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- <strong>Fatigue, aging, and recuperation</strong>
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- <hr />- Old people and sick people tire easily. Surprisingly, little is known to explain that common fact.-
- Myths about lactic acid and oxygen debt have misdirected most fatigue research.- The cellular processes involved
- in fatigue overlap with those of aging.- Knowledge about the mechanisms of fatigue should be useful in
- preventing some tissue swelling disorders, organ failure, degenerative calcification, and other energy-related
- problems. <hr />GLOSSARY:* Uncoupling--In cellular respiration, oxidation of "fuel" in the mitochondrion is
- coupled to the phosphorylation of ADP, forming ATP. Uncouplers are chemicals that allow oxidation to proceed
- without producing the usual amount of ATP.* DNP--Dinitrophenol, an uncoupler that was once popular as a
- weight-loss drug.* NAD+ and NADH--Nicotinamide adenine dinucleotide, and its reduced form are coenzymes for many
- oxidation and reduction reactions in cells.* Hyperammonemia--The presence of too much ammonia in the blood.*
- Vicinal water--water near surfaces, especially hydrophobic surfaces, that is physically and chemically different
- from ordinary water.* Hydrophobic--insoluble in water, a nonpolar oil-like molecule that repels water.<hr
- />Unlike the somewhat technical medical concept of "stress," the idea of fatigue is something everyone
- understands, to some extent. Hans Selye's studies of stress weren't widely accepted until about 40 years after
- their publication, but some of the main investigators of the fatigue phenomenon are still practically unknown in
- the universities, many years after they published their work. Several things have kept fatigue research
- from advancing, including the common feeling that fatigue is already sufficiently understood, and that it is
- somehow trivial, compared to problems such as growth, reproduction, and disease.Fatigue is usually described as
- decreased responsiveness resulting from over-exertion: For example, a muscle's decreased strength or speed of
- contraction, or a nerve's decreased speed of conduction, or a sense organ's decreased ability to detect or to
- discriminate. Another meaning of fatigue, a decreased resistance or strength, can be applied to materials, as
- well as to some biological functions, for example when fatigue leads to sickness or
- infections. "Responsiveness" implies sensitivity, and decreased sensitivity to stimulation can be seen in
- fatigued sense organs, nerves, muscles, and many other types of cell--immune cells, secretory cells, etc. Even
- plant cells have very similar processes of excitability that can be depleted by repetition.In a series of
- lectures to the Royal Society in England (1895-1901), the physicist Jagadis Chandra Bose described work that at
- first excited, and then disturbed, many physicists and biologists. He had invented devices for both producing
- and detecting electromagnetic waves, and he had been the first to produce millimeter length radio waves
- (microwaves). In Marconi's first transatlantic radio transmission Bose's signal detecting device was used. This
- device was based on the fact that two pieces of metal in superficial contact became electrically fused (cohered)
- in the presence of an electrical or electromagnetic field. After they cohered, a mechanical shock would separate
- them, breaking the electrical fusion.When Bose was experimenting with his "self-restoring coherer," a
- semiconducting device that spontaneously broke the connection without being mechanically shaken, he observed
- that it became insensitive after prolonged use, that is, it lost its self-restoring capacity, but that after a
- rest, it recovered its sensitivity. He recognized the complex behavior of his instrument as being very similar
- to the electrical physiology of living cells.He then began a series of experiments on plants, animals, and
- minerals, that showed similar responses to all kinds of stimulation, including mechanical and thermal and
- electromagnetic.The idea of metal fatigue wasn't new, but Bose was able to think far beyond the ideas of the
- metallurgists. Biologists were thinking of electrical responsiveness as a defining feature of life, and Bose
- demonstrated that plants had electrical responsiveness very similar to that of animals, but also that similar
- reactions could be demonstrated in minerals.This was what disturbed the English scientists. Sensitivity,
- irritability, fatigue, and memory were supposed to be special properties related to life, and maybe to
- consciousness. For the Englishmen, there were religious implications in this Hindu's research.There were several
- reasons that European and American scientists couldn't accept the universal nature of the electrical properties
- that they were studying in animals. One of their motives was to see life as something immaterial, or of an
- absolutely different nature than inorganic matter. Another problem had to do with the developing belief that the
