Recent Studies Cast Shadow Over High Dose BCAA Intake: Increased Protein Wasting, Lower Brain Serotonin and More

To guzzle BCAAs all day or not - is that still a question or is the answer settled with the publication of two recent studies?
From previous SuppVersity articles about BCAA you will know that I don't buy into the hype supplement producers generate about the muscle-building and/or muscle-protective effects of high dose BCAA- or leucine-only supplementation.

One of the previously mentioned issues with BCAAs are their putative ill effects on neurotransmitter levels in the brain - effects that had only been observed in rodents, though. Now, a recent study in pigs, who are a much better model of human metabolism (even much better than most apes | Miller. 1987), is fueling the concerns about the pro-depression effects of high dose leucine supplementation.
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The corresponding study  (Wessels. 2016), which happens to have been sponsored by the BCAA producer Ajinomoto (quite ironic, isn't it?), sought to elucidate the response of high leucine diets on the activity of the BCAA metabolizing enzyme branched-chain keto acid dehydrogenase complex (BCKDH) and subsequent changes in the concentrations of free amino acids and amino acid derivates in several tissues, including the brain.

Figure 1: Brian tryptophan and serotonin levels in response to diets containing normal or two- (white) and four-fold (grey bar) elevated amounts of leucine (Wessels. 2016).
What the scientists found was a significant decrease in brain tryptophan with twice and a significant reduction of both brain tryptohan and serotonin levels with four times the regular amount of leucine in the piglets' diets (that's 1% vs. 2% vs. 4%). Bad news!? Well, 4% leucine in the diet are a very high amount with questionable practical implications. Even though the study confirms the potentially negative effects of the tryptophan blocking effects of leucine and BCAAs in general, the good think is that it assigns a relatively high number to the required dosage to see effects - whether lower doses would suffice to mess with all three BCAAs, as they were used by Choi et al. (2013), remains elusive, though.
In vivo comparison of the central action of isoleucine, valine, and leucine on glucose kinetics during pancreatic insulin clamps (Arrieta-Cruz. 2016).
It's not all bad news: While the potentially depression promoting effects of high dose leucine and the anti-anabolic / pro-catabolic effects of BCAA supplementa-tion in rodents are bad news, another recent study from the Mexican Ministry of Health supports the previously discussed anti-diabetic effects of isoleucine and sug-gests that valine may have similar effects. In view of the fact that the putative mechanism, for the increased glucose infusion rate (GIR | see Figure on the left) is an increased inhibitory effect of insulin on endogenous glucose production (EGP), not an increase in peripheral glucose utilization, it is yet questionable how relevant the results of Arrieta-Cruz' recent study in diet-induced o-bese rats are for athletes / healthy individuals for whom exuberant glycolysis / gluconeogenesis isn't a problem.
While it obviously depends on the severity of your BCAA addiction, whether the Wessels study is bad news for you, it is it is unfortunately too early to rejoice: More potentially bad news for BCAA junkies comes from a recent study by Milan Holecek et al. (2016) whose efforts to prove that diets containing extra BCAAs (valine, leucine, and isoleucine | HVLID), or a high(er) content of leucine (HLD) would have beneficial effects on the protein balance of rats in a two months study produced results neither the scientists nor I would have expected: In high doses BCAAs make your body waste protein!
Figure 2: BCAA content of the standard (SLD), high BCAA (HVLID) and high leucine (HLD) diets (Holecek. 2016).
Needless to say that this result is in diametrical contrast to what the scientists expected. Not only did Holecek et al. fail to demonstrate the expected positive effects of the chronic consumption of a BCAA- / leucine-enriched diet on protein balance in skeletal muscle. The results of their latest study actually "indicate rather negative effects from a leucine-enriched diet" (Holecek. 2015).
But BCAAs are muscle-builders how can leucine & co ruin protein synthesis? A reliable answer to this question has unfortunately yet not been found, but the results of the Holecek study suggest that an overabundance of BCAAs triggers an overexpression of the BCAA degrading enzyme BCKA dehydrogenase and the subsequent conversion of BCAAs to BCAA keto acids and / or eventually alanine or glutamine which are then (ab-)used as energy source by the liver (cf. modified figure from Holeček. 2001)
Instead of reducing the breakdown of protein, Holecek et al. found that a BCAA- or leucine-enriched diet tends to increase not just the breakdown of BCAAs, as well as the production of branch-chain keto acids (BCKA), alanine and glutamine and their utilization in visceral organs, it also impaired the rodent's protein synthetic response to a meal in postabsorptive state - particularly in fast-twitch (white) muscles.
Figure 3: Fractional rate of protein synthesis. Means ± SE, p < 0.05. *compared to the corresponding control (SLD or SLD + S); # compared to the corresponding fed group; † HLD (HLD + S) group vs. HVLID (HVLID + S) group (Holecek. 2016).
In spite of the fact that this increase in protein wastefulness, as I would call it, is bad news and the exact opposite of what the shiny BCAA ads and product write-ups promise, a significant loss in muscle weight was only observed in the soleus and ext. digitorum longus of the rodents in the high BCAA, but not the high leucine group. Accordingly, the study sheds a whole new light on the usefulness of BCAAs as 'muscle builders' or 'muscle protectors' and may, as Holecek et al. rightly point out...
"[...] explain the discrepancy between the protein anabolic effects of BCAA or leucine on muscles that were reported under in vitro conditions and/or shortly after BCAA intake and their reduced or lack of effects following chronic administration" (Holecek. 2016).
With the present study being conducted in healthy rodents without any of the condition that lead to muscle wasting (e.g. disorders like diabetes, or natural processes like aging) and in the absence of the stimulatory effect of exercise on signalling pathways that activate protein synthesis, future studies will have to determine, whether the ill effects on protein synthesis and increases in protein breakdown are (a) even more severe in muscle-wasting disorders, the elderly, and / or during endurance exercise, and how (b) the effects are modified by resistance training.
Figure 4: The previously not discussed ill (BCAA) and beneficial (leucine) effects of different levels of said amino acids on the HDL to LDL ratio of the rodents in the Holecek study should be taken into account, as well.
Bottom line: While the main outcomes of the two studies I discussed in detail in today's SuppVersity article do in fact cast a dark shadow on the health and performance benefits of BCAAs, it's not all bad news. Why's that? Here's why: (A) the Wessels study suggests that the amount of BCAAs that is required to produce practically significant reductions in brain serotonin is very high; (B) the significant reduction in the LDL/HDL ratio Holecek observed in the high leucine group of their study (Figure 4) and the lack of visible effects on actual muscle mass in the same group put the relevance of the increased protein breakdown in response to (at least) high dose leucine into perspective; and (C) there's still the Arrieta-Cruz study which shows that even isoleucine and valine of which the Holecek study draws a rather negative image, can have benefits - at least in the obese | Comment!
  • Arrieta-Cruz, Isabel, Ya Su, and Roger Gutiérrez-Juárez. "Suppression of Endogenous Glucose Production by Isoleucine and Valine and Impact of Diet Composition." Nutrients 8.2 (2016): 79.
  • Choi S, Disilvio B, Fernstrom MH, Fernstrom JD. Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines. Amino Acids. 2013 Aug 1. [Epub ahead of print] 
  • FAO (Food and Agriculture Organization of the United Nations. "Food and nutrition in numbers." Rome, 2014; Food and Agriculture Organization of the United Nations.
  • Holeček, Milan. "The BCAA–BCKA cycle: its relation to alanine and glutamine synthesis and protein balance." Nutrition 17.1 (2001): 70.
  • Holeček, Milan, et al. "Alterations in protein and amino acid metabolism in rats fed a branched-chain amino acid-or leucine-enriched diet during postprandial and postabsorptive states." Nutrition & metabolism 13.1 (2016): 1.
  • Miller, E. R., and D. E. Ullrey. "The pig as a model for human nutrition." Annual review of nutrition 7.1 (1987): 361-382.
  • Wessels, et al. "Branched-Chain Amino Acid Degradation and Modify Serotonin and Ketone Body Concentrations in a Pig Model." PLoS ONE 11.3 (2016).
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