Chronic High Dose BCAA Supplementation Reduces Endurance Performance by 43% Plus: How Ammonia, Glutamine, Arginine & Low Carb Could be Involved

Tired, exhausted, had to cut your workout short today? Is it the flu, or just too much BCAAs?

When some is good and more is better, even more is not necessarily going to be 'betterer' - and that's not simply due to the fact that there is no comparative to an adjective that's already in the comparative. Therefore it is actually not surprising that a team of researchers from the Department of Food and Experimental Nutrition at the Faculty of Pharmaceutical Sciences, the Department of Nutrition at the School of Public Health and the Department of Physiology and Biophysics at the Institute of Biomedical Sciences of the University of Sã o Paulo in Brazil has just published the results of a study (Falavigna. 2012) which demonstrates that there is an upper limit to the benefits of BCAA supplementation. What I guess will be surprising at least for some not so regular SuppVersity visitors, is that there is more than just a saturation effect: Too much BCAAs can actually have ergolytic (= anti-ergogenic) effects - at least under certain circumstances.

Another chapter in the book of good things that turn against you, when taken in excess

In their latest paper that has just been published in nutrients, Gina Falavigna and her colleagues analyzed effects of chronic BCAA supplementation on exercise performance in male Wistar rats. Based on previous animal and human data and the still widely supported, though actually experimentally non-validated (cf. Meeusen. 2007) theory that BCAAs would work their non-hypertrophy specific, endurance enhancing magic via the blockade of exercise induced 5-HT (serotonin) accumulation in the brain, the researchers speculated that ...

"[...] chronic BCAA supplementation (through the diet, using different BCAA  concentrations) would increase performance in rats subjected to a swimming exhaustion  test." (Falavigna. 2012)

To verify this hypothesis, Flavigna et al. randomized their rats to three different groups receiving either the standard AIN-93M diet for the maintenance of adult rodents (control group) or the same diet with additional additional 3.57% (group S1) and 4.76% (group S2) BCAAs at a ~2:1:1 ratio of lecine : valine : isoleucine (the BCAAs were manufactured by the Brazilian branch of Ajinomoto). The rodents in the S1 and S2 groups did thus receive 50% and 100% more branched-chain amino acids than the rodents in the control group which had to contend themselves with the BCAAs in the casein fraction of their diets (see figure 1, right). In order to assure that the diets would be isocaloric, an amount of starch equivalent to the amoung of BCCAs that had been added to the chow was removed from the supplemented diets.

Overall, the study lasted for six weeks. During this time the rodents were subjected to a 1h/day weight bearing swimming protocol five times a week. In the first two weeks, the rats were ...

"[...] adapted to the water medium and exercised with increasing overloads attached to the tail until an overload corresponding to 5% of total body weight was reached. This final overload was used until the end of the training protocol [...] The overloads were corrected weekly according to the variations in animal weight.  The efficiency of the training protocol was assessed on the basis of maximum activity of the enzyme citrate synthase in the soleus muscle, with a group of sedentary animals being used as the control for this parameter." (Falavigna. 2012)

Neither the overall amount of food nor the body weight gain of the rodents in the control, and the two exercise groups showed any statistically significant difference. The latter cannot be said about the exercise performance, as well as the accumulation of ammonia, though (see figure 1):

Figure 1: Exercise duration and plasma ammonia levels during / after swmming test (left) and macronutrient composition of the experimental diets (right; based on Falavigna.. 2012)

While the rodents in the +50% BCAA group (S1) do show the expected increase in endurance (+37%) their peers in the high dose (+100%) BCAA group (S2) experienced an even more pronounced drop in endurance performance (-43% vs. control), which went hand in hand with a profound increase in blood ammonia (+34%).

