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A Brief but Updated Scientific Look at the "F" Word: Fatigue

By Alan Cocchetto, NCF Medical Director
Researchers from England and Japan have recently fully clarified the mechanism
of fatigue, known as central fatigue, implicated in Chronic Fatigue Syndrome. Dr. Eric Newsholme, from Oxford University, and Dr. Takanobu Yamamoto, from Tezukayama University, have made numerous research discoveries about fatigue and the mechanisms that define it.

     For starters, there are at least five metabolic causes of fatigue that have been reported in the medical literature. These include 1) a decrease in the phosphocreatine level in the muscle, 2) a proton accumulation in the muscle, 3) depletion of the glycogen store in muscles, 4) hypoglycemia and 5) an increase in the plasma concentration ratio of free tryptophan to branched-chain amino acids.

     "Central fatigue" is of keynote importance here due to the fact that it has been implicated in clinical conditions such as Chronic Fatigue Syndrome (CFS) as well as Post-Operative fatigue.  Central fatigue is defined as fatigue in the central nervous system (CNS). The implications are important because the fatigue in CFS is central fatigue, in other words, fatigue in the central nervous system (CNS)! According to these researchers, fatigue in the CNS results from fatigue that occurs in a large portion of intercerebral control circuits caused by suppression in the level of voluntary exciting, which are suppressed in the number of motor units to the level of voluntary neuromuscular junction - muscle fibers and the firing frequency. In other words, CFS fatigue is a fatigue different from the fatigue in the motile muscles themselves. Moreover, these researchers have found that this fatigue is different from the so called tiredness feeling caused by physical (muscular) fatigue and, in fact, is generated in a state that is not accompanied by physical fatigue. This is something most of us hadn't read previously!

     Dr. Newsholme has been researching central fatigue mechanisms for over twelve years.  Along with Dr. Yamamoto, these researchers have now fully clarified the mechanism for central fatigue in the CNS. They found that specific inhibitors of the L-system transporter on the blood-brain barrier (BBB) make it possible to suppress the fatigue in the CNS. Furthermore, two components were found to be therapeutically effective in suppressing this CNS fatigue. The first was a lab based research chemical known as BCH. However, the second component was one that is readily available. That component was branched-chain amino acids otherwise known as BCAA's. BCAA's are essential amino acids for the human body. BCAA's are made up of a mixture of three individual amino acids that include L-leucine, L-isoleucine and L-valine which have a branched-chain in its carbon chain. BCAA's are commonly used supplements by bodybuilders.

     In a nutshell, these researchers proved that by inhibiting the L-system transporter, experiments verified that BCAA's and/or BCH suppressed the uptake of tryptophan thereby alleviating fatigue in the central nervous system and thus improved endurance capacity in the animals tested. Research has proven that fatigue in the CNS doesn't show a reduction in the serotonergic system function in the central and peripheral nerves but, in contrast, an enhanced nerve transmission response and this implies a relation to a change in the transmission of extracellular fluid 5-HT (5-hydroxytryptamine) that depends on an increase in tryptophan.
This change in the transmission of extracellular fluid 5-HT causes suppression in the surrounding brain nerves, resulting in fatigue in the CNS. This is the basis for the tryptophan/5-HT hypothesis. The fatigues in both of the central system (CNS) and the peripheral system (muscle system) exist in a related manner. The tryptophan, which is a causal substance of the fatigue, is transferred from the peripheral system (in blood) to the central system (brain) through the blood-brain barrier (L-system transporter) to give inhibiting (negative) information to the CNS. In other words, an excessive amount of tryptophan or 5-HT in the brain suppresses the CNS, causes a reduction in the motor system output that is released through pyramidal tracts and x-motor neurons. This causes inhibition of animal treadmill running performance. It is this mechanism that causes the fatigue phenomena (central fatigue) derived from the CNS. For all CFS patients, this is much more than just "being tired!" Most importantly, however, is the fact that this scientific research may have vital clinical implications for CFS patients due to the applicability of BCAA's.
1.) The role of tryptophan in fatigue in different conditions of stress; Castell LM, Yamamoto T,
Phoenix J, Newsholme EA; Adv Exp Med Biol. 1999;467:697-704
2.) Changes in the albumin binding of tryptophan during postoperative recovery: a possible link
with central fatigue?; Yamamoto T, Castell LM, Botella J, Powell H, Hall GM, Young A,
Newsholme EA; Brain Res Bull. 1997;43(1):43-6
3.) Diminished central fatigue by inhibition of the L-system transporter for the uptake of
tryptophan; Yamamoto T, Newsholme EA; Brain Res Bull. 2000 May 1;52(1):35-8
4.) The effect of tryptophan deficiency in the brain on rat fatigue levels: a rat model of fatigue
reduction; Yamamoto T, Newsholme EA; Adv Exp Med Biol. 2003;527:527-30
5.) The plasma level of some amino acids and physical and mental fatigue; Newsholme EA,
Blomstrand E; Experientia. 1996 May 15;52(5):413-5
6.) Tryptophan, 5-hydroxytryptamine and a possible explanation for central fatigue; Newsholme
EA, Blomstrand E; Adv Exp Med Biol. 1995;384:315-20
7.) Physical and mental fatigue: metabolic mechanisms and importance of plasma amino acids;
Newsholme EA, Blomstrand E, Ekblom B; Br Med Bull. 1992 Jul;48(3):477-95
8.) Characterisation of L-tryptophan transporters in human placenta: a comparison of brush
border and basal membrane vesicles; Kudo Y, Boyd CA; J Physiol. 2001 Mar 1;
531(Pt 2):405-16
9.) Amino acids and central fatigue; Blomstrand E; Amino Acids. 2001;20(1):25-34


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