This is the first part of a two-part discussion on the controversy surrounding BCAAs and EAAs. In it, I focus primarily on an article by Dr. Robert Wolfe (1) because it has formed the evidentiary core of the popular opinion that BCAAs are incapable of increasing muscle protein synthesis. Assessed in an even and fair manner, I suggest one cannot derive this conclusion from the article itself. (Though it is certainly structured to give that impression.) Of course, other data exists to buttress the claim that EAAs are more effective than BCAAs for increasing the fractional synthetic rate of muscle protein synthesis fMPS, and I take up and consider those data in the second part of this analysis.
The superiority of essential amino acids over branched-chain amino acids: myth or reality?
A multi-million-dollar industry has grown around the concept that dietary supplements containing a blend of essential amino acids are superior to those containing branched chained amino acids for increasing muscle protein synthesis. In this brief review, some of the theoretical and empirical bases for that claim are discussed. One article, by Dr. Robert Wolfe, the lynchpin for the argument that EAAs are superior for stimulating muscle protein synthesis, has serious methodological defects. These defects perhaps warrant the article’s exclusion from serious consideration. The empirical research studies provided and analyzed as a part of that article do not constitute sufficient evidence for the claim that this article disputes. Given that the article by Wolfe represents the evidentiary core for the assertion that BCAAs do not increase muscle anabolism, we conclude that this assertion is unwarranted.
As anyone familiar with the debate on essential amino acids will recognize, both the title of and abstract to this article are direct mirrors of Dr. Robert Wolfe’s August 2017 article “Branched-chain amino acids and protein synthesis in humans: myth or reality?” (1). This rhetorical move is deliberate. In the approximately 12 months since the publication of Dr. Wolfe’s meta-analysis, a consensus has emerged in the dietary supplement industry that dietary supplements containing EAAs (essential amino acids) are superior to those containing BCAAs (branched-chain amino acids) alone for increasing skeletal muscle protein synthesis. Though other articles discussed below contribute to this emerging consensus, Dr. Wolfe’s article is the primary determinant. Mirroring that article’s structure, and therefore its contextual and evidentiary standards, produces a clean comparison of one article to the other and the most robust response to the emerging consensus.
Despite being lauded as the definitive work on the muscle synthetic response to dietary amino acids, Dr. Wofle’s article presents with serious methodological defects. These defects not only call into question the veracity of Dr. Wolfe’s claims, but perhaps exclude his article from serious consideration. Further, if Dr. Wolfe’s article is the foundation for the consensus that dietary EAAs are superior to dietary BCAAs for increasing skeletal muscle protein synthesis, to the extent that Dr. Wolfe’s claims are disconfirmed, the consensus is also disconfirmed. The primary purpose of this paper, therefore, is to evaluate the theoretical and empirical basis for the claim that EAAs are superior to BCAAs for increasing the synthesis of skeletal muscle protein.
Though variously lauded as “comprehensive” (2), definitive, or authoritative, Dr. Wolfe’s article has received little critical examination in the popular media. While the normal course of science is to assess whether the methodology and results of a research study substantiate the conclusions an author derives, few have examined whether Dr. Wolfe’s research – and by extension, the body of literature comparing EAAs and BCAAs – support his conclusions. A detailed examination of Dr. Wolfe’s article suggests that neither his methodology, nor the results he derives, support the aim of his article. To that end, it seems appropriate to measure Dr. Wolfe’s conclusions against the thesis of his article: namely, that “the claim that consumption of dietary BCAAs stimulates muscle protein synthesis or produces an anabolic response in human subjects is unwarranted” (1).
There are two distinct but interrelated defects to Dr. Wolfe’s article that necessitate questioning the author’s above conclusion:
- The article’s scope and methodology are limited such that its conclusion is prejudiced.
- The article fails to consider alternative explanations for the empirical research that disconfirm its conclusion.
The following section will assess each of these claims.
- Methodology and scope.
According to Dr. Wolfe, his conclusions are based on both theoretical considerations and an “extensive search of the literature” (2). The theoretical case that Dr. Wolfe details is incontestable: in the post-absorptive state, due to the rate of MPB (muscle protein breakdown) exceeding MPS (muscle protein synthesis), the rate of MPT (muscle protein turnover) will be net negative (2). That is, because BCAAs require EAAs to increase muscle protein synthesis, and because in the post-absorptive state the only source of endogenous EAAs is muscle protein breakdown, BCAAs necessarily cannot overcome the breakdown threshold. As Wolfe notes, BCAAs can at best increase the recycle rate of EAAs – conserving them from oxidation or plasma release to other tissues – by 50%. As the accepted rate of MPB exceeds the accepted rate of MPS in the post-absorptive state by 30% (3), BCAAs can maximally stimulate muscle protein synthesis by 15% (30% x .5 = 15%) (2). Wolfe diagrammatically represents the physiology as follows:
Fig 1. Representation of normal (a) and ideal (b) processes for essential amino acid recycling in the post-absorptive state. Both figures represent the normal efflux of EAAs from skeletal muscle because of muscle protein breakdown in the post-absorptive state. As both oxidation and tissue uptake reduce the EAAs available for reincorporation into muscle tissue, the rate of MPB (muscle protein breakdown) will necessarily exceed the rate of MPS (muscle protein synthesis).
Wolfe RR. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality?. J Int Soc Sports Nutr. 2017;14:30.
While we will explore this issue in greater depth soon, it is worth provisionally noting, here, that the above description holds in the post-absorptive, or fasted state. Many commenters or interpreters of this article ignore this metabolic distinction and proceed as if the described physiology is true in both the absorptive (fed) and post-absorptive (fasted state). I hesitate to use the terms “anabolic” and “catabolic” because the average person typically interprets these terms to denote on/off switches that turn from one to the other (the reality is considerably more complex). That said, we can also say that the absorptive state is one in which anabolism exceeds catabolism, and the post-absorptive state is one in which catabolism exceeds anabolism. The physiological explanation that Dr. Wolfe provides above is thus an explanation for amino acid metabolism where catabolism already exceeds anabolism. In the coming sections, we will explore how and why introducing this distinction does not adequately mirror the common use case for dietary supplements containing BCAAs.
After describing the theoretical impossibility of BCAAs alone increasing skeletal muscle protein synthesis in the post-absorptive state, Wolfe cites two empirical studies to buttress the theory section. The first, by Louard et al., primed 10 healthy subjects in the post-absorptive state, after an overnight fast, with a 5h infusion of L-phenylalanine and L-leucine into a brachial artery (3). After a 2h tracer equilibration period, subjects received a constant (3h) infusion of either saline (for control) or a 4% solution consisting of leucine, isoleucine, and valine (Branchamin). Arterial samples were then assessed for phenylalanine disposal (Net balance = Rd (rate of disappearance) – Ra (rate of appearance), taken as an indication of MPS because muscle uptake of phenylalanine occurs only in protein synthesis. The researchers found that, despite significant increase to arterial concentrations of the BCAAs and their a-keto acids, phenylalanine disposal was not stimulated by infusion of branched-chain amino acids (3).
In the second study, also by Louard et al., (4) the BCAA concentration (4% Branchamin) and infusion rate were kept from the previous study, but the total infusion length increased from 3 to 16h. Healthy subjects were admitted to hospital the day before and beginning at 8PM received an overnight infusion of BCAAs via an antecubital vein. Results were similar between trials. Though arterial BCAA concentrations were substantially increased, phenylalanine disposal was not impacted, and a catabolic state persisted.
The empirical evidence that Wolfe provides seems to validate his theoretical considerations. Due to the insufficiency of EAAs, BCAAs administered alone in the post-absorptive state do not seem to increase MPS at a rate that exceeds MPB. Even when administered in doses considerably higher than typical BCAA dosages found in dietary supplements, BCAA administration does not result in net positive MPB.
There are three problems with the way Wolfe selects and represents the data, increasing in severity from one to the other. The first problem is that, despite containing a section whose conclusions are based on an “extensive review of the literature,” the article contains almost none of the features of a robust systematic review. The second problem is the inaccuracy of the arterial phenylalanine flux method of estimating muscle protein synthesis. The third, and most material problem, is that Wolfe misrepresents the relevancy of his theoretical considerations and empirical data to common use case for BCAA dietary supplements.
Though standards differ by the journal, the research question being asked, and the availability and type of data on the question, systematic reviews generally share several features (6, 7). These include, but are not limited to:
- A clear research question;
- An exhaustive, clearly described, and reproducible search strategy;
- Explicitly described selection (inclusion and exclusion) criteria;
- A description of the methodology for each (or most) included studies and an assessment of their quality, and;
- In the case of meta-analyses, a quantitative (statistical) synthesis of the data presented according to an explicit methodology (8).
Wolfe’s article, though he represents his literature review as “extensive” and though it is widely considered exhaustive, possesses none of these features save for one. (As there is arguably a clear research question.) At no point in Wolfe’s article does he describe the methods and procedures he uses to search for includible research data. We are not given a list of databases, terms (and their derivations), or even a broad outline of how he came upon the studies included in his article. At no point in Wolfe’s article does he describe the selection criteria by which he either excluded or included a piece of research. He intimates two conditions – that BCAAs were administered alone and that they were administered in the post-absorptive state – but, as we discuss below, he does not describe how these two conditions are linked to the wider research question or specify further how these conditions are employed in a search strategy. And, finally, at no point in Wolfe’s article does he describe the implications for the methodologies used in the included studies, nor does he assess their quality. As we will also discuss below, presenting data on BCAAs and muscle protein synthesis requires critical examination to determine whether these data correspond to the common use case. Wolfe undertakes no such critical examination.
Taken together, the absence of these features represents a methodological black hole: as readers and potentially impartial assessors of Wolfe’s article, we have no idea how, why, and through which mechanisms the author either selects or assesses the research included in this systematic review.
Recent research (5) demonstrates that the net phenylalanine balance method employed by both pieces of data that Wolfe cites (and as they are methodologically representative, most research on BCAAs) underestimates the fractional synthetic rate of muscle protein synthesis. As Tran et al., describe, the limitation of the blood amino acid enrichment method, which uses the rate at which the stable isotopes for L-phenylalanine and L-leucine are incorporated into muscle to measure muscle protein synthesis rates, is the dilution of isotope tracers by the “continuous appearance of unlabeled amino acids from tissue protein breakdown” (5). In other words, as MPB occurs, as it does in the post-absorptive state in which the referenced studies tested subjects, amino acids enter plasma and thus the amino acid enrichment of blood is higher than the amino acid enrichment of muscle. Measuring the amino acid enrichment via phenylalanine disposal results in a discrepancy between the true fractional synthetic rate and the rate measurable by arterial concentration (5). Tran et al., provide a graphical representation of this discrepancy here:
Fig 2. Fractional synthesis rate in the basal period (Basal) and during intravenous infusion of amino acids (AA infusion) determined using either endogenously introduced d9-leucine tracer (via intravenous infusion of d10-leucine) or intravenously introduced 13C6-phenylalanine tracer, and using the blood (A) or muscle (B) amino acid enrichment as the precursor amino acid enrichment. *P < 0.05, basal versus AA infusion; †P < 0.05, d9-leucine versus 13C6-phenylalanine.
Tran L, Masters H, Roust LR, Katsanos CS. A new method to measure muscle protein synthesis in humans by endogenously introduced d9-leucine and using blood for precursor enrichment determination. Physiological Reports. 2015;3(8):e12479. doi:10.14814/phy2.12479.
To correct for this discrepancy, Tran and colleagues developed a method for directly introducing isotope tracer into the muscle. As described in their study, Tran et al., intravenously administer d10-leucine and measure the endogenous rate of d9-leucine appearance via d10-leucine metabolism. They elaborate:
A way to introduce a tracer directly into the muscle is by intravenous infusion of l-[2,3,3,4,5,5,5,6,6,6-2H10]leucine (d10-leucine) that results in endogenously formed d9-leucine..[I]n line with this evidence, preliminary experiments in our laboratory indicated that d9-leucine enrichment represents about 88% of the sum of d9-leucine + d10-leucine enrichment in muscle fluid following intravenous administration of d10-leucine in human subjects. Under these conditions, d9-labeled and unlabeled leucine isotopomers from muscle spill over into the blood and can minimize the gradient between blood and muscle fluid d9-leucine enrichments. Therefore, introducing the tracer directly into the muscle by the endogenous formation of d9-leucine can provide more accurate determination of muscle protein synthesis compared to when the tracer is introduced first into the blood and then transported into the muscle, and when using blood amino acid enrichment as the precursor
As Fig 2. demonstrates, the result of this improved method is a lower ratio between both phenylalanine and leucine isotopes, relatively, and a lower ratio between muscle and blood amino acid enrichment. As Wolfe notes the importance of phenylalanine disposal (measured relative to the rate of disappearance for BCAAs) for measuring protein synthesis, we can conclude that the referenced studies that Wolfe provides as his empirical case underestimate the rate at which BCAAs increase the fractional synthetic rate of muscle protein synthesis when administered alone in the post-absorptive state. This finding alone is insignificant, as Wolfe admits for the possibility of a theoretical scenario where exogenous BCAA administration increases the recycle rate of EAAs by 50%.
The potential inaccuracy of this methodology is not relevant for the data it produces, but the fact that it was selected at all. There is a strong possibility that Dr. Wolfe knew he was utilizing research with outdated and inaccurate methodology to substantiate his preferred conclusion. The evidence for this position is that Wolfe, along with two co-authors, published an article in 2004 describing how extracellular methods of measuring muscle protein synthesis underestimate the rate of true fractional synthetic rate of muscle protein synthesis (6). It is likely, therefore, that Wolfe willingly and knowingly selected data that privileged his preferred conclusion without qualifying this data and/or elaborating on how this data fit his inclusion criteria. This choice is significant, because it is of a piece with the second and wider problem in this article: that Wolfe is willing to misrepresent how his selected research corresponds to the common BCAA use case.c. Common BCAA use case
To illustrate the third problem, consider how Wolfe presents his argument in the abstract and background sections of his article. The abstract notes that “An extensive search of the literature has revealed no studies in human subjects in which the response of muscle protein synthesis to orally-ingested BCAAs alone was quantified,” and that “the claim that consumption of dietary BCAAs stimulates muscle protein synthesis or produces an anabolic response in human subjects is unwarranted” (1). He continues in the background section, stating “At the center of the marketing for these products is the widely-believed claim that consumption of BCAAs stimulates muscle protein synthesis, and as a result elicits an anabolic response” and “The primary purpose in this paper to evaluate the assertion that BCAAs alone are anabolic is adequately supported either theoretically or empirically by studies in human subjects” (1). Notice that Wolfe frames his meta-analysis without reservation or qualification: the article ostensibly does not limit itself to certain physiological or metabolic conditions in the abstract or background. In the broadest sense, the article appears to consider whether exogenous BCAAs administered alone increase the rate of muscle protein synthesis.
In the next section, however, Wolfe introduces a critical physiological parameter with no exploration of which ways and to what extent this new physiological parameter privileges EAAs and prejudices BCAAs in analysis of skeletal muscle protein synthesis. Nor does he explain how this new physiological parameter results in an analysis that does not mirror the common BCAA use case. In the second paragraph of the second section of his article, “Muscle protein turnover and dietary protein intake,” Wolfe demarcates his first, unqualified and unreserved argument (that BCAAs do not increase muscle protein synthesis) from a second, highly-qualified and reserved argument (that BCAAs do not increase muscle protein synthesis in a specific physiological condition) with an unassuming sentence. He states, “In the post-absorptive state the plasma EAA levels fall below the post-prandial values because amino acids are no longer being absorbed” (1).
From this point forward, Wolfe effectively separates his article into two portions with divergent evidentiary standards. The first portion, necessitating both a broad and deep overview of the literature on amino acid metabolism in various use and study conditions, suggests that BCAAs are ineffective for increasing the rate of skeletal muscle protein synthesis overall. The reaction in the dietary supplement industry to this article suggests nearly all who read it took this conclusion as being substantiated. The second portion, allowing for a truncated, highly-specific, and highly-selective review of the literature on amino acid metabolism, suggests that BCAAs administered alone and in the post-absorptive state are ineffective at increasing the rate of muscle protein synthesis. Nowhere in the article does Wolfe explain and/or consider:
- Alternative explanation
In the second section of his article, “Muscle protein turnover and dietary protein intake,” Wolfe accurately describes the essential conditions for muscle protein synthesis in both the absorptive and post-absorptive state. He notes that “[a]n abundant availability of all EAAs is a requisite for a significant stimulation of muscle protein synthesis” (1). While the BCAAs (and leucine alone) can phosphorylate translation initiation factors and ribosomal proteins like 4E-BP • eIF4E complex and S6K1, skeletal muscle protein synthesis requires both initiators and substrates. Absent substrates, which as Wolfe notes are the remaining EAAs, no amount of translation initiation will result in the so-called “anabolic state.” Or, as Wolfe states, “…activation of the anabolic signaling pathways can only coincide with increased muscle protein synthesis if there are ample EAAs to provide the necessary precursors to produce complete protein" (1).
This observation holds for both the absorptive and post-absorptive states. Wolfe’s entire article rests, however, on not qualifying the time interval to transition from the absorptive to post-absorptive state. Nor does he detail the physiological changes that take place under this time interval. (Represented in Figure 3.) (9) For all the reader of Wolfe’s article knows, the post-absorptive state is a permanent condition in which supplemental EAAs, as both substrate and catalyzer for translation initiation, are required to kickstart protein metabolism again. If the absorptive state’s length roughly synchronizes with the frequency of whole protein intake for the average BCAA consumer, then both Wolfe’s theoretical and empirical conditions are moot. The theoretical conditions are moot, because they describe a protein metabolic environment in which most users are not consuming BCAAs. The empirical evidence is moot, because the studies that Wolfe provides measure the effect of administering exogenous BCAAs to test subjects in conditions that do not mirror the use case for the common or typical BCAA user. To that end, the absorptive state lasts anywhere from 4 to 4.5 hours (8). At approximately 4 hours post-feeding, due to a host of physiological processes, muscle and amino acid catabolism has reached a point where muscle protein turnover is negative (8).
Fig 3. Energy metabolism in the absorptive and post-absorptive states.
In the absorptive state following a meal, macronutrients (protein, carbohydrates, and dietary fats) are broken down into their constituent elements (amino acids, simple sugars, and lipids) for energy provision and/or tissue synthesis. In this state, all tissues increase the rate at which they uptake amino acids for protein synthesis and glucose for energy provision (to fuel protein synthesis).
At approximately three to four hours, the post-absorptive state begins. Peripheral tissues (skeletal muscle, for example) begin to catabolize their glycogen into glucose. After a prolonged period, the body catabolizes its liver glycogen stores in response to dropping blood glucose. As the duration of the post-absorptive state lengthens, the body will divert more glucogenic amino acids to the liver for gluconeogenesis.
The importance of this point for the proper interpretation of not only Wolfe’s article, but the body of amino acid metabolism literature, cannot be overstated. Wolfe’s assertions about BCAAs rest in total on the average BCAA consumer not consuming intact protein every 4 to 4.5 hours. Stated in reverse, if a BCAA supplement user intakes whole protein every 4 to 4.5 hours, they will create the very conditions that Robert Wolfe describes as being adequate for BCAAs to stimulate muscle protein synthesis. How? Recall the immutable metabolic fact that BCAAs cannot (and do not) initiate MPS without the remaining six EAAs. The implicit suggestion in the Wolfe article is that supplemental EAAs are therefore necessary to render BCAAs active in the protein synthetic machinery. But the EAA blood pool remains substantially elevated above baseline for approximately 4 hours post whole protein-feeding, meaning that anyone consuming intact protein every 4 to 4.5 hours does not need EAAs to complement BCAAs to increase protein synthesis. Extensive data on amino acid kinetics exists demonstrating the AUC for amino acid enrichment. In a comparative analysis of the increase to MPS from various compositions of EAAs and whey protein, for example, Wilkinson et al (10) note that in response to 40g whey, plasma EAA enrichment is elevated to levels sufficient for increasing MPS for 4h post-feeding. Again: provided an average BCAA user consumes whole protein every 4 to 4.5 hours, the free-floating pool of EAAs is already high enough that orally-ingested BCAAs will increase protein synthesis. (I will provide empirical data to validate this claim in Pt. II.)
