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Thread: Amino 411

  1. Back To Top    #1

    Amino 411

    Amino 411
    There are three types of amino acids; the indispensable amino acids, the conditionally dispensable amino acids, and the dispensable amino acids. Indispensable amino acids, also called essential amino acids, must be supplied to the body from food or supplements. Conditionally dispensable amino acids are based on the body's ability to actually synthesize them from other amino acids. Dispensable amino acids, also called nonessential amino acids, can be synthesized by the body from other amino acids. Here is the amino acid guide and their benefits.

    The Indispensable Amino acids


    A branched chain amino acid readily taken up and used for energy by muscle tissue.
    Used to prevent muscle wasting in debilitated individuals
    Essential in the formation of hemoglobin


    A branched chain amino acid used as a source of energy
    Helps reduce muscle protein breakdown
    Modulates uptake of neurotransmitter precursors by the brain as well as the release of enkephalins, which inhibit the passage of pain signals into the nervous system.
    Promotes healing of skin and broken bones.


    A branched chain amino acid
    Not processed by the liver; rather actively taken up by muscle
    Influences brain uptake of other neurotransmitter precursors (trptophan, phenylalanine and tryosine).


    One of the major ultraviolet absorbing compounds in the skin
    Important in the production of red and white blood cells; used in the treatment of anemia
    Used in the treatment of allergic diseases, rheumatoid arthritis and digestive ulcers.


    Low levels can slow protein synthesis, affecting muscle and connective tissue
    Inhibits viruses; used in the treatment of herpes simplex
    Lysine and Vitamin C together form L-carnitine, a biochemical that enables muscle tissue to use oxygen more efficiently, delaying fatigue
    Aids bone growth by helping form collagen, the fibrous protein that makes up bone, cartilage and other connective tissue.


    Precursor of cystine and creatine
    May increase antioxidant levels (glutathione) and reduce blood cholesterol levels.
    Helps remove toxic wastes from the liver and assists in the regeneration of liver and kidney tissue


    The major precursor of tyrosine
    Enhances learning, memory, mood and alertness
    Used in the treatment of some types of depression
    Is a major element in the production of collagen
    Suppresses appetite


    One of the amino detoxifers
    Helps prevent fatty buildup in the liver
    Important component of collagen
    Generally low in vegetarians


    Precursor of key neurotransmitter serotonin, which exerts a calming effect
    Stimulates the release of growth hormones
    Free form of this amino acid is unavailable in the U.S.
    It is only available in natural food sources

    Conditionally Dispensable Amino Acids


    Can increase secretion of insulin, glucagon, growth hormones
    Aids in injury rehabilitation, formation of collagen and immune system stimulation.
    Precursor of creatine, gamma amino butric acid (GABA, a neurotransmitter in the brain)
    May increase sperm count and T-lymphocyte response


    Detoxifies harmful chemicals in combination with L-aspartic acid and L-citruline
    Helps prevent damage from alcohol and tobacco use
    Stimulates white blood cell activity


    Precursor of the neurotransmitters dopamine, norepinephrine and epinephrine, as well as thyroid and growth hormones and melanin (the pigment responsible for skin and hair color).
    Elevates mood

    Dispensable Amino Acids


    Major component of connective tissue
    Key intermediate in the glucose alanine cycle, which allows muscles and other tissues to derive energy from amino acids
    Helps build up the immune system

    Aspartic Acid

    Helps convert carbohydrates into muscle energy
    Builds immune system immunoglobulins and antibodies
    Reduces ammonia levels after exercises


    Contributes to strong connective4e tissue and tissue antioxidant actions
    Aids in healing processes, stimulates white blood cell activity and helps diminish pain from inflammation
    Essential for the formation of skin and hair

    Glutamic Acid

    A major precursor of glutamine, proline, ornothine, arginine, glutathione, and GABA
    A potential source of energy
    Important in brain metabolism and metabolism of other amino acids.