- special properties of life were enclosed in the hereditary substance of each cell, and that the electrical
- functions of cells were produced entirely by the presence of a membrane, surrounding a drop of water containing
- randomly moving dissolved chemicals. For the membrane electricity theory, it was essential to believe in
- the random behavior of things dissolved in the cell water.So they considered the electrical-mechanical reactions
- and interactions of minerals to be so unlike the processes of life that it was inappropriate to see analogies
- between them. Minerals were composed of atoms, and, according to the doctrine of the time, they could have no
- "physiological" functions except on the atomic scale. It was more than 20 years before mainstream physicists
- began thinking about "delocalized" forces and fields in minerals. Between 1915 and 1934, Michael Polanyi
- made many observations that made it clear that the old kind of electrical atomism was completely unfounded. The
- behavior of mineral crystals, and the interactions between different phases of material, such as gas or liquid
- with a solid, could be understood only in terms of relatively long-range forces. Polanyi's experiments showed,
- for example, that events on the surface of a crystal modified the strength and deformability of the
- crystal. Many others between 1900 and 1940-- Lepeschkin, Nasonov, Bungenberg de Jong, and Solco Tromp, for
- example--argued that the sensitivity of protoplasm had to be understood in terms of long range order, something
- like a liquid crystalline state of matter that would require some of the kinds of knowledge of matter that were
- being developed by physicists, metallurgists, and a variety of others investigating the condensed states of
- matter.But the mainstream biologists preferred to describe cells in terms that would make impossible any of the
- responsivities or sensitivities seen in the "simple" solid state of minerals. To defend their ideology of the
- immateriality of life, they denied that the subtlest features of matter had anything to do with life, reducing
- life to a debased set of special, merely theoretical, mechanisms. The now defunct physical theory of merely
- localized atomic electrical forces became the paradigm for the new biology. The many demonstrations of coherent,
- ordered physical behavior of the cytoplasm, for example Gurwitch's mitogenic radiation, were dismissed with
- prejudice. During G. W. Crile's long career (1889-1941), understanding shock, biological energy, and
- fatigue were his main concerns. He believed that shock was the result of brain exhaustion, and in one of his
- last publications he showed that the brains from exhausted animals produced less bioluminescence than those from
- rested animals. His importance was in demonstrating that fatigue and shock are systemic conditions of the
- organism, rather than isolated events in muscles and nerves. Recent publications are showing the validity of
- this view. Crile's approach to the prevention and treatment of shock was based on isolating the damaged area
- with local anesthetics. Blocking the nerves from one injured part of the body, for example the sciatic nerve in
- the leg, could preserve energy production (and normal cell functions) throughout the rest of the body.About 30
- years earlier (1901), Vvedensky had demonstrated that some types of fatigue appear to be a defensive blocking of
- responsiveness, such that intense stimulation would produce no response, while weak stimulation could sometimes
- produce a response. These changes affected cell functions in a variety of ways, that he called narcosis and
- parabiosis.There have been two popular ways to "explain" fatigue, one by saying that the cell's energy (usually
- thought of as ATP or glycogen) is used up, the other saying that the accumulation of a metabolic product
- (usually lactic acid) prevents further functioning. The obvious problem with these explanations is that the
- fatigue response is quite independent of those metabolic changes. Another problem is that those ideas don't
- explain the real changes that occur in cells that are demonstrating fatigue.Fatigued cells take up water, and
- become heavier. They also become more permeable, and leak. When more oxygen is made available, they are less
- resistant to fatigue, and when the organism is made slightly hypoxic, as at high altitude, muscles have more
- endurance, and are stronger, and nerves conduct more quickly. These facts don't fit with the standard model of
- the cell, in which its sensitivity is strictly governed by the behavior of its "membrane." (For example, how can
- a membrane leak large molecules at the same time that it is intact and causing the cell to swell osmotically?)
- They are consistent with the model of the cell that treats protoplasm as a special phase of matter.Another
- feature of fatigue (and often of aging, stress, and sickness) is that the relaxation of muscles is retarded and
- impaired.Hypothyroidism causes muscle relaxation to be slowed, both in skeletal muscles and in the heart. F/Z.