"Ammonia is a ubiquitous metabolic product producing multiple effects on physiological and biochemical systems. Its concentration in several body compartments is elevated during exercise, predominantly by the increased activity of the purine nucleotide cycle in skeletal muscle. Depending on the intensity and duration of exercise, muscle ammonia may be elevated to the extent that it leaks (diffuses) from muscle to blood, and thereby can be carried to other organs. The direction of movement of ammonia or the ammonium ion is dependent on concentration and pH gradients between tissues. As such, ammonia can also cross the blood-brain barrier, although the rate of diffusion of ammonia from blood to brain during exercise is unknown. It seems reasonable to assume that exhaustive exercise may induce a state of acute ammonia toxicity which, although transient and reversible relative to disease states, may be severe enough in critical regions of the central nervous system (CNS) to affect continuing coordinated activity. Regional differences in brain ammonia content, detoxification capacity, and specific sensitivity may account for the variability of precipitating factors and latency of response in CNS-mediated dysfunction arising from an exercise" stimulus, e.g., motor incoordination, ataxia and stupor. There have been numerous suggestions that elevated ammonia is associated with, or perhaps is responsible for, exercise fatigue, although evidence for this relies extensively on temporal relationships." (Falvigna. 2012; my emphasis)

Mark the last words of the previously cited paragraph: "[E]vidence for [the role of ammonia] in exercise fatigue relies extensively on temporal relationships". It is thus - as for now - a solely corollary, not yet a causative association, of which I do however feel that it would be very likely to turn into a causal one if someone actually measured the influx of ammonia into the brain during a workout.

Wait, ammonia? But ain't it more likely that the BCAAs block the uptake of tryptophan?

What's for sure is that another hypothesis, which relates to the blockade of tryptophan uptake can be ruled out as an underlying reason of the differences. After all the scientists who argue that ...

"[t]he increased synthesis of serotonin during exercise may be related to the development of central fatigue, because this neurotransmitter has several physiological functions, since it operates by  mood, lethargy, individual behavior, regulation of sleep, body temperature and blood  pressure, appetite suppression and changes in perceived exertion." (Falavigna. 2012)

...actually measure the 5-HT levels and observed no differences between the dietary groups. Overall, the study results to thus clearly indicate that both, medium nor high dose "chronic BCAA supplementation was not effective in improving the main parameters indicative of central fatigue" (Falavigna. 2012) - well, at least as long as we still stick to the hypothesis that the latter is induced by the accumulation of 5-HT in the brain.

Forget about tryptophan and serotonin, focus on ammonia

The fact that neither the high, nor medium dose of BCAAs did exert any effects on the serotonin levels in the brain does yet not explain why the medium dose supplementation regimen produced ergogenic, while the high dose regimen induced ergolytic effects.

The occurrence of direct toxic effects due to (too) high amounts of branched-chain amino acids can be ruled out based on previous studies in which the administration of more than 10g/kg body weight of BCAAs (the human equivalent would be 130g+ per day), as well as dosages of 2.5g/kg body weight chronically did not entail any toxic side effects (Shimomura.  2004). The same is true for other confounding variables, such as the citrate synthase activity, a measure of the general efficiency of the training protocol, bood glucose, insulin,free fatty acids, and lactate levels, as well as liver and muscle glycogen content, which were virtually identical in both groups. This leaves us with the increase in plasma ammonia as our 'last resort' to explain the -58% shorter swimming time in the high (S2) vs. medium (S1) dose BCAA group (-43% lower vs. non-supplemented control).

Figure 2: The reduced performance of the high BCAA group could well be related to peripheral and/or central ammonia build-up as a results of increased BCAA oxidation, camparably low glutamine intakes and the rate-limited enzymantic conversion and recycling of gluatmine (illustration originally from Earrante. 2003). Studies by Snow (2000) and Carvalho-Peixoto (2007) suggest: Both carbohydrate & glutamine supplements could help.

Based on what we know about the mammalian body, the increased build-up of ammonia in the high BCAA group could be a result of the unfortunate combination of temporary energy shortage and learned wastefulness' in a situation, where the otherwise sparse BCAAs are available in abundance. Furthermore, with a glutamine content of only 9-13% in the casein fraction of their diets (Swails. 1992), the rodents in the high BCAA group did ingest more than 2.6-3.8 times more BCAAs than glutamine; a fact which may have contributed to a temporary glutamine deficiency as a result of its increased use in the detoxification of the ammonia that's generated when the BCAAs are oxidized. The resulting peripheral and possibly central ammonia build-up (see figure 2) could then have begun to intoxicate liver and brains of the rodents and thus hampered gluconeogensis (normal levels stimulate, high levels of ammonia hamper gluconeogensis; cf. Fritz. 1988) and induced central fatigue (Wagenmakers. 1990; Nybo. 2004) -- and that not despite, but rather due to the chronic "high dose" BCAA supplementation (HED ~50g/day).