    Most abundant amino acid
    Plays a key role in immune system functions
    An important source of energy, especially for kidneys and intestines during caloric restrictions.
    A brain fuel that is an aid to memory and a stimulant to intelligence and concentration


    Aids in the manufacture of other amino acids and is a part of the structure of hemoglobin and cytochromes (enzymes involved in energy production)
    Has a calming effect and is sometimes used to treat manic depressive and aggressive individuals
    Produces glucagon, which mobilizes glycogen
    Can inhibit sugar cravings


    May help increase growth hormone secretion in high doses
    Aids in immune and liver function
    Promotes healing


    A major component in the formation of connective tissue and heart muscle
    Readily mobilized for muscular energy
    Major constituent of collagen


    Important in cells' energy production
    Aids memory and nervous system function
    Helps builds up immune system by producing immuno-globulins and antibodies


    Aids in the absorption and elimination of fats
    May act as a neurotransmitter in some areas of the brain and retina

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  2. Back To Top    #2
    First, what is an amino acid? Amino Acids are chemical substances that make up protein. There are 20 amino acids, of those there are 8 essential amino acids. An essential amino acid is one that cannot be synthesized from other available resources, and therefore must be supplied as part of the diet. Not all amino acids need to be supplied. Alanine can be synthesized from pyruvate in humans, but humans cannot synthesize phenylalanine and hence it is an essential amino acid.

    The boundary between an essential amino acid and one that is not can sometimes be unclear. Methionine and homocysteine, sulfur-containing amino acids, can be converted into each other, but neither can be synthesized from scratch in humans. Cysteine can be made from homocysteine, but it cannot be synthesized from scratch either. So, for convenience, people will sometimes count the sulfur-containing amino acids as a single pool. Likewise, because of the urea cycle, arginine, ornithine, and citrulline are interconvertible, and therefore form a single pool of nutritionally-equivalent amino acids.

    Foodstuffs that are lacking essential amino acids are poor sources of protein equivalents, as the body will tend to deaminate the amino acids obtained and convert proteins into fats and carbohydrates instead. Therefore, a balance of essential amino acids is necessary for a high degree of net protein utilization, which is the mass ratio of amino acids converted to proteins to amino acids supplied. This figure is somewhat affected by salvage of essential amino acids in the body, but otherwise is profoundly affected by the limiting amino acid content, which is the essential amino acid found in the smallest quantity in the foodstuff.


  3. Back To Top    #3
    Amino acids play central roles both as building blocks of proteins and as intermediates in metabolism. The 20 amino acids that are found within proteins convey a vast array of chemical versatility. The precise amino acid content, and the sequence of those amino acids, of a specific protein, is determined by the sequence of the bases in the gene that encodes that protein. The chemical properties of the amino acids of proteins determine the biological activity of the protein. Proteins not only catalyze all (or most) of the reactions in living cells, they control virtually all cellular process. In addition, proteins contain within their amino acid sequences the necessary information to determine how that protein will fold into a three dimensional structure, and the stability of the resulting structure. The field of protein folding and stability has been a critically important area of research for years, and remains today one of the great unsolved mysteries. It is, however, being actively investigated, and progress is being made every day.

    As we learn about amino acids, it is important to keep in mind that one of the more important reasons to understand amino acid structure and properties is to be able to understand protein structure and properties. We will see that the vastly complex characteristics of even a small, relatively simple, protein are a composite of the properties of the amino acids which comprise the protein.

    Essential amino acids
    Humans can produce 10 of the 20 amino acids. The others must be supplied in the food. Failure to obtain enough of even 1 of the 10 essential amino acids, those that we cannot make, results in degradation of the body's proteins—muscle and so forth—to obtain the one amino acid that is needed. Unlike fat and starch, the human body does not store excess amino acids for later use—the amino acids must be in the food every day.

    The 10 amino acids that we can produce are alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine and tyrosine. Tyrosine is produced from phenylalanine, so if the diet is deficient in phenylalanine, tyrosine will be required as well. The essential amino acids are arginine (required for the young, but not for adults), histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. These amino acids are required in the diet. Plants, of course, must be able to make all the amino acids. Humans, on the other hand, do not have all the the enzymes required for the biosynthesis of all of the amino acids.


  4. Back To Top    #4
    Eating quality food is the most common way to get amino acids into the diet, especially high protein foods like lean meats and nonfat dairy products. Even some vegetables and legumes can offer high levels of most amino acids. For serious athletes and those on the run, protein powders and pure free form amino acids provide a convenient and effective means to supplement dietary needs.

    Why would people pay relatively large sums of money for only a few grams of pure cheaply? Because of bioavailability.

    Bioavailability gauges the extent to which an administered substance reaches its site of action or utilization in the body. Bioavailability is thus a measure of the efficiency of delivery - how much of what is ingested is actually used for its intended purpose.

