CoverModule 1.0. Homeostasis, Membranes, Electrophysiology and ANS (Essay Questions)1.1. Homeostasis1.1.1. Homeostasis Defined1.1.2. Homeostatic Control Systems1.1.3. Feedback Response Loop1.2. Cell Transport; Water & Solutes1.2.1. Fluid Compartments1.2.2. Osmosis1.2.3. Diffusion of Solutes1.2.4. Active Transport1.2.5. Bulk Transport1.3. Electrophysiology1.3.1. Ions and Cell Membranes1.3.2. Membrane Potentials1.3.3. Graded Potential1.3.4. Action Potentials1.3.5. Refractory Periods1.3.6. Propagation of an Action Potential1.4. THE SYNAPSE1.5. THE AUTONOMIC NERVOUS SYSTEM1.5.1. Organization of the Nervous System1.5.2. Structural Organization of the ANS1.5.3. The SNS and the PNS1.5.4. The Enteric Nervous System1.5.5. Physiology of the ANS1.5.6. Neurotransmitters of the ANS1.5.7. Receptors of the ANS1.5.8. Actions of the Autonomic Nervous System1.5.9. Table of Actions for the SNS and PNS and Some Common DrugsModule 2.0. Skeletal Muscle and Special Senses2.1. Structural Organization of Skeletal Muscle2.2.1. Neuromuscular Junction, Excitation-Contraction Coupling2.2.2. Muscle Contractures and Cramps2.3. Whole Muscle Contraction, Fiber Type, Fatigue and Muscle Pharmacology2.3.1. Motor Units2.3.2. Factors that Influence the Force of Contraction2.3.3. Energy Source for Muscle Contraction2.3.4. Skeletal Muscle Fiber Types2.3.5. Fatigue2.3.6. Muscle Pharmacology2.4. Smooth Muscle2.4.1. Smooth Muscle Contraction2.5. Control of Body Movement2.5.1. Voluntary Control of Muscle2.5.2. Reflexes2.6. Taste and Smell2.6.1. Taste2.6.2. The Sense of Smell2.7. Vision2.7.1. Structure of the Eye2.7.2. Focusing Light on the Retina2.7.3. Converting Light to Action Potentials2.7.4. The Retina2.7.5. Phototransduction2.7.6. Receptive Fields2.8. Hearing and Equilibrium2.8.1. The Nature of Sound2.8.2. The Hearing Apparatus2.8.3. Sound Vibrations to Action Potentials2.8.4. The Sense of Balance and EquilibriumModule 3.0. Cardiovascular System3.1. Structure of the Heart3.1.1. Chambers and Circulation3.2. Cardiac Cell Action Potentials3.2.1. Action Potentials in Cardiac Muscle Cells3.2.2. Action Potentials in Cardiac Autorhythmic cells3.2.3. Cellular Mechanisms of Inotropy and Chronotropy3.3. Electrophysiology of Heart Muscle3.3.1. Heart Conduction System3.3.2. Electrocardiogram (ECG)3.3.3. Abnormal ECG - Current of Injury3.4. The Cardiac Cycle3.4.1. Cardiac cycle3.4.2. Cardiac Measurements and Pressure Volume Loops3.5. Blood vessels and Blood Pressure3.5.1. Arteries and Veins3.5.2. Capillaries3.5.3. Blood Pressure Regulation and Shock3.5.4. Capillary Exchange3.5.5. Myogenic and Paracrine Regulation of Vasoconstriction and