Dramatic Increase In Anabolic Response From New Research-Based Nutrient Combination

In order to gain muscle, it’s imperative that we repeatedly attain an anabolic response to our training and nutrition.

This anabolic response or net protein balance is the difference between whole body protein synthesis minus breakdown. There are many variables that can influence both protein synthesis and breakdown, thus impacting net whole body protein balance.

One of these key variables is nutrition and supplementation.  

Intact proteins are popular dietary supplements that increase muscle mass by stimulating protein synthesis.

Supplementation with intact proteins may take the form of protein-fortified prepared foods, or as pure protein, and whey protein isolate is the most popular pure protein supplement.

Essential amino acids (EAA) are the primary “active” components of dietary protein.

They cannot be produced in the body, but are primarily responsible for the stimulation of muscle protein synthesis (1) and are comprised of the following amino acids:

• Histidine
• Isoleucine
• Leucine
• Lysine
• Methionine
• Phenylalanine
• Threonine
• Tryptophan
• Valine

The response of muscle protein synthesis following ingestion of a composition of free EAA is more than twice the response to consumption of a comparable dosage (gram for gram) of whey protein isolate (2).

This robust anabolic effect of free-form EAA can be attributed to the more rapid increase in plasma concentrations following ingestion of EAA, as well as the higher peak concentrations. Furthermore, EAA supplements can be formulated to address altered metabolic conditions, such as aging (3).

While EAA supplements have distinct advantages, isolated intact proteins, such as whey protein isolate, have advantages as well.

One of these advantages is sustained protein synthesis over a longer time than the response to free-form EAA because of the slower absorption of the component amino acids in dietary protein (4).

In addition, peptides formed in the digestion of dietary proteins (particularly whey protein) have been proposed to have unique nutritional advantages (5).

Also, taste preferences may favor intact protein compositions. Therefore, the idea of a nutritional composition that combines the beneficial effects of both free-form EAA and isolated dietary protein is attractive.

We know from previous research that the branched-chain amino acid leucine is a potent trigger to protein synthesis.

Previous studies have added free leucine to whey protein isolate to amplify the synthetic response, with mixed results (6,7).

The justification of combining leucine with intact protein is that leucine can activate the molecular mechanisms involved in the initiation of protein synthesis, so that the tissue is “primed” for a greater response to the amino acids absorbed from the dietary protein. 

Here is an important finding of using only leucine with whey protein:

Although the addition of free leucine may enhance the acute synthetic response to whey protein, an imbalance in the plasma concentrations of EAA will likely occur.

This happens because the EAA with the lowest concentration relative to demand will be a limiting factor in the anabolic response, regardless of the extent of excess of the other EAA, including leucine. Therefore, it’s quite important to maintain a balance of EAA that is roughly proportionate to the demand for each individual EAA. 

Given this important fact, the idea of combining a balanced formulation of all of the EAA with an intact protein is very appealing.

A combination of a balanced formulation of EAA and a high-quality intact protein should provide the beneficial effect of a rapid and large increase in leucine concentration to activate muscle protein synthesis at a molecular level, while also providing sufficient other EAA to maintain a prolonged availability of all the necessary precursors for protein synthesis.

This specific concept hasn’t been addressed in controlled research until very recently.

The study investigated the acute response of protein kinetics to two doses of a composition containing free EAA and whey protein, as well as the response to a popular commercial whey-based protein supplement.

The same group of participants consumed each of the two doses of the proprietary free-form EAA/whey protein study supplement separated by a wash-out period. The low-dose EAA group included 3.2 g of free EAA and 2.4 g whey protein, whereas the high-dose EAA group included 6.4 g of free EAA and 4.8 g of whey protein. 

Another group of subjects (with similar gender composition) ingested a commercial product containing 12.6 g of whey protein powder. 

Major findings of this research:

• The principal finding of this study is that a combination of free EAA and whey protein is highly anabolic in healthy young volunteers. The anabolic response to the free EAA/protein composition was dose-dependent. Interestingly, the gain in net protein balance following consumption of high-dose EAA was significantly greater than the response of net protein balance to the low-dose EAA product when normalized for the amount of product consumed. This greater net protein balance was mostly due to a greater suppression of protein breakdown. 

• The anabolic responses of either dose of EAA/whey protein product was greater than the response to a whey protein-based commercial beverage when normalized to the amount consumed. When normalized for the amount of product consumed, the low dose EAA/protein response of net protein balance was approximately three- fold greater than the whey protein product. The response of net protein balance to the high dose EAA/protein product was approximately six times greater than the response to the whey protein product alone. 