    Conceivably, two diets could contain exactly the same amount of particular amino acids (the same amino acid profile) but have significant differences in their absorption. A number of factors affect amino acid bioavailability (see Factors Affecting Amino Acid Bioavailability.

    The most reliable way to deliver specific amino acids is to administer the particular amino acids themselves. The most bioavailable source for oral use is powdered free form amino acids.

    A singular (unbonded) amino acids can specifically elevate its level in the general circulation within 15 minutes, making it readily available for metabolism at the site where it's needed. Hence, for example, the recommendation to use BCAAs before, during and after training both to prevent central / mental fatigue, as well as to provide a source of energy to help prevent muscle protein catabolism and to speed recuperation.


  5. Back To Top    #5
    Supplement manufacturers recognized the potential value of free-form amino use was limited by their expense and a relative lack of convincing supportive research for a number of years, their popularity has recently increased dramatically. Prepackaged workout and recovery drinks containing hydrolyzed (predigested) proteins and often some free-form amino acids now fill gym refrigerators. Capsules and powdered free-form amino acids, although still somewhat expensive, are likewise being used by increasing numbers of top amateur and professional athletes.

    The value of free-form amino acids is first and foremost that they don't require digestion. The term 'free-form' means exactly that: They are free of chemical bonds to other molecules and so move quickly through the stomach and into the small intestine, where they're rapidly absorbed into the bloodstream.

    Upon absorption, amino acids are processed by the liver. When you eat a steak, for example, only relatively few amino acids escape the metabolic actions of the liver. Yet the liver can process only so many at one time, and taking a dose of 3-4 grams of rapidly absorbed amino acids exceeds the liver's capacity, resulting in the aminos being directed to the tissues that require them, such as muscle in the case of bodybuilder recovering from training. Thus, the concept of 'directed amino acids'.

    While sound in theory, does it work in practice? As early as 1990, the Bulgarian national weightlifting team began trials to determine if free-form amino acids were a boost to muscular growth. The work was so successful that part of the study was replicated on the Colorado Springs Olympic Training Center. Since then, top bodybuilders and powerlifters around the world today - including Mr. Olympia Dorian Yates, and 'Mr. Powerlifting' Ed Coan - have benefited from this new research.


  6. Back To Top    #6
    Many misconceptions exist about the muscle contraction and the use of energy substrates during heavy during heavy, high-intensity weight training. When you're engaged in a repetitive power workout, a substantial portion of your energy comes from noncarbohydrate sources. When muscle contracts, it uses its stores of adenosine triphosphate (ATP, a substance vital to the energy processes of all living cells) for the first few seconds. The compound used to immediately replenish these stores is creatine phosphate (CP). The recent explosion of creatine supplements in the market attests to its value to hard training bodybuilders and other strength / power athletes.

    CP is made from three amino acids: arginine, methionine and glycine. To keep CP and ATP levels high, these amino acids must be elevated in the bloodstream. Traditionally, these proteins have been supplied by foods in the diet. Elevating levels of these amino acids or of CP with conventional foods takes a great deal of time (for digestion) and isn't specific, typically providing levels of fats and carbohydrates that may or may not be desired. The use of free-form amino acids, alone and in combination with creatine supplements, can provide directed source of energy for power and growth.


  7. Back To Top    #7
    In fat loss, two major processes must occur: 1) the mobilization and circulation of stored fats in the body must increase; and 2) fats must be transported and converted to energy at the powerhouse site of cells, the mitochondria. Several nutrients can assist in the conversion of fat to energy, including lipotropic agents such as choline, inositol and the IAA methionine which, in sufficient quantities, can help improve the transport and metabolism of fat.

    Supplementation with complete IAA mixtures, BCAAs and glutamine can also help keep calorie and food volume down while providing targeted support directly to the muscles, liver and immune systems so critical to optimizing body composition.


  8. Back To Top    #8
    The branched-chain amino acids (BCAAs) are leucine, isoleucine, and valine. BCAAs are considered essential amino acids because human beings cannot survive unless these amino acids are present in the diet.

    BCAAs are needed for the maintenance of muscle tissue and appear to preserve muscle stores of glycogen (a storage form of carbohydrate that can be converted into energy). BCAAs also help prevent muscle protein breakdown during exercise.

