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,**,4
* Merton College, Oxford, UK, University College of Physical Education and Sports, and ** Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
4 To whom correspondence should be addressed. E-mail: eva.blomstrand{at}gih.se.
ABSTRACT
An account of the tryptophan (Trp)–5-hydroxytryptamine (5-HT)–central fatigue theory is provided and an explanation of how oral administration of BCAAs can decrease fatigue on the basis of this theory is given. The rate-limiting step in the synthesis of 5-HT is the transport of Trp across the blood–brain barrier. This transport is influenced by the fraction of Trp available for transport into the brain and the concentration of the other large neutral amino acids, including the BCAAs, which are transported via the same carrier system. During endurance exercise, there is an uptake of Trp by the brain, suggesting that this may increase the synthesis and release of 5-HT in the brain. Oral intake of BCAAs may reduce this uptake and also brain 5-HT synthesis and release, thereby delaying fatigue. Other hypotheses for the effect of BCAAs on central fatigue are included.
KEY WORDS: • branched-chain amino acids • 5-hydroxytryptamine • tryptophan
Physical fatigue is defined as the inability to maintain power output. The fatigue can be either central or peripheral in its origin. Several factors have been identified as a cause of peripheral fatigue (e.g., depletion of muscle glycogen or phosphocreatine, accumulation of protons, and failure of neuromuscular transmission), whereas the factors underlying central fatigue are less well known (1). Central fatigue is demonstrated experimentally when the maximal effort that can be achieved voluntarily is less than that which can be achieved when the muscle is stimulated directly by electrical stimulation of the motor nerve (2,3). Several mechanisms, which are not mutually exclusive, have been proposed to explain central fatigue; these include: 1) an increase in the level of key compounds in muscle during physical activity, such as protons, K+-ions, bradykinin, phosphate, prostaglandins that could, via binding to specific fatigue receptors in muscle, transmit information via sensory nerves from muscle to brain; 2) a decrease in the blood glucose level and hence the level in the brain could restrict glucose utilization by some neurons in some parts of the brain that are involved in control of motor activity. Fatigue has been reported during endurance events, such as ultra marathons, at a time when the blood glucose level is low; and 3) an increase in the concentration of tryptophan (Trp) in the blood and hence the neurotransmitter 5-hydroxytryptamine (5-HT) in some neurons, which are involved in control of motor activity in the brain, could lead to central fatigue. Figure 1 illustrates possible causes of central and peripheral fatigue.
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This should not be too surprising because changes in neurotransmitter levels in the brain can account for a number of diseases: depression is due to a low level of catecholamines; Parkinson's disease is due to a low level of dopamine; schizophrenia is due to an excess level of dopamine (4). Hence the Trp–5-HT–central fatigue hypothesis depends upon the same biochemical principle as those applying to these diseases.
The amount of neurotransmitter released and diffused across the synapse can be limited by the concentration of neurotransmitters in the presynaptic nerve. The concentration of a neurotransmitter depends upon the rate of synthesis in the presynaptic nerve. Of importance, the rate of synthesis of 5-HT is regulated by the concentration of Trp in the blood, which regulates the transport into the neurons (i.e., the uptake of Trp by the brain is an important factor in the regulation of 5-HT synthesis and hence the concentration in the presynaptic nerve) (5). An increase in blood Trp level increases the level of 5-HT, which increases electrical activity in the postsynaptic nerve, thus expanding the activity of a process leading to fatigue (6).
The extension of this hypothesis leads to the role of BCAAs in central fatigue. The transport of Trp into the brain is regulated not only by the concentration of Trp in the bloodstream, but also by the concentration of other large neutral amino acids, in particular the BCAAs, which compete with Trp for transport into the brain (7–9). During sustained exercise, BCAAs are taken up by the muscle and the plasma concentration decreases. In addition, when exercise elevates the plasma level of free fatty acids (FFAs)5, it also increases the plasma level of free Trp because FFAs and Trp compete for the same binding sites to albumin (10,11). An increase in the plasma ratio of free Trp:BCAAs, which is found during and, particularly after, sustained exercise (12), will thus favor the transport of Trp into the brain. In fact, an uptake of Trp by the brain, evaluated from arteriojugular venous concentration differences, was found in human subjects during sustained exercise (13,14). Enhanced entry of Trp leads to increased 5-HT levels in specific areas of rat brains (Fig. 2) and in the cerebrospinal fluid of rats running on a treadmill (15–17). Assuming this is also the case in humans, exercise should increase the synthesis, concentration, and release of 5-HT from some neurons, which could be responsible for fatigue during and after sustained exercise (Fig. 3).
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Several experiments have provided evidence for this theory. For example, when BCAAs are supplied to human subjects during standardized cycle ergometer exercise, their ratings of perceived exertion and mental fatigue are reduced (12); in a competitive 30-km cross-country race, provision of BCAAs during the race improved the subjects' performance in different cognitive tests after the race (19), suggesting an effect in the brain possibly due to a decrease in the 5-HT level.
The theory has received both support and rejection from other studies (20–24). However, the philosophy of science tells us that a theory is, by definition, never correct: it can never be proved; it can only be disproved by accumulation of evidence against the theory. Once this has occurred, a new theory is proposed that should be better or more interesting than the first. Thus it can be argued that the positive effect of administration of BCAAs in reducing fatigue in exercise is not due to decreasing the 5-HT level in the brain, but by influencing other biochemical events in the brain. A proposal is as follows: several amino acids are precursors for neurotransmitters (Table 1) and, indeed, two well-known amino acids that are central in metabolism, glutamate and aspartate, are neurotransmitters. Hence it is hypothesized that a BCAA (e.g., leucine) acts as a neurotransmitter per se, and one role as a neurotransmitter is to decrease fatigue. Alternatively, a BCAA (e.g., leucine) may be converted to a metabolite, which is a novel neurotransmitter that also decreases fatigue, just as, for example, tyrosine is converted to dopamine, which has a large number of central effects. Such new hypotheses could perhaps account for some of the conflicting evidence for the Trp hypothesis.
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FOOTNOTES
1 Published in a supplement to The Journal of Nutrition. Presented at the conference "Symposium on Branched-Chain Amino Acids" held May 23–24, 2005, in Versailles, France. The conference was sponsored by Ajinomoto USA, Inc. The organizing committee for the symposium and guest editors for the supplement were Luc Cynober, Robert A. Harris, Dennis M. Bier, John O. Holloszy, Sidney M. Morris, Jr., and Yoshiharu Shimomura. Guest editor disclosure: L. Cynober, R. A. Harris, D. M. Bier, J. O. Holloszy, S. M. Morris, Y. Shimomura: expenses for travel to BCAA meeting paid by Ajinomoto USA; D. M. Bier: consults for Ajinomoto USA; S. M. Morris: received compensation from Ajinomoto USA for organizing BCAA conference. 
2 Author Disclosure: No relationships to disclose.
3 Supported by the Swedish National Centre for Research in Sports and Carlsberg Sweden.
5 Abbreviations used: FFA, free fatty acid.
LITERATURE CITED
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