The operative question then becomes: are the articles that Wolfe provides as empirical evidence administering BCAAs to subjects in the absorptive or absorptive state? Or stated otherwise: are the articles that Wolfe provides as empirical evidence administering BCAAs to subjects in conditions that mirror common use conditions? The answer for both studies, along with the overwhelming majority of BCAA research, is that these studies were conducted in the post-absorptive state. In the first study, for example, the researchers note that subjects presented in the lab after an overnight fast of an undefined time and subsequently received a 5h infusion of phenylalanine and leucine isotope tracers, waited through a 2h equilibrium period, and finally received a 3h infusion of BCAAs (3). Generously assuming that the total time from last whole protein intake to presentation at the lab is 9h, the subjects in this study were in the post-absorptive state for 16h prior to being challenged with a BCAA infusion (3).
Though Wolfe implicitly criticizes the “multi-million-dollar” BCAA industry and its deceptive marketing, even Wolfe must concede that not even the most egregious marketing suggests that BCAAs administered after a 16h fast will be effective for enhancing skeletal muscle protein synthesis. Moreover, very few (if any) responsible dietary supplement companies suggest consuming BCAAs alone in the first place (the second of Wolfe’s physiological parameters). In fact, the very nature of a dietary supplement is that it is supplemental to the diet; in the case of BCAAs, supplemental to the recommended daily intake of whole protein.
The bare minimum standard for scientific rigor in an article with Wolfe’s stated conclusion (“The claim that consumption of dietary BCAAs stimulates muscle protein synthesis or produces an anabolic response in human subjects is unwarranted”) is considering the applicability of research studies to the research question. Ideally, a sustained and detailed assessment of the quality and applicability of these studies would result in one of two outcomes. One, retaining the stated conclusion but finding new and different data to substantiate the claim. Or two, abandoning or at least modifying the stated conclusion, such that it reflects the existing data. Robert Wolfe does neither.
As we noted above, the framing and content of Wolfe’s article are out of sync. The article is framed as possessing both the theory and evidence to wholesale reject BCAAs as an effective supplement for increasing skeletal muscle protein synthesis. The article’s content is more specific and relegated to considering whether BCAAs administered in the fasted or post-absorptive state are effective for increasing skeletal muscle protein synthesis. The fundamental contradiction and defect of Wolfe’s article is that he provides answers for the latter and applies them erroneously to the former.
Nowhere is this contradiction more apparent than in the article’s conclusion. There, with no mention of alternative explanations of the study results, necessary qualifiers regarding protein intake, protein-controls for empirical research, or any qualifications regarding the absorptive or post-absorptive state, Wolfe confidently asserts that, “We conclude that dietary BCAA supplements alone do not promote muscle anabolism.”” (1). Recall that this assertion is based on an “extensive search of the literature.” Ostensibly, if one could provide and assess research studies that contradict this claim, then Wolfe’s empirical case would be further weakened.
Such data indeed exists. A June 2017 analysis featuring exercise-trained subjects, controlled for protein intake, and in the post-absorptive state shows that BCAAs alone increased MPS by approximately 22% over placebo. While we will discuss this article in full in Pt. II of this analysis, we should note the damage this research does to Wolfe’s position: in an experimental design much closer to the average use case for BCAAs, and therefore not susceptible to the criticism detailed in this article, BCAAs were found to directly and substantially do what Wolfe erroneously suggests they cannot.
We will explore that data, along the with existing empirical research on “EAAs vs BCAAs” in Part II of this series. Stay tuned.
- Wolfe, RR; “Branched-chain amino acids and muscle protein synthesis in humans: myth or reality?”; J Int Soc Sports Nutr; 14(1):30; 2017; https://jissn.biomedcentral.com/articles/10.1186/s12970-017-0184-9
- https://blog.priceplow.com/eaa-vs-bcaa. Why EAAs are the New BCAAs: Essential Amino Acids Stage a Coup
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