So do I have to drop my BCAAs now or what? Whether these results are relevant for you will probably depend on a whole host of parameters, which include

• the type, intensity and duration of exercise you do, 
• the ratio of BCAAs to glutamine in your diet,
• the amount of arginine, which acts as a substrate for the urea cycle and is therefore necessary to for the excretion of ammonia by the kindeys (Schaefer. 2002),
• the amount of carbohydrates in your diet (with more = less amino acid oxidation = lower ammonia and very low carb = you are in trouble; e.g. Czarnowski. 1995; Snow. 2000; Carvalho-Peixoto. 2007), 

... and those factors I will probably have forgotten to mention now. Unless you don't forget that you can neither lifve from BCCAs and protein alone, but accept the neflglected truth that too much protein is about as bad a too little protein, you can file this post under "show your stupid friends" and get back out, when they complain about feeling sick, bloated and fat "despite" eating a BCAA supplemented high protein, low carb (and often even low fat) diets.

References:

• Carvalho-Peixoto J, Alves RC, Cameron LC. Glutamine and carbohydrate supplements reduce ammonemia increase during endurance field exercise. Appl Physiol Nutr Metab. 2007 Dec;32(6):1186-90.
• Errante LD, Petroff OA. Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations. Seizure. 2003 Jul;12(5):300-6.
• Falavigna G, de Araú jo Junior JA, Rogero MM, de Oliveira Pires IS, rio Graç a Pedrosa R, Martins Junior E, Alves de Castro I, Tirapegui J. Effects of Diets Supplemented with Branched-Chain Amino Acids on the Performance and Fatigue Mechanisms of Rats Submitted to Prolonged Physical Exercise. Nutrients 2012. 4; 1767-1780.
• Fritz S, Bohnensack R. Stimulation of alanine metabolism in rat liver by ammonia. Biomed Biochim Acta. 1988;47(12):923-32.
• Meeusen R, Watson P. Amino acids and the brain: do they play a role in "central fatigue"? Int J Sport Nutr Exerc Metab. 2007 Aug;17 Suppl:S37-46.
• Nybo L, Dalsgaard MK, Steensberg A, Møller K, Secher NH. Cerebral ammonia uptake and accumulation during prolonged exercise in humans. J Physiol. 2005 Feb 15;563(Pt 1):285-90. Epub 2004 Dec 20. 
• Schaefer A, Piquard F, Geny B, Doutreleau S, Lampert E, Mettauer B, Lonsdorfer J. L-arginine reduces exercise-induced increase in plasma lactate and ammonia. Int J Sports Med. 2002 Aug;23(6):403-7.
• Shimomura, Y.; Murakami, T.; Nakai, N.; Nagasaki, M.; Harris, R.A. Exercise promotes BCAA catabolism:  Effects  of BCAA supplementation on skeletal muscle during exercise.  J. Nutr.  2004, 134, 1583S–1587S.
• Snow RJ, Carey MF, Stathis CG, Febbraio MA, Hargreaves M. Effect of carbohydrate ingestion on ammonia metabolism during exercise in humans. J Appl Physiol. 2000 May;88(5):1576-80.
• Swails WS, Bell SJ, Borlase BC, Forse RA, Blackburn GL. Glutamine content of whole proteins: implications for enteral formulas. Nutr Clin Pract. 1992 Apr;7(2):77-80.
• Wagenmakers AJ, Coakley JH, Edwards RH. Metabolism of branched-chain amino acids and ammonia during exercise: clues from McArdle's disease. Int J Sports Med. 1990 May;11 Suppl 2:S101-13.