    Some research has shown that BCAA supplementation (typically 10-20 grams per day) does not result in meaningful changes in body composition, nor does it improve exercise performance or enhance the effects of physical training. However, BCAA supplementation may be useful in special situations, such as preventing muscle loss at high altitudes and prolonging endurance performance in the heat. Studies by one group of researchers suggest that BCAA supplementation may also improve exercise-induced declines in some aspects of mental functioning.

    BCAAs can active glutamate dehydrogenase—an enzyme that is deficient in amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease. In one double-blind trial, 26 grams per day of BCAA supplements helped those with ALS maintain muscle strength. However, a larger study was ended early when people using BCAAs not only failed to improve, but experienced higher death rates than the placebo group. Other studies have shown no benefit of BCAA supplementation for ALS or other neuromuscular diseases, though a small group of people suffering from diseases of the nervous system collectively called spinocerebellar degeneration did improve when given BCAAs in a preliminary study.

    One study investigating the advantages of BCAA supplementation for people with diabetes undergoing an intense exercise program found no additional benefit of BCAAs on reducing abdominal fat or improving glucose metabolism.

    Patients with liver diseases that lead to coma—called hepatic encephalopathy—have low concentrations of BCAAs and excess levels of certain other amino acids. Preliminary research suggested that people with this condition might be helped by BCAAs. Double-blind studies have produced somewhat inconsistent results, but a reanalysis of these studies found an overall benefit for the symptoms of encephalopathy. Therapeutic effects of BCAAs have also been shown in children with liver failure and adults with cirrhosis of the liver. Any treatment of people with liver failure requires the direction of a physician.

    People with chronic kidney failure may also benefit from BCAA supplementation. A preliminary study found improved breathing and sleep quality in people given intravenous BCAAs during kidney dialysis.

    Phenylketonuria (PKU) is a genetic disease that causes abnormally high amounts of phenylalanine and its end products to accumulate in the blood, causing damage to the nervous system. A controlled trial demonstrated that regular use of BCAAs by adolescents and young adults with PKU, improved performance on some tests of mental functioning. This outcome makes sense because BCAAs may compete with phenylalanine, reducing its toxic effects.

    In tardive dyskinesia, phenylalanine levels have also been reported to be elevated. As a result, one group of researchers gave tardive dyskinesia patients BCAAs (from 150 mg per 2.2 pounds body weight up to 209 mg per 2.2 pounds body weight) after breakfast and one hour before lunch and dinner for two weeks. The BCAA mixture included equal parts valine and isoleucine plus 33% more leucine than either of the other two amino acids. Of nine patients so treated, six had at least a 58% decrease in symptoms, and all people in the study had a decrease of at least 38% in symptoms.

    Where are they found?
    Dairy products and red meat contain the greatest amounts of BCAAs, although they are present in all protein-containing foods. Whey protein and egg protein supplements are other sources of BCAAs. BCAA supplements provide the amino acids leucine, isoleucine, and valine.


  9. Back To Top    #9
    Muscular fatigue is commonly defined as a failure to maintain the required or expected force or power output. The causes of muscular fatigue involve specific impairments within the muscle itself, including transmission of the neural stimulus to the muscle at the motor end plate and propagation of that stimulus throughout the muscle, disruption of calcium release and uptake within the sarcoplasmic reticulum, substrate depletion, and various other metabolic events that impair energy provision and muscle contraction. Fatigue can also result from alterations within the central nervous system (CNS) although essentially nothing is known about the specific mechanisms underlying this type of fatigue (central fatigue).

    The potential role of central fatigue during prolonged exercise has received very little scientific attention, even though it is well known that "psychological factors" can affect exercise performance. In fact, the lack of adequate CNS drive to the working muscles is the most likely explanation of fatigue in most people during normal activities. Furthermore, the often debilitating fatigue that accompanies viral or bacterial infections, recovery from injury or surgery, chronic fatigue syndrome, and depression almost certainly cannot be explained by a dysfunction within the muscles themselves. Fatigue under these circumstances probably involves the CNS, but the specific causes have not been elucidated.

    An important role for central fatigue during exercise in healthy people has been suggested in a number of studies, but most of these investigations have failed to provide plausible physiological mechanisms. Recently, however, interesting new theories have been proposed that implicate various neurotransmitters such as serotonin (5-hydroxytryptamine, or 5-HT), norepinephrine, and dopamine in central fatigue during exercise. This review will focus primarily on the scientific evidence regarding brain 5-HT as a potential mediator of central fatigue during prolonged exercise. The exciting, but more limited, evidence that proper nutrition may be able to alter brain 5-HT synthesis and delay central fatigue will also be discussed. For this review, a working definition of central fatigue will be used which suggests that central fatigue is a subset of fatigue that is associated with specific alterations in CNS function and that cannot reasonably be explained by peripheral markers of muscle fatigue.


    Serotonin was first proposed as a potential mediator of central fatigue by Newsholme and colleagues in 1987. There is a large body of literature linking alterations in brain 5-HT activity to various psychological responses such as arousal, lethargy, sleepiness, and mood, all of which could play a role in the central mechanisms of fatigue. This, along with the realization that the mechanisms controlling 5-HT synthesis and metabolism in the brain are likely to be affected by prolonged exercise, makes 5-HT a particularly attractive candidate for this role.

    In general, the central fatigue hypothesis suggests that increased concentrations of brain 5-HT can impair CNS function during prolonged exercise and thereby cause a deterioration in sport and exercise performance . Increased brain 5-HT synthesis occurs in response to an increased delivery to the brain of blood-borne tryptophan (TRP), an amino acid precursor to 5-HT. Most of the TRP in blood plasma circulates loosely bound to albumin, but it is the unbound or free tryptophan (f-TRP) that is transported across the blood/brain battier. This transport occurs via a specific mechanism that TRP shares with other large neutral amino acids, most notably the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Thus, brain 5-HT synthesis will increase when there is an increase in the ratio of the concentration of f-TRP in blood plasma to the total plasma concentration of BCAAs, that is, when f-TRP/BCAAs rises. It has been proposed that this would occur during prolonged exercise as (a) BCAAs are taken up from the blood and oxidized for energy in contracting skeletal muscles and (b) plasma free fatty acids (FFAs) increase in the blood, causing a parallel increase in plasma f-TRP because FFAs displace TRP from its usual binding sites on plasma albumin molecules.

    Figure 1: Primary components of the central fatigue hypothesis at rest and during prolonged exercise. (a) The situation at rest with regard to plasma concentrations of branched-chain ammo acids (BCAAs), free fatty acids (FFAs), and tryptophan (TRP) (bound and unbound to albumin) and their proposed effects on transport of TRP across the blood-brain barrier for the synthesis of serotonin (5-HT) in serotonergic neurons. (b) What happens during prolonged exercise to increase the synthesis of 5-HT in the brain and lead to central fatigue. Adapted from J.D. Fernstrom. ammo acids and brain function. J. Am. Diet. Dietary Assoc. 94:71-77, 1994.

    Investigators have begun to test the validity of this hypothesis in experiments involving both humans and animals. Several fundamental questions have begun to be addressed, including the following: Is fatigue during prolonged exercise associated with increases in brain concentrations of 5-HT and its major metabolite, 5-hydroxy-indoleacetic acid (5-HIAA), and is this a consequence of increases in plasma f-TRP/BCAAs? Do experimental alterations of brain 5-HT activity cause appropriate changes in exercise fatigue without any apparent effects on peripheral markers of muscle fatigue? Can nutritional supplementation alter the increase in f-TRP/BCAAs and thereby enhance endurance performance? There is now good evidence, albeit preliminary in many ways, to support the central fatigue hypothesis with regard to the first two questions. The evidence regarding the effects of various nutritional strategies designed to alter brain 5-HT and delay central fatigue is more tenuous.


    The initial animal studies were done in laboratories headed by Professors Chaouloff and Newsholme. Chaouloff et al. showed that 1-2 hr. of treadmill running (20 m/min) in rats had no effect on plasma total TRP concentration but caused a marked increase in plasma f-TRP that was accompanied by an increase in brain TRP and a small but significant increase in 5-HIAA (primary metabolite of 5-HT). They later showed that similar increases in TRP and 5-HIAA occurred in the cerebrospinal fluid (CSF) during exercise and that these increases returned to basal levels by about 1 hour thereafter. These results and subsequent date showing increases in both 5-HT and 5-HIAA in various brain regions following 90 min. of treadmill running were the first to support the theory that endurance running in rats can increase brain 5-HT synthesis and turnover. They also showed quite nicely that the increase in plasma f-TRP was the primary factor leading to this response. However, the relevance of these findings to the mechanisms of fatigue was not addressed in these studies.

    Blomstrand et al. examined rats who had run to exhaustion on a tread-mill and found that plasma f-TRP (but not total TRP) and regional brain TRP, 5-HT, and 5-HIAA concentrations were higher at exhaustion in both trained (~180 min. run time) and untrained (~72 min. run time) rats. We extended those observations to include a study of the time course of changes in brain 5-HT and dopamine (DA), a neurotransmitter known to play an important role in motivation, arousal, and neuromuscular control during endurance running to fatigue. Measurements of 5-HT and DA and their primary metabolites, 5-HIAA and DOPAC, were made in the midbrain, striatum, hypothalamus, and hippocampus of rats sacrificed at rest, after 1 hr. of treadmill exercise, and at fatigue (which occurred in approximately 3 hrs.). The treadmill speed and grade were set to elicit about 60-65% of VO2max in rats (20 m min-l, % grade). After 1 hr. of exercise, the concentrations of 5-HT and 5-HIAA were higher in all brain regions studied except the hippocampus, where only 5-HIAA was elevated. Brain 5-HT remained elevated at fatigue, whereas 5-HIAA increased even further in the midbrain and striatum. DA and DOPAC also increased in the midbrain, striatum, and hypothalamus after 1 hr. but then decreased back to baseline levels at fatigue. These results indicate that brain 5-HT activity increases during prolonged exercise and appears to peak at the time of fatigue. Interestingly, brain dopamine activity that is usually associated with increased arousal and muscular coordination actually decreases toward the end of prolonged exercise as fatigue develops. The significance of this apparent inverse relationship between the potentially suppressive effects of brain 5-HT versus the stimulating effects of DA is interesting in the context of central fatigue but requires further investigation.


    Even though there appears to be a good relationship between elevated brain 5-HT and exercise-induced fatigue, it would be premature to conclude from this association that alterations in brain 5-HT activity actually cause central fatigue. In order to better approach this question of cause and effect, we completed a series of experiments to determine whether specific drug-induced alterations in brain 5-HT activity could influence endurance performance in rats. We proposed that if increased brain 5-HT was the cause of central fatigue during prolonged exercise, the administration of drugs known to specifically increase 5-HT activity (5-HT agonists) would cause easy fatigue, whereas drugs known to decrease brain 5-HT activity (5-HT antagonists) would delay fatigue. In a preliminary experiment, various doses of a specific 5-HT1c receptor agonist, m-chlorophenyl piprazine (m-CPP), were administered to rats, and this drug caused a decrease in run time to exhaustion in a dose related manner. This was followed by an experiment in which another, more general, 5-HT agonist (quipazine dimaleate, QD) or a 5-HT antagonist was administered. Run time to fatigue was again reduced in a dose-dependent manner by the 5-HT agonist, whereas the 5-HT antagonist delayed fatigue. The supposition that these drug-induced effects resulted from altered brain function is supported by the observation that fatigue could not be explained by alterations in body temperature, blood glucose, muscle and liver glycogen, or various stress hormones.

    These results, using a pharmacologic approach in a rat model, have recently been confirmed in two investigations using human subjects. In these studies, brain 5-HT activity was increased by the administration of either paroxetine or fiuoxetine, both of which block the reuptake of 5-HT from nerve terminals, are approved for use in humans, and act as 5-HT agonists (because they inhibit removal of 5-HT) upon acute administration. When these drugs were administered prior to prolonged running or cycling at 70% VO2max, exercise time to fatigue occurred earlier and perceived exertion was higher than when a placebo was administered. The subjects did not report any strange side effects, and there were no differences in various markers of cardiovascular, thermoregulatory, and metabolic function between the drug and placebo trials.

    The aforementioned studies in both rats and humans appear to provide good evidence that brain 5-HT activity increases during prolonged exercise and that this may cause central fatigue. However, the strength of these findings will continue to be questioned until methods are available to more directly measure central fatigue during dynamic exercise in humans and until more is known about the specific physiological mechanisms for such an effect.

    Investigators are only now beginning to explore the possible physiological mechanisms underlying a possible effect of elevated brain 5-HT on central fatigue. The serotonergic system is associated with numerous brain functions that could Fositively or negatively affect endurance performance. Increased serotonergic activity may induce fatigue through inhibition of the dopaminergic system and/or by reducing arousal and motivation to perform. Furthermore, serotonergic activity can affect the hypothalamic-pituitary-adrenal axis, thermoregulation, pain, and mood, depending on the specific situation and the species studied. Based on our observations that fatigue during prolonged exercise in rats is associated with increased brain 5-HT and reduced brain dopamine, our working hypothesis is that a low ratio of 5-HTA in the brain favors improved performance (i.e., increased arousal, motivation, and optimal neuromuscular coordination), whereas a high 5-HTA ratio favors decreased performance (i.e., decreased motivation, lethargy, tiredness, and loss of motor coordination). The latter would constitute central fatigue.


    For obvious ethical reasons, investigators have used the rat model to study the effects of fatigue on regional brain concentrations of 5-HT and metabolites. Investigations in humans have focused primarily on nutritional factors that affect TRP availability to the brain (i.e., proposed markers of central fatigue).

    Blomstrand and Associates were the first to approach the problem in humans. They initially studied 22 subjects before and after a marathon race and found that plasma f-TRP was -2.4 times higher and BCAAs were slightly lower (-19%) after the race. They also reported similar responses after a soccer match (45% increase in f-TRP; 29% decrease in BCAAs) and prolonged cross-country skiing (28% decrease in BCAAs; f-TRP not reported). The drop in f-TRP/BCAAs following exercise in these studies was consistent with their hypothesis that TRP availability to the brain is increased by prolonged exercise and that increased brain 5-HT activity and central fatigue may occur as a result. These data also provided the basis for their theories involving possible nutritional strategies that may help to delay central fatigue during prolonged exercise.

    The theoretical possibility that central fatigue could be delayed by nutritional strategies that alter the f-TRP/BCAA ratio is intriguing. Investigations have centered around two primary strategies that involve supplementation with BCAAs and/or carbohydrates during exercise. Both of these strategies would theoretically decrease the f-TRP/BCAA ratio and thereby decrease the availability of f-TRP to the brain for 5-HT synthesis.

    Blomstrand, Newsholme, and colleagues have focused on the administration of BCAAs as a way to delay central fatigue. They reported that the administration of 7.5-21 g of BCAAs prior to and during a marathon race, a cross-country ski race, or a soccer match was associated with small improvements in some subjects in both physical and mental performance. However, while field studies such as these are designed to mimic athletes' actual situations, such studies are often limited in scientific value. For example, subjects are often not appropriately matched prior to their assignment to control and experimental groups; such matching is useful to prevent performance differences between groups caused by differences in fitness, training, body composition, or other factors. In addition, studies of this nature often do not (or cannot) "blind" subjects to the experimental treatments to prevent bias on the part of the subjects toward the treatment they believe to be the better one. Finally, these studies often fail to control important variables such as exercise intensity and food and water intake across treatments. These limitations and others increase the likelihood that benefits ascribed to a particular nutritional supplement may have actually resulted from subject bias, inherent differences in the groups of subjects, and/or one or more of the uncontrolled variables.

    Skepticism about the results of these early field studies is heightened by the observations in recent well-controlled laboratory experiments that BCAA supplementation has no beneficial effects on endurance exercise performance. Vainer et al. infused approximately 20 g BCAAs or saline over 70 min. prior to exercise using a double-blinded, cross-over design and found no differences in performance of a graded incremental exercise test to fatigue. Verger et al. also reported that feeding rat subjects relatively large amounts of BCAAs (compared to water or glucose) actually caused early fatigue during prolonged treadmill running.

    It is important to note that the administration of large amounts of BCAAs required to produce physiologically relevant alterations in plasma f-TRP/BCAAs during exercise is likely to increase plasma ammonia, which can be toxic to the brain and may also negatively affect muscle metabolism. Acute ammonia toxicity, although transient and reversible, may be severe enough in critical regions of the central nervous system to impair performance (coordination, motor control) and/or produce severe symptoms of central fatigue. The buffering of ammonia could also cause fatigue in working muscles by depleting glycolytically derived carbon skeletons (pyruvate) and by draining intermediates of the tricarboxylic acid cycle that are coupled to glutamine production by transamination reactions. This could conceivably impair oxidative metabolism in the muscle and lead to early fatigue.

