"It never gets easier, you just go faster." - Greg Lemond

Monday, October 3, 2011

BCAA and the CNS Fatigue Hypothesis

An elegant hypothesis with limited laboratory support
(In my humble opinion)

            What is bonking I ask?  As participation in marathons, triathlons, and other endurance endeavors increases this question becomes more pertinent (a recent survey by Running USA suggested that over 500,000 people completed a 26.2 mile marathon in 2010, a 9.9% increase over the number in 2009).  Also known as exercising to exhaustion or “hitting the wall,” the idea of fatigue resulting in failure to maintain a desired pace that sets in late in a long event has been an interesting concept for nutritionist as well as exercise physiologists.  The short answer to the question is that we don’t know exactly what results in “bonking.” 
            The long answer is that this is probably the result of several metabolic changes resulting in fatigue.  While most acknowledge that muscle glycogen depletion and lactate accumulation contribute to peripheral fatigue, they do not fully explain the induction of fatigue during sub-maximal exercise such as endurance events or high altitude climbing (1).  One prevailing hypothesis is that exhaustion is regulated by the central nervous system (CNS). Peripheral biochemical changes that occur during exercise influence the CNS, resulting in failure to recruit more skeletal muscle and reduced performance.  One peripheral biochemical change resulting in CNS fatigue is hypoglycemia due to liver glycogen depletion.  In this respect, carbohydrate intake is thought to attenuate CNS fatigue by maintaining blood glucose levels (2).  Interestingly, another cause of CNS fatigue is thought to be increasing concentrations of serotonin or 5-hydroxy-tryptamine (5-HT) in the brain which is derived from the large neutral amino acid tryptophan.  The neurotransmitter 5-HT is known to play a role in sensory perception, depression, sleepiness and mood, making it a likely candidate for the CNS fatigue hypothesis (3).
            While BCAAs are metabolized by skeletal muscle during prolonged exercise, they also compete with free tryptophan for uptake across the blood brain barrier (BBB) by L-type amino acid transporters.  However, as endurance exercise continues, skeletal muscle increasingly oxidizes BCAAs, diminishing the plasma BCAA pool, which reduces competition with tryptophan for transport across the BBB (3).  A unique amino acid, tryptophan is the only amino acid that binds albumin in plasma (4).  Indeed, under normal circumstances, approximately 90% of plasma tryptophan is bound to albumin (3).  However, as muscle and liver glycogen stores are depleted, free fatty acids are released to support metabolic demands.  In turn, free fatty acids bind albumin, resulting in competition for binding sites on albumin with tryptophan (4).  This results in an increase in unbound tryptophan that can be transported across the BBB. 
            Thus it is hypothesized that by increasing BCAA consumption during endurance exercise one might be able to attenuate CNS fatigue by increasing competition with tryptophan for transport to the brain. Despite the elegant science behind this hypothesis, data regarding the efficacy of this approach appears to be limited.  A field trial reported increased mental performance in trained runners consuming BCAAs during a 30km competitive event (5).  Interestingly, this has not been replicated in well controlled laboratory conditions (6).  Similarly, consumption of an isocaloric solution containing BCAAs and carbohydrate did not influence the time to exhaustion in glycogen depleted cyclists compared to those consuming carbohydrate alone (7). 
One important caveat is that consumption of exogenous carbohydrates is a must for endurance athletes.  It has been shown that consumption of carbohydrates diminishes the release of free fatty acids, in turn influencing the amount of free tryptophan in plasma that results from prolonged exercise, possibly negating any benefit derived from BCAA consumption (8).  Furthermore, large doses of BCAAs can increase the ammonia concentration in plasma due to their metabolism resulting in the release of nitrogen, requiring buffering by TCA cycle intermediates, which could lead to early fatigue in working muscles (9).  It is entirely possible that by consuming BCAAs during exercise one is able to offset the effects of CNS fatigue, only to increase peripheral fatigue (9).  It is also important to point out that the hypothesis discussed in here does not take into account the role of BCAAs in supplementing skeletal muscle metabolism.  In summary, while combating CNS fatigue with BCAAs is certainly an intriguing nutritional intervention, there seems to be limited laboratory data supporting its efficacy.   
This leads me to share my feelings on laboratory science and the nature of ultra-endurance sports.  To me, it seems as though it is nearly impossible to replicate a true ultra event in the laboratory.  Whether it be due to ethical concerns, athletic desire, or simply lack of a truely difficult labortaory training environment, I feel it is hard to re-create the extreme conditions an ultrarunner might face.  Heat, alititude, mud, 15-16+ hours of running, sleep deprivation, hypothermia, all these are very difficult to recreate.  In this aspect when considering nutritional interventions for sport, I try very hard to fully grasp the science behind the supplement.  Nutrition, in particular can be masked by many variables, and in the end may only result in a 1% improvement which in the end may missed due to the insane number of variables that go into exercise performance.  Based on these observations, I look for what is called Biological Plausibility - does the supplement have a large amount of molecular and biochemical support, even if the observations on performance gains in humans or animal models are limited?   In the case of BCAA in limiting CNS fatigue, I think yes!

Works Cited

1.         Noakes TD, St Clair Gibson A, Lambert EV. From catastrophe to complexity: a novel model of integrative central neural regulation of effort and fatigue during exercise in humans: summary and conclusions. Br J Sports Med. 2005 Feb;39:120-4.
2.         Karelis AD, Smith JW, Passe DH, Peronnet F. Carbohydrate administration and exercise performance: what are the potential mechanisms involved? Sports Med.  Sep 1;40:747-63.
3.         Blomstrand E. A role for branched-chain amino acids in reducing central fatigue. J Nutr. 2006 Feb;136:544S-7S.
4.         Curzon G, Friedel J, Knott PJ. The effect of fatty acids on the binding of tryptophan to plasma protein. Nature. 1973 Mar 16;242:198-200.
5.         Hassmen P, Blomstrand E, Ekblom B, Newsholme EA. Branched-chain amino acid supplementation during 30-km competitive run: mood and cognitive performance. Nutrition. 1994 Sep-Oct;10:405-10.
6.         Cheuvront SN, Carter R, 3rd, Kolka MA, Lieberman HR, Kellogg MD, Sawka MN. Branched-chain amino acid supplementation and human performance when hypohydrated in the heat. J Appl Physiol. 2004 Oct;97:1275-82.
7.         van Hall G, Raaymakers JS, Saris WH, Wagenmakers AJ. Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance. J Physiol. 1995 Aug 1;486 ( Pt 3):789-94.
8.         Blomstrand E, Moller K, Secher NH, Nybo L. Effect of carbohydrate ingestion on brain exchange of amino acids during sustained exercise in human subjects. Acta Physiol Scand. 2005 Nov;185:203-9.
9.         Davis JM, Alderson NL, Welsh RS. Serotonin and central nervous system fatigue: nutritional considerations. Am J Clin Nutr. 2000 Aug;72:573S-8S.

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