- Meerson showed that stress causes heart muscles to be exposed to increased calcium, followed by breakdown of
- fats and proteins, and that these changes keep the injured heart in a continuous state of partial contraction,
- making it stiff, and resistant to complete contractile shortening. When many cardiologists talk about the
- heart's stiffness, they are thinking of muscular thickening and fibrosis, but those are late consequences of the
- kind of contractile, unrelaxed stiffness that Meerson described.The hypothyroid heart does eventually become
- fibrotic, but before that, it is just unable to relax properly, and unable to contract fully. This failure to
- empty fully with each contraction is a kind of "heart failure," but it can be corrected very quickly by
- supplementing thyroid. Even the fibrotic heart can recover under the influence of adequate thyroid.The analogy
- of the "coherer" would suggest that the overstimulated muscle isn't able to decohere itself, until it has had a
- rest. It responds to stimulation, lets the energy flow, but then can't turn it off, and the energy keeps
- flowing, because of a change in physical state. Albert Szent-Gyorgyi was probably the first person to
- seriously investigate the semiconducting properties of living material. Since he was aware of W.F. Koch's idea
- of a free radical catalyst to support oxidative metabolism, his suggestion in 1941 that cellular proteins could
- function as electrical conductors (or semiconductors) was very likely based on his research in cellular
- respiration, as well as on his work with muscle proteins. He had observed that ATP lowers the viscosity of a
- solution of the muscle protein myosin, and that it would cause a filament formed by precipitating myosin to
- contract. The polymerization and contraction of proteins under the influence of free radicals was at the heart
- of F.W. Koch's therapeutic ideas, but Koch's work was about 100 years too early, by medical
- standards.Szent-Gyorgyi observed that, although ATP was involved in the contraction of muscles, its post-mortem
- disappearance caused the contraction and hardening of muscles known as rigor mortis. When he put hardened dead
- muscles into a solution of ATP, they relaxed and softened. The relaxed state is a state with adequate energy
- reserves.After Szent-Gyorgyi moved to the U.S., in 1947, he demonstrated the effect of muscle cytoplasm on the
- behavior of fluorescent substances, which was analogous to that of ice, until the muscle was stimulated. During
- contraction, the fluorescent material behaved as it would in ordinary liquid water. This effect involved the
- stabilization of the excited state of electrons. This single demonstration should have caused biologists to
- abandon the membrane theory of cellular excitation, and to return to basic physics for their understanding of
- cell behavior. The implications of Szent-Gyorgyi's work were enormous for biology and medicine, and even for the
- understanding of semiconductors, but most of the world was hypnotized by a simple textbook model of cell
- membranes.Szent-Gyorgyi also demonstrated that the combination of properly balanced electron donors and electron
- acceptors (D-A pairs) would cause a muscle to contract. He compared this to "doping" an inorganic
- superconductor, to regulate its electronic behavior. Although these experiments were done half a century after
- Koch's application of free radical chemistry to medicine, they still didn't rouse the pharmaceutical industry
- from its toxic slumber.I suspect that it was Szent-Gyorgyi's research with those interesting electronic
- properties of cellular water and proteins that in 1960 gave Linus Pauling the idea to explain anesthesia,
- specifically noble gas anesthesia, in terms of water clathrate formation, the restructuring of cellular water by
- the hydrophobic atom or molecule of an anesthetic. His suggestion caused a reaction among biologists that
- discouraged research into the subject for about 40 years.Gilbert Ling's view of cytoplasmic structure gives a
- different emphasis to the function of electrons, which I think is an essential complement to Szent-Gyorgyi's
- view. Ling's emphasis is on how the inductive effect of adsorbed substances (for example, ATP and progesterone
- has powerful adsorptive effects) on proteins changes the charge concentration on ionizable groups. When the
- charge concentration is in one configuration (more acidic), the preferred counterion is potassium, and in
- another (less acidic) configuration, it is sodium. Gilbert Ling's biophysical calculations were useful to
- physical chemists, and were soon put to practical use for understanding ion exchange resins, such as water
- softeners. Many sorts of evidence showed their validity for cell physiology, but nearly all biologists rejected
- them, preferring to talk about membranes, pumps, and channels, despite the evidence showing that the properties
- ascribed to those are simply impossible. NMR imaging (MRI) was developed by Raymond Damadian specifically as an
- application of Ling's description of cell physiology.Although metals are conductors, the function of the
- coherers of Bose and others shows that the surface is a semiconductor, that requires the slight excitation of an
- electromagnetic wave to become conductive, at which point the conduction band of electrons in the metal becomes