    Because of this and the fact that giving large doses of BCAAs during exercise is likely to slow water absorption across the gut and to cause gastrointestinal disturbances, we performed a double-blinded, cross-over study to determine the effects of a smaller, more palatable, dose of BCAAs (approximately 0.5 g hr-1 consumed in a carbohydrate-electrolyte drink) during cycling exercise at 70% VO2 max to fatigue. This low dose of BCAAs was chosen to replace the calculated maximal amount of BCAA uptake and metabolism by muscle that would likely occur under these conditions and to decrease the likelihood that the BCAA supplements would impair water absorption rates in the gut, produce gastrointestinal distress, or otherwise be unpalatable. The results of this study showed that the low-dose BCAA supplement was palatable when added to a carbohydrate-electrolyte drink, did not cause gastrointestinal distress, and prevented the slight drop in plasma BCAA concentration that occurred during prolonged cycling when subjects consumed the carbohydrate-electrolyte drink without the BCAA supplement. However, the added BCAA supplement did not affect ride times to fatigue, perceived exertion, or various measures of cardiovascular and metabolic function.

    We therefore reasoned that a more appropriate strategy for delaying central fatigue might involve carbohydrate feedings because such a strategy could cause very large attentions in f-TRP and f-TRP/BCAAs during exercise without the potential negative consequences of administering large doses of BCAAs. This is because of the well-established suppressive effects of carbohydrate feedings on mobilization of free fatty acids that compete with f-TRP for binding sites on plasma albumin molecules. We proposed that carbohydrate feeding would reduce concentrations of f-TRP and f-TRP/BCAAs which would likely suppress the production of 5-HT in the brain and thereby minimize central fatigue. These effects might occur in addition to the well-known benefits of carbohydrate supplements on peripheral mechanisms of fatigue.

    This hypothesis was tested in a double-blinded, placebo-controlled study in the laboratory in which subjects drank 5 ml kg-1 hr-1 of either a water placebo, a 6% carbohydrate-electrolyte drink, or a 12% carbohydrate-electrolyte drink during prolonged cycling at 70% V02 max to fatigue. When subjects consumed the water placebo, plasma f-TRP increased -sevenfold (in direct proportion to plasma free fatty acids), whereas total-TRP and BCAAs changed very little during the fide. When subjects consumed either the 6% or 12% carbohydrate-electrolyte solutions, the increases in plasma f-TRP were greatly reduced and fatigue was delayed by approximately 1 hr. The carbohydrate feedings caused a slight reduction in plasma BCAAs (~19% and 31% reductions in the 6% and 12% carbohydrate-electrolyte groups, respectively), but this decrease was probably inconsequential with respect to the very large attenuation (fivefold to sevenfold) of plasma f-TRP. Although it was not possible to distinguish between the beneficial effects of carbohydrate feedings on central versus peripheral mechanisms of fatigue in this study, it was interesting that the substantial delay in fatigue could not be explained by typical markers of peripheral muscle fatigue involving cardiovascular, thermoregulatory, and metabolic functions.


    Fatigue during prolonged exercise has traditionally been associated with mechanisms that result in dysfunction of the contractile process within muscle. More recently, however, interest in possible central mechanisms of fatigue has grown as our under-standing of the physiological workings of the central nervous system has improved. Unfortunately, progress in this area has been hampered by a lack of good methodologies to distinguish central from peripheral mechanisms of fatigue during dynamic, whole-body exercise in humans.

    However, good evidence is beginning to emerge to support a role for brain 5-HT in central fatigue during prolonged exercise, although the exact mechanisms have not been established. Studies show that (a) the concentrations of 5-HT and its major metabolite, 5-HIAA, increase in several brain regions during prolonged exercise and reach their peaks at fatigue, (b) the increase in brain 5-HT synthesis and turnover almost certainly results from an increase in plasma f-TRP and f-TRP/BCAAs, and (c) the administration of 5-HT agonist and antagonist drugs can decrease and increase run times to fatigue in the absence of any apparent peripheral markers of muscle fatigue.

    Although there is good reason to believe that proper nutrition might play a role in delaying central fatigue during prolonged exercise, the scientific data in this area are much more tenuous. Studies on the proposed role of BCAA supplementation are limited, and there are reasons to believe that this approach may not be a viable one. Carbohydrate supplementation, on the other hand, is associated with large decreases in f-TRP and f-TRP/BCAAs, and fatigue is clearly delayed by this nutritional strategy. In this case, however, it is not possible to distinguish with certainty between the effects of carbohydrate feedings on central fatigue mechanisms and the well-established beneficial effects of carbohydrate supplementation on the contracting muscle.

    The exciting possibility that relation-ships exist among nutrition, brain neurochemistry, and sport performance is likely to develop into a new frontier in sports nutrition research. However, while the evidence is intriguing and makes good intuitive sense, our knowledge in this area is rudimentary at best.


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