food from entering the airway.
• The trachea (windpipe) is a rigid tube lined with cartilage rings that keeps the airway open while conducting air to the lungs.
• The trachea splits into two main-stem bronchi, with one leading to each lung.
• The bronchi further branch into smaller bronchioles, which lack cartilage and regulate airflow through smooth muscle contraction.
• Air moves into the respiratory bronchioles & alveolar ducts, the smallest airways, leading to the alveoli.
• Alveolar Sacs - Clusters of alveoli, the site of gas exchange where oxygen enters the blood, and carbon dioxide is expelled.

Mechanics of Breathing: How Air Moves

• Airflow follows Boyle’s Law, which states that pressure and volume are inversely related.
• Inhalation (Inspiration): Diaphragm contracts (moves downward), and the external intercostal muscles expand the ribcage, increasing lung volume. This expansion decreases intrapulmonary pressure below atmospheric pressure, drawing air into the lungs.
• Exhalation (Expiration): Diaphragm relaxes, and the ribcage recoils, decreasing lung volume. This increases intrapulmonary pressure, forcing air out.
• Chemoreceptors stimulate increased breathing rate and depth due to elevated CO₂ and decreased pH, ensuring excess CO₂ removal and proper blood pH balance.

Asthma

• Asthma is an obstructive disease where airflow is difficult to maintain.

Key Features of Asthma:

• Bronchoconstriction The smooth muscles around the airways tighten in response to triggers (such as allergens, exercise, or irritants), reducing the diameter of the airways.
• Inflammation: The lining of the airways becomes swollen and produces excess mucus, further obstructing airflow.
• Air Trapping: During an asthma attack, exhalation is particularly difficult because air becomes trapped in the lungs due to narrowed airways, resulting in decreased ability to expel air, breathlessness, and wheezing.
• Airway resistance is increased during an asthma attack due to increased pressure inside the lungs.
• Treatment often involves bronchodilators to relax the airway muscles and anti-inflammatory medications to reduce swelling and mucus production.

Oxygen Transport

• Oxygen is inhaled into the lungs, reaching the alveoli where gas exchange occurs (O2 moves into the bloodstream, and CO2 moves into the alveoli).
• Oxygen diffuses into red blood cells, binding to hemoglobin molecules, forming oxyhemoglobin, which is influenced by the high partial pressure of oxygen (pO2) in the lungs.
• Oxygen-rich blood is pumped by the heart through arteries to tissues, including muscles, and the partial pressure of oxygen (pO2) decreases.
• Oxygen is used in cellular respiration to produce energy (ATP), producing carbon dioxide (CO2).
• The high CO2 concentration in active tissues leads to gas exchange, where CO2 diffuses from the tissues into the blood, and oxygen moves from the blood into the tissues.
• The buildup of CO2 lowers the pH of the blood, triggering the Bohr effect, causing hemoglobin to release oxygen.
• Blood reaches the tissues with higher CO2 levels and lower pO2, hemoglobin releases oxygen.
• At the same time, carbon dioxide binds to hemoglobin to form carbaminohemoglobin, which helps carry the CO2 back to the lungs.
• Blood returns to the heart and then to the lungs, where the partial pressure of oxygen (pO2) is high, and CO2 is released from hemoglobin, due to low CO2 levels.
• In the lungs, CO2 diffuses from the blood into the alveoli, while oxygen diffuses from the alveoli into the blood, where it can bind to hemoglobin once more.
• The oxygen transport cascade describes the journey of oxygen from the atmosphere to the tissues.
• The gas exchange process ensures that oxygen is delivered where needed and carbon dioxide is efficiently removed.
• Changes in the partial pressures of oxygen and carbon dioxide, along with factors like pH and temperature, regulate the release of oxygen from hemoglobin and the binding of CO2.
• High CO2 concentrations in cerebrospinal fluid trigger chemoreception that cause Hyperventilation, to exhale more CO2.
• Chemoreceptors in the medulla oblongata of the brain are especially sensitive to changes in the pH of the cerebrospinal fluid.
• Peripheral chemoreceptors in the aortic arch and carotid arteries monitor CO2 levels and primarily respond to changes in oxygen (pO2).
• Decreases in oxygen levels (hypoxia) and Increases in CO2 levels which lower pH, increase breathing rate

Partial Pressures

• Dalton's Law of Partial Pressures: states that in a mixture of gases, the total pressure is the sum of the partial pressures of each individual gas.
• The formula to calculate the partial pressure of a gas is: Pgas=Ptotal×fraction of gas in mixture
• Where Pgas is the partial pressure of the gas you're interested in, Ptotal is the total pressure of the gas mixture, and Fraction of gas in mixture is the mole fraction of that gas in the mixture.
• Example: Oxygen (O₂) and nitrogen (N₂) with a total pressure of 760 mmHg. Suppose the mole fraction of oxygen is 0.21 (21% oxygen) and the mole fraction of nitrogen is 0.79 (79% nitrogen).
• PO₂=760 mmHg×0.21=159.6 mmHg so the partial pressure of oxygen is 159.6 mmHg.
• Myoglobin has a higher affinity for oxygen because its role is to store oxygen in muscle tissues, while hemoglobin's role is to pick up oxygen in the lungs and release it in tissues where it's needed most.
• The inflection point where ventilatory equivalent (VE) increases exponentially is known as the ventilatory threshold (VT) or anaerobic threshold (AT).
• Ventilation (VE) starts to increase at a faster rate due to the accumulation of lactic acid in the blood as exercise intensity increases.

Diaphragm Contraction

• When the diaphragm contracts, the lungs expand.
• During exercise, pulmonary ventilation increases due to increased demand for oxygen, increased production of carbon dioxide (CO2), chemoreceptor stimulation, and increased motor activity.
• The partial pressure of oxygen is 160 mmHg in the atmosphere at sea level, about 100 mmHg in the alveoli, and varies in the blood (95–100 mmHg in arterial blood, 40 mmHg in venous blood).
• The Ventilatory Threshold is the point during exercise when ventilation increases more rapidly than oxygen uptake, typically due to lactic acid and increased CO2.