- coherent and extends from one particle into the others. The surface of any phase of a substance has electronic
- properties distinct from those of the bulk phase, and in a sense the interface constitutes a special phase of
- matter. When the electrons of the interface lose their special properties, the structure of the whole
- system changes.When a muscle cell is stimulated enough to cause a contraction, the interruption of its resting
- phase causes a shift in the charge concentration on the proteins, potassium ions are exchanged for sodium ions,
- calcium ions enter, and phosphate ions separate from ATP, and are replaced by the transfer of phosphate to ADP
- from creatine phosphate. Since the quantum physicist E. Schroedinger wrote his book, Time's Arrow, people
- have often thought of life in terms of negentropy, going against the general tendency of entropy to increase,
- except for aging and death, which are seen as obeying a law of increasing entropy. But A. Zotin investigated
- organisms, rather than abstractions about electrons, and shows that aging involves a decrease in entropy, and a
- slowing of metabolism. The decrease of entropy with aging, according to his view, would be analogous to
- crystallization, a sort of progressive freezing.When a nerve is stimulated, it releases energy suddenly, and
- much of this heat seems to be the result of a change of structure in the cytoplasm, since (in crustaceans'
- nerves, which can function at low temperature) during the resting recovery of the nerve, its temperature goes
- slightly below the ambient temperature, despite the release of some heat from the chemical changes of
- metabolism, stimulated by the nerve's activity. When a physical change is endothermic, as the nerve's
- recovery is, that can be interpreted as an increase in overall entropy, as when a rubber band spontaneously
- contracts, and becomes cooler.Bose's rested coherer, which, with time, spontaneously recovered its
- semiconductive (i.e., relatively insulating) property, wasn't being powered by metabolism. As the particles
- returned to their relatively isolated state, there was a decrease of order, and the change was probably somewhat
- like the spontaneous energy change in the stimulated crustacean nerve. I assume the change would result from the
- absorption of environmental heat, possibly with infrared resonance with electron conduction bands.Seeing the
- structure of the cytoplasm as something like a spring-driven mechanism, able to bounce between two states or
- "phases," makes it easier to see cellular fatigue as something different from the various metabolic energy
- sources, ATP, glycogen, and oxygen, which--contrary to conventional assumptions--aren't closely tied to the
- functional losses occurring in fatigue.The role of metabolism, then, becomes analogous to the role of the
- "tapper" in the early forms of the coherer.Water in its normal state is a dielectric. But when it is polarized
- by an electrical charge, or by the presence of a phase boundary, its normal state is altered. This is the
- special interfacial water, or vicinal water. With the movement of ions (mainly potassium, sodium, calcium, and
- magnesium) during excitation, the state of the cellular water is necessarily changed by the presence of
- different substances. In the excited state, cell water is less hydrophobic, more hydrophilic than in the relaxed
- state. A network of "hydrophobic" interactions extends through the relaxed cell. One of the properties of a
- dielectric is that it tends to move into the space between charges, with a force similar in principle to that
- involved in dielectrophoresis. In the resting state, potassium is the main inorganic ion, and it is
- associated with acidic groups, such as aspartic and glutamic acid. During excitation, potassium is partly
- exchanged for sodium, which becomes the preferred counter-ion for the acid groups, and calcium enters the cell
- along with the sodium. Potassium's interaction with water is very weak (its hydration has been called negative),
- allowing water to form the structures that are stable in the presence of hydrophobic surfaces. Sodium and
- especially calcium (smaller atoms, with higher surface charge concentration) powerfully interact with water
- molecules, more strongly than water interacts with itself, disrupting the delicate somewhat hydrophobic
- structures of the intracellular water.(Calcium, with its two charges, has important binding and stabilizing
- functions in the resting cell. In the excited cell, these internal calcium ions are released, while
- extracellular calcium ions enter the cell.)With the increased movement of charged particles during the
- stimulation of a nerve or muscle, as one kind of counterion is exchanged for another, and the destruction of
- some of the water's structure, there are more opportunities for bulk dielectric water to enter cells,
- interfering with the arrangement of proteins, and tending to cause swelling and separation of the structural
- elements of the cell. Electron micrographs of fatigued muscle show a remarkable separation of the actin and
- myosin proteins.In the excited state, NMR studies show that cell water behaves more like bulk water, that is,
- its molecular movements are relatively free, indicating the momentary loss of the interfacial state. In this
- state, the uptake of water, and the fatigue-related swelling of nerves and muscles, would be driven at least
- partly by the principle that a dielectric tends to be pulled into the spaces separating charges. The bulk water
- that enters a cell during the breakdown of vicinal water functions as an extraneous material somewhat beyond the
- cell's control.These bulk-like high dielectric properties of water in the excited cellular state can explain
- many changes of enzyme activity. Previously nonpolar lipids would develop a negative surface charge (from
- accumulating hydroxyl groups: Marinova, et al., 1996), which would tend to increase their oxidation and
- degradation. With the loss of the interfacial water, the cell's high energy resting state is replaced by an
- active mobilization of its resources, to maintain and restore the cell's structure. Metabolic energy begins to
- flow into the processes of restoration, serving the function of the tapper in the earliest coherers.Looking at
- fatigability, muscle contraction, and nerve conduction in a variety of situations, we can test some of the
- traditional explanations, and see how well the newer "bioelectronic" explanations fits the facts. Osmotic
- pressure, hydrostatic pressure, atmospheric pressure, and the degree of metabolic stimulation by thyroid hormone
- affect fatigue in ways that aren't consistent with the membrane-electrical doctrine.The production of lactic
- acid during intense muscle activity led some people to suggest that fatigue occurred when the muscle wasn't
- getting enough oxygen, but experiments show that fatigue sets in while adequate oxygen is being delivered to the
- muscle. Underwater divers sometimes get an excess of oxygen, and that often causes muscle fatigue and soreness.
- At high altitudes, where there is relatively little oxygen, strength and endurance can increase.An excess of
- oxygen can slow nerve conduction, while hypoxia can accelerate it. (Increasing the delivery of oxygen at higher
- pressure doesn't increase the cellular use of oxygen or decrease lactic acid production in the exercising muscle
- [Kohzuki, et al., 2000], but it will increase lipid peroxidation.)High hydrostatic pressure causes muscles to
- contract, though for many years the membrane-doctrinaires couldn't accept that. Underwater divers experience
- brain excitation under very high pressure. Since vicinal water has a larger volume than ordinary water
- (analogous to the expansion when ice is formed, though the volume increase in cell water is slightly less, about
- 4%, than in ice, which is 11% more voluminous than liquid water), compression under high pressure converts
- vicinal cell water to the state that occurs in the excited cell, the way ice melts under pressure. The excited
- state exists as long as water remains in that state.These changes of state under pressure are reminiscent of
- Bose's use of pressure in some of his coherers, and of the fact that pressure alters the sensitivity of
- electrons in a semiconductor, by altering their "band gap," the amount of energy needed to make them enter the
- conductive zone.One of the early demonstrations that cell water undergoes a phase change during muscle
- contraction involved simply measuring the volume of an isolated muscle. With stimulation and contraction, the
- volume of the muscle decreases slightly. (The muscle was immersed in water in a sealed chamber, and the volume
- decrease in the whole chamber was measured.) This corresponds to the conversion of vicinal water to
- bulk-like (dielectric) water. (The threatening implications of those experiments with spontaneous volume
- change were very annoying to many biologists of my professors' generation.)In the stimulated state, the cell's
- uptake of water from its environment coincides closely with its electrical and thermal activity, and its
- expulsion of water coincides with its recovery. In a small nerve fiber, or near the surface of a larger fiber,
- these changes are very fast, and in a large muscle the uptake of water is faster than the flow of water from
- capillaries can match, but it will become massive if stimulation is continued for several minutes. For example,
- two minutes of stimulation can cause a muscle's overall weight to increase by 6%, but its extracellular
- compartment loses 4%, so the muscle cells gain much more than 6% of their weight in that short time (Ward, et
- al., 1996). The water that is taken up by cells is taken from the blood, which becomes relatively dehydrated and
- thicker in the process.The belief in "semipermeable membranes" (which hasn't been a viable explanation of cell
- physiology for a very long time) forces people to explain cell swelling osmotically, which means that they
- simply assume that the number of solute particles inside the cell has drastically increased in a very short
- time. In Tasaki's experiments (1980, 1981, 1982), the swelling in a nerve coincides with the electrical action
- potential, which, according to the osmotic explanation, means that a very large increase in internal osmolarity
- happened in essentially no time. The action potential comes and goes in about 2 milliseconds. The swelling also
- coincides with heat production and shortening of the nerve fiber. The shrinkage of the nerve fiber after the end
- of the action potential may be just as rapid, and the membrane theory offers no explanation for that, either.
- (But the restoration of the unswollen state can be very prolonged, depending on conditions extrinsic to the
- particular muscle or cell.) Troshin's survey of the theory of osmotic regulation of cell volume showed that the
- idea of the cell as a membrane osmometer was false, but very few biologists read his book.Since the excited or
- fatigued muscle or nerve swells and gains weight, it's interesting to see what happens to their sensitivity and
- strength when they are exposed to hypotonic solutions that tend to promote swelling, or to hypertonic solutions,
- that help to prevent swelling.In a hypotonic solution, cells are excited (Lang, et al., 1995: "Exposure of
- aortic strips from guinea-pigs to hypotonic extracellular fluid is followed by marked vasoconstriction..."), but
- the early excitation is followed by decreased responsiveness (Ohba, et al., 1984: "Exposure of muscle to
- hypotonic solutions [70% of normal solution] produced initially a transient increase in twitch after which
- twitch declined below the control level"). Hypertonic solutions tend to produce relaxation in normal muscles,
- including the aorta (Tabrizchi, 1999), but when muscle function is impaired (especially in the circulatory
- system, as in shock) they improve contractile function (Elgjo, et al., 1998: "The maximum contraction force
- measured in isolated right papillary muscles ex vivo was significantly greater in HSD-treated than normal
- saline-treated animals"). Athletes can lose 4% of their weight by dehydration without decreasing their muscular
- strength.Hypothyroidism tends to cause loss of sodium from the blood, and the hyponatremia sometimes leads to a
- generalized hypotonicity of the body fluids. The thyroid hormone itself functions as an antioxidant, but much of
- its protective effect against cell damage is probably the result of preventing cell swelling and accelerating
- the removal of calcium from the cell. (Swelling, like fatigue, causes intracellular calcium to increase.)The
- electrical surface charging of lipids in bulk water probably accounts for the increased lipid peroxidation that
- occurs in fatigue, edema, and hypothyroidism, when water loses its normal partial hydrophobicity. Increased
- carbon dioxide is known to decrease lipid peroxidation, and its production requires adequate thyroid
- function.Thyroid stimulation of oxygen consumption tends to prevent lactic acid production, because it keeps the
- cytoplasm in a state of relative oxidation, i.e., it keeps the concentration of NAD+ hundreds of times higher
- than that of NADH. NADH is required for the conversion of pyruvate to lactate. It is also the source of reducing
- potential in many kinds of toxic redox cycling, that generate lipid peroxides, and it maintains the sulfhydryl
- system, involving the balance of reduced glutathione with the sulfhydryl-disulfide system of protein bonds,
- which governs the cell's electronic state and affects its balance of hydrophobicity and hydrophilicity.The
- harmful lipid oxidation interferes with energy production and regulatory processes, and is responsible for some
- of the prolonged effects of fatigue, swelling, and hypothyroidism. These lingering effects of lipid oxidation
- are undoubtedly amplified by the presence of larger amounts of unstable polyunsaturated fats, as the energy
- demands of the fatigued state mobilize free fatty acids from the tissues. One of the oldest tests for
- hypothyroidism was the Achilles tendon reflex test, in which the rate of relaxation of the calf muscle
- corresponded to thyroid function--the relaxation is slow in hypothyroid people. Water, sodium and calcium are
- more slowly expelled by the hypothyroid muscle. Exactly the same slow relaxation occurs in the hypothyroid heart
- muscle, contributing to congestive heart failure, because the semi-contracted heart can't receive as much blood
- as the normally relaxed heart. The hypothyroid blood vessels are unable to relax properly, contributing to
- hypertension. Hypothyroid nerves don't easily return to their energized relaxed state, leading to insomnia,
- paresthesias, movement disorders, and nerves that are swollen and very susceptible to pressure damage. With
- aging, hypothyroidism, stress, and fatigue, the amount of estrogen in the body typically rises. Estrogen is
- catabolic for muscle, and causes systemic edema, and nerve excitation. It weakens muscle contraction in the
- bladder, although it lowers the threshold for stimulation of sensation and contraction (Dambros, et al., 2004).
- This is the pattern that causes people to wake up frequently, to pass a small amount of urine. (Progesterone has
- the opposite effect in the urinary bladder, raising the threshold of response, but strengthening contraction, as
- it does in the gallbladder.) Estrogen lowers stimulation threshold in the gallbladder, as it does in the brain.
- Part of its excitatory action might be the result of increased hypotonic tissue water, but its effects on nerve
- thresholds are practically instantaneous. In 1971 and '72, I gave some of the reasons for thinking that
- estrogen's biological effects result from its direct effects on cell water, causing it to become more like bulk
- (high dielectric) water. For example, NMR (spin echo) of estrogen treated uterus and of the uterus from an old
- animal were closer to bulk water than that of a young animal. Estrogen, like fatigue or excessive oxygen, slows
- nerve conduction.Lactic acid production increases with fatigue, aging, hypothyroidism, estrogen excess, and
- other inefficient biological states. Its presence, when oxygen is available, indicates that something is
- interfering with efficient oxidative energy metabolism. Ammonia, free fatty acids, and various inflammatory
- cytokines are also likely to increase in those stress states.A dangerously high level of ammonia in the blood
- (hyperammonemia) can be produced by exhaustive exercise, but also by hyperbaric oxygen (or a high concentration
- of oxygen), by high estrogen, and by hypothyroidism. It tends to be associated with an excess of lactic acid,
- probably because ammonia stimulates glycolysis. Excess oxygen, like hypothyroidism, is equivalent to
- "hyperventilation," in producing an abnormally low level of carbon dioxide in the blood. The Krebs cycle, during
- stress, is limited by the unavailability of carbon dioxide. These factors result in the waste of glucose,
- turning it into lactic acid, rather than carbon dioxide and energy. In these ways, the metabolism of fatigued
- muscle (or any cell under stress) is similar to tumor metabolism.Hyperammonemia disturbs excitatory processes,
- and can cause seizures, as well as stupor, and is probably involved in mania and depression. Lithium happens to
- complex electronically with ammonia, and I think that accounts for some of its therapeutic effects, but carbon
- dioxide is the main physiological factor in the elimination of ammonia, since it combines with it to form urea.
- The changes in cell water in the excited/fatigued state represent an increase in the water's "structural
- temperature," and that would imply that less carbon dioxide could remain dissolved during excitation.Eating
- sugar and using caffeine, which increases the oxidation of sugar (Yeo, et al., 2005), can reduce fatigue, both
- subjectively and objectively. Metabolically, they increase the production of carbon dioxide. Increasing sugar
- decreases the liberation and use of fatty acids, and by a variety of mechanisms, helps to lower the production
- of ammonia, lactate, and inflammatory cytokines. (Lactic acid, in combination with acidosis and free
- phospholipids, can interfere with efficient cell functions [Pacini and Kane, 1991; Boachie-Ansah, et al.,
- 1992].) Free fatty acids release tryptophan from albumin, contributing to the formation of serotonin, which
- increases the sense of fatigue.Aspirin and niacin help to prevent fatigue symptoms, and to prevent many of the
- harmful systemic oxidative after-effects. (Both are antilipolytic; aspirin uncouples mitochondria.)Uncoupling of
- mitochondrial oxidative metabolism from ATP production helps to consume the sugar which otherwise would be
- diverted into lactic acid, and converts it into carbon dioxide instead. Mild hypoxia, as at high altitude,
- suppresses lactic acid production ("the lactate paradox"), and increases the amount of carbon dioxide in
- tissues. Aspirin and thyroid (T3) increase uncoupling. A drug that used to be used for weight reduction,
- DNP, also uncouples mitochondrial metabolism, and, surprisingly, it has some of the beneficial effects of
- thyroid and aspirin. It stimulates the consumption of lactic acid and the formation of carbon dioxide.The
- squirrel monkey, which on average weighs about 2 or 3 pounds as an adult, lives much longer than other mammals
- of its size, usually about 20 years, as long as 27. It has an extremely high rate of oxygen consumption. This is
- probably the result of natural uncoupling of the mitochondria, similar to that seen in long-lived mice. Mice
- with 17% higher resting oxygen consumption lived 36% longer than slow respiring mice of a related strain
- (Speakman, et al., 2004).Living at a high altitude, people tend to eat more and stay leaner than when they live
- near sea level. Apparently, their mitochondria are relatively uncoupled, and they have more mitochondria, which
- would partly account for their lower production of lactic acid during muscular exertion. Increased thyroid
- activity, too, tends to increase mitochondrial mass, as well as their uncoupling.Most of the things that we
- think of as fatigue result from disturbances of the hydration of cells, whose sensitivity, composition, and
- structure change according to the extent of the disturbance. The hydration is governed by the cells'
- "electrical" properties, which are regulated by internal metabolic processes and by systemic processes. When
- cellular fatigue reaches a certain point, only the interactions of all the organs can restore stable cellular
- structure and functions. The liver eliminates lactic acid and ammonia, the adrenals and gonads provide
- stabilizing steroids, and the brain alters activity and behavior, in ways that can reverse most of the effects
- of fatigue.But, when the tissues contain large amounts of polyunsaturated fats, every episode of fatigue and
- prolonged excitation leaves a residue of oxidative damage, and the adaptive mechanisms become progressively less
- effective. When the most powerful adaptive mechanisms, such as the timely synthesis of progesterone,
- pregnenolone, DHEA, T3, and the inhibitory transmitters, GABA and glycine, fail, then some of the primitive
- defense mechanisms will become chronically activated, and even sleep may fail to restore normal cellular water
- and metabolism. Hyperventilation often becomes a problem, making capillary leakiness worse.Water in the body
- occupies three major compartments--blood vessels, extracellular matrix, and the moist cell substance itself--and
- its condition in each compartment is a little different, and subject to variation. There are no textbooks in use
- in the U.S. that treat intracellular water scientifically, and the result is that physicians are confused when
- they see patients with edema or with disturbances in blood volume. It rarely occurs to physicians to consider
- disturbances of water distribution in problems such as chronic fatigue, fibromyalgia, sleep disturbances,
- frequent urination, slow bladder emptying, anxiety, paresthesia, movement disorders, the tunnel syndromes, or
- even slowed thinking, but "intracellular fatigue" leading to over-hydration is probably the central problem in
- these, and many other degenerative and inflammatory problems. The improvements in cell functions and water
- distribution that are inversely related to oxygen pressure, and directly related to carbon dioxide, won't be
- discussed in medical textbooks until they have given up the idea of membrane-regulated cells. The
- "treatment" for intracellular fatigue consists of normalizing thyroid and steroid metabolism, and eating a diet
- including fruit juice, milk, some eggs or liver, and gelatin, assuring adequate calcium, potassium sodium, and
- magnesium, and using supplements of niacin-amide, aspirin, and carbon dioxide when necessary. Simply increasing
- carbon dioxide decreases lactic acid and ammonia, increases GABA (the sleep improving nerve inhibitor), and
- regulates mineral and water disposition.One of the outcomes of the study of the physiology of fatigue is that it
- leads to a better understanding of cells in general, and offers some new insights into aging, inflammation, and
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