• A key finding was the greater increase in net protein balance with the high-dose EAA/protein composition which was due to both a greater increase in the rate of whole-body protein synthesis and greater suppression of whole-body protein breakdown as compared to the low-dose EAA/protein and whey protein only group.  

Key points regarding this research:  

As mentioned, leucine by itself has traditionally been added to dietary protein or to complete meals with disappointing results. The problem with adding only leucine to dietary protein is that the availability of the other EAA becomes rate limiting. In particular, the plasma concentrations of the other branched chain amino acids (valine and isoleucine) fall below the fasting level when only extra leucine is added to intact protein (6).

The current study was the first to which I’m aware in where a balanced formulation of free EAA has been combined with whey protein.

The formulation differed from most EAA nutritional compositions in that leucine comprised only 20% of the free EAA. It has been proposed that the magnitude of anabolic response to dietary protein is determined by the increase in plasma leucine concentration, rather than to the amount of protein consumed (8).

In support of this viewpoint, EAA compositions designed for elderly individuals require an excessively high percentage of leucine to maximize the anabolic response than would be predicted from the composition of muscle protein (3).

However, the disproportionately high leucine content in compositions designed to stimulate an anabolic response in younger heathy volunteers is not necessary (9). 

Rather, in the current study the leucine content of the EAA/protein composition was based on the amount required to maintain a balance among all the protein synthetic precursors. By including only 20% of EAA as leucine, the relative proportions of the other EAA were increased which provided all of the precursors necessary for synthesis of body proteins.

Even with a low dose (3.2 g) of free EAA comprised of only 20% leucine, the plasma leucine concentration rose almost 3-fold, while the concentrations of the other EAA were increased in proportion to their requirements for muscle protein synthesis.

Free EAA have the advantage of being rapidly and completely absorbed (10). This rapid peak response in plasma EAA is likely a key reason for their effectiveness (11).

A caveat to this is that the total duration of the response is limited, because just as the concentrations of EAA in the blood rise rapidly, they fall rapidly as well.

With this knowledge, the current study included a composition that also contains intact protein in addition to the EAA in order to prolong the anabolic response during the period following consumption of the beverage. That is exactly what they found. The addition of these free EAA to whey protein prolonged the anabolic response compared to just whey protein powder alone!

In fact, the high-dose EAA/protein showed the greatest anabolic response which remained elevated during the time after consuming the beverage.

Another key finding in this research was that whole body protein breakdown was significantly suppressed with the highest dose of the EAA/protein composition (12).

A very recent study from the lab I’m affiliated with found similar results in military personnel undergoing a 30% energy deficit for 5 days. They found that EAA-enriched whey enhanced net protein balance versus whey isolate and a mixed-macronutrient meal with the same nitrogen content during a 30% energy deficit.

These findings indicate that protein-containing food formats which have a high EAA content and achieve rapid and sustained peripheral EAA concentrations can enhance whole-body protein status and efficiently support muscle protein synthesis during the catabolic stress of underfeeding (13).

This study utilized a composition containing much higher levels of EAA and whey protein than the previous study. The total amounts in the EAA + Whey were 34.7 g protein which included a total of 24 g of EAA. The composition (% of EAA) were similar in both studies.

I think it’s quite practical to go with a higher level of both whey protein and EAA given the fact that these participants were underfed 30% of their baseline intake for 5 days. Even with these amounts, it was quite astonishing to see such a greater net protein balance during a catabolic stress of underfeeding.

Summary & Practical applications

It’s very clear from the recent evidence that there is an interactive effect between free EAA and whey protein that makes their combination highly anabolic in a dose dependent manner. This combination exceeds the anabolic response to a whey-protein only based supplement by approximately 3- and 6-fold for the low- and high-doses of free EAA/protein, respectively, when evaluated on a g/g basis.

This research is extremely exciting and demonstrates a novel approach to enhancing the acute anabolic response from a combination of whey protein & EAA. 

A great follow up study to this would be to see chronic effects on body composition in trained personnel over a longer period of time (e.g. 12 weeks). We know that intense resistance training enhances protein synthesis and also greatly enhances protein breakdown.

This is why nutrition/supplementation after your training is so important.

It’s clear there is an anabolic response when combining EAA & whey protein in a dose-dependent manner. It would be interesting to see what this relates to in enhancing muscle tissue over time. I’ll keep you informed of any new research in this area.