Vasodilation3.6. Blood3.6.1. Composition of Blood3.6.2. Hematopoeisis3.6.3. Breaking Down Red Blood Cells3.6.4. HemostasisModule 4.0. Urinary and Respiratory Systems4.1. Function and Structure of the Kidney4.1.1. Urinary System Function4.1.2. Functional Anatomy of the Urinary System4.1.3. The Nephron: Functional Unit of the Kidney4.1.4. The Renal Corpuscle: Bowman's Capsule4.2. Physiology of Urine Production4.2.1. Filtration4.2.2. Renal Clearance4.2.3. Tubular Reabsorption4.2.4. Urine Concentration and Dilution4.2.5. Hormonal Regulation of Urine Production4.3. Acid/Base Balance4.3.1. Buffers4.3.2. Acid/Base Disturbances4.4. The Respiratory System4.4.1. Respiratory System Structure and Function4.4.2. Respiratory Membrane4.4.3. Respiratory pressures and Inspriation/Expiration4.4.4. Alveoli and Surfactant4.4.5. Pneumothorax4.5. Gas Exchange and Transport4.5.1. Gas Laws4.5.2. Partial Pressure Gradients in the Lung4.5.3. Alveolar Gas Equation4.5.4. Oxygen and Carbon Dioxide Transport in the Blood4.5.5. Alveolar Ventilation4.5.6. Ventilation/Perfusion Ratio4.6. Chronic Bronchitis and Emphysema4.6.1. Respiratory Control by the Medulla Oblongata4.6.2. Chemicals that Regulate VentilationModule 5.0. Digestive, Endocrine and Reproductive Systems5.1. Functional Anatomy of the Digestive System5.1.1. Layers of the Digestive Tract5.1.2. Enteric Nervous System5.1.3. Organs of the Digestive System5.2. Digestion5.2.1. Carbohydrates5.2.2. Proteins5.2.3. Lipids5.2.4. Lipoproteins5.3. Regulation of Digestive Secretions5.4. Endocrine System5.4.1. Overview of the Endocrine System5.4.2. Hormone Receptors5.4.3. Hormones of the Body5.4.4. Other Hormones: Melatonin and Pheromones5.5. The Hypothalamus and Pituitary Gland5.5.1. Structure and Function of the Hypothalamus and Pituitary Gland5.5.2. The Posterior Pituitary5.5.3. The Anterior Pituitary5.5.4. Growth Hormone5.5.5. Prolactin5.5.6. Thyroid Hormones5.5.7. Adrenal Hormones5.6. Pancreas5.6.1. Insulin and Glucagon5.6.2. Diabetes Mellitus5.7. Reproductive System Anatomy5.7.1. Female Reproductive Anatomy5.7.2. Male Reproductive Anatomy5.7.3. Sexual Development at Puberty5.7.4. Male Reproductive Endocrine Axis5.7.5. Spermatogenesis5.7.6. Female Reproductive System: Oogenesis5.7.7. Ovulation and Fertilization5.7.8. The Ovarian Cycle5.7.9. The Uterine Cycle5.7.10. PregnancyAppendix A. GenderAppendix B. The Placebo EffectB.2.1. The Placebo EffectB.2.2. Examples of the Placebo EffectB.2.3. How do Placebos Work?B.2.4. Are Placebos Ethical?B.2.5. How do we validate actual effectiveness of placebosB.2.6. Tips for evaluating scientific evidenceB.2.7. What about Faith Healings


When we think of skeletal muscles getting tired, we often use the word fatigue, however, the physiological causes of fatigue vary considerably. At the simplest level, fatigue is used to describe a condition in which the muscle is no longer able to contract optimally. To make the discussion easier, we will divide fatigue into two broad categories: Central fatigue and peripheral fatigue. Central fatigue describes the uncomfortable feelings that come from being tired, it is often called "psychological fatigue." It has been suggested that central fatigue arises from factors released by the muscle during exercise that signal the brain to "feel" tired. Psychological fatigue precedes peripheral fatigue and occurs well before the muscle fiber can no longer contract. One of the outcomes of training is to learn how to overcome psychological fatigue. As we train, we learn that those feelings are not so bad and that we can continue to perform even when it feels uncomfortable. For this reason, elite athletes hire trainers that push them and force them to move past the psychological fatigue.

Peripheral fatigue can occur anywhere between the neuromuscular junction and the contractile elements of the muscle. It can be divided into two subcategories, low frequency (marathon running) and high frequency (circuit training) fatigue. High-frequency fatigue results from impaired membrane excitability as a result of imbalances of ions. The list of potential causes include; inadequate functioning of the Na+/K+ pump, subsequent inactivation of Na+ channels and impairment of Ca2+ channels. Muscles can recover quickly, usually within 30 minutes to as little as 30 seconds, following high-frequency fatigue. Low-frequency fatigue is correlated with impaired Ca2+ release, probably due to excitation coupling contraction problems. It is much more difficult to recover from low-frequency fatigue, taking from 24 hours to 72 hours.

In addition, there are many other potential fatigue contributors, these include: accumulation of inorganic phosphates, hydrogen ion accumulation and subsequent pH change, glycogen depletion, and imbalances in K+. Please note that a factor not on the list is lactic acid as it does not contribute to fatigue or muscle soreness. The reality is we still don't know exactly what causes fatigue and much research is currently devoted to this topic.

You should also recognize that a factor not on the list causing fatigue is ATP. This is because experiments performed with muscles show that even in the most severe fatigued conditions of skeletal muscle, 70% of available ATP is still found within the cell! It would appear that ATP is so important for muscle function that other factors will induce fatigue before ATP becomes too low for physiological function. To ensure that ATP is conserved while still maintaining force under constant demand is our next discussion topic.

The current research seems to be supporting the following hypothesis. To conserved ATP without compromising force, the muscle cell must modify the actions of two of the highest consumers of ATP: the SERCA pump and the myosin ATPase enzyme. The SERCA pump can be slowed by reducing the amount of calcium in the sarcoplasm, but reducing the amount of calcium effects myosin’s ability to bind to actin. Thus, the conundrum is the paradox encountered when trying to slow down the SERCA pump with less calcium but without the letting the reduced calcium compromise contraction strength. This is solved by altering the affinity of myosin for actin, but first lets explain how to reduce calcium.

It has been hypothesized that an increase in intracellular Mg2 decreases the responsiveness of the RYR channel. Since Mg2+ is a stabilizing agent for ATP and subsequently released after each hydrolytic reaction, the more intense the contraction, the more Mg2+ will be released. The increase in concentration of Mg2+ will then act to alter RYR, thereby reducing intracellular calcium.

Although not yet well understood, this alteration in calcium triggers the activation of an enzyme complex made up of calmodulin and myosin light chain kinase (MLCK). Once activated, MLCK acts to phosphorylate one of the light chains on the myosin molecule, altering the myosin/actin binding affinity. In short, this modification results in an increase rate of engagement (higher binding affinity for myosin to actin) so that less calcium is required to move troponin. Stated another way, the additional phosphorylation gives the myosin molecule the ability to simply push tropomyosin out of the way. Collectively, these modifications result in the muscle being able to generate force while conserving ATP under conditions of lower intracellular Ca2+.

A second problem with fatigue is the ion imbalance that results from constant depolarization and repolarization. When a muscle membrane is constantly depolarizing and repolarizing the thin diameter of the T-tubule can experience a build-up in extracellular K+. Normal extracellular K+ concentrations range from 3.5 to 5 mM, but under conditions of constant depolarization/repolarization the concentrations can rise to over 11mM in the T-tubules. This high extracellular concentration in K+ results in a membrane potential that repolarizes to a value well above threshold. This high membrane potential inactivates voltage gated channels making it more difficult to propagate action potentials, leaving the muscle cells with even less calcium. To compensate, the T-tubules have additional proteins channels for the Cl- ion. T-tubules contain both leak and voltage-gated Cl- channels as well as ATP sensitive Cl- channels. At concentrations around 11mM K+, the voltage gated Cl- channels can open and help the membrane repolarize. In fact, the importance of Cl- cannot be overstated as studies show that even under resting conditions, the negative 85mV resting potentials of skeletal muscle cells is the result of Cl- channels (80%) rather than K+ channels (20%). The importance of Cl- channels was discovered from observations and studies of the fainting goat. A species that “faints” when overexcited. We now know that the fainting goat lacks Cl- channels in their T-tubules.  Even though muscles will still fatigue, without these compensatory mechanisms they would fatigue even faster.

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