Steel stack recommended to enhance this acute anabolic response.

I recommend combining Steel’s BCAA/EAA and Whey-Iso together immediately following training. 

The amount of EAA in BCAA/EAA is similar to the amount used in this research, and I think 1 scoop of each is a good start if you are currently meeting your calorie requirements or in and calorie surplus.

If you are dieting and restricting calories, evidence shows that more EAA and protein combined is beneficial to enhance the anabolic response, and you may want to take this into account to maximize your anabolic response if you are in a calorie deficit.

References: 

1. Volpi, E., Kobayashi, H., Sheffield-Moore, M., Mittendorfer, B., and Wolfe, R. R. (2003) Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults. Am J Clin Nutr 78, 250-258

2. Paddon-Jones, D., Sheffield-Moore, M., Katsanos, C. S., Zhang, X. J., and Wolfe, R. R. (2006) Differential stimulation of muscle protein synthesis in elderly humans following isocaloric ingestion of amino acids or whey protein. Exp Gerontol 41, 215-219

3. Katsanos, C. S., Kobayashi, H., Sheffield-Moore, M., Aarsland, A., and Wolfe, R. R. (2006) A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab 291, E381-387

4. Churchward-Venne, T. A., Burd, N. A., Mitchell, C. J., West, D. W., Philp, A., Marcotte, G. R., Baker, S. K., Baar, K., and Phillips, S. M. (2012) Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men. J Physiol 590, 2751-2765

5. Athira, S., Mann, B., Sharma, R., and Kumar, R. (2013) Ameliorative potential of whey protein hydrolysate against paracetamol-induced oxidative stress. J Dairy Sci 96, 1431-1437

6. Tipton, K. D., Elliott, T. A., Ferrando, A. A., Aarsland, A. A., and Wolfe, R. R. (2009) Stimulation of muscle anabolism by resistance exercise and ingestion of leucine plus protein. Appl Physiol Nutr Metab 34, 151-161

7. Churchward-Venne, T. A., Breen, L., Di Donato, D. M., Hector, A. J., Mitchell, C. J., Moore, D. R., Stellingwerff, T., Breuille, D., Offord, E. A., Baker, S. K., and Phillips, S. M. (2014) Leucine supplementation of a low-protein mixed macronutrient beverage enhances myofibrillar protein synthesis in young men: a double-blind, randomized trial. Am J Clin Nutr 99, 276-286

8. Devries, M. C., McGlory, C., Bolster, D. R., Kamil, A., Rahn, M., Harkness, L., Baker, S. K., and Phillips, S. M. (2018) Leucine, Not Total Protein, Content of a Supplement Is the Primary Determinant of Muscle Protein Anabolic Responses in Healthy Older Women. J Nutr 148, 1088-1095

9. Katsanos, C. S., Kobayashi, H., Sheffield-Moore, M., Aarsland, A., and Wolfe, R. R. (2005) Aging is associated with diminished accretion of muscle proteins after the ingestion of a small bolus of essential amino acids. Am J Clin Nutr 82, 1065-1073

10. Adibi, S. A., Gray, S. J., and Menden, E. (1967) The kinetics of amino acid absorption and alteration of plasma composition of free amino acids after intestinal perfusion of amino acid mixtures. Am J Clin Nutr 20, 24-33

11. West, D. W., Burd, N. A., Coffey, V. G., Baker, S. K., Burke, L. M., Hawley, J. A., Moore, D. R., Stellingwerff, T., and Phillips, S. M. (2011) Rapid aminoacidemia enhances myofibrillar protein synthesis and anabolic intramuscular signaling responses after resistance exercise. Am J Clin Nutr 94, 795-803

12. Park, S., Church, D. D., Azhar, G., Schutzler, S. E., Ferrando, A. A., and Wolfe, R. R. (2020) Anabolic response to essential amino acid plus whey protein composition is greater than whey protein alone in young healthy adults. J Int Soc Sports Nutr 17, 9

13. Gwin, J. A., Church, D. D., Hatch-McChesney, A., Allen, J. T., Wilson, M. A., Varanoske, A. N., Carrigan, C. T., Murphy, N. E., Margolis, L. M., Carbone, J. W., Wolfe, R. R., Ferrando, A. A., and Pasiakos, S. M. (2021) Essential amino acid-enriched whey enhances post-exercise whole-body protein balance during energy deficit more than iso-nitrogenous whey or a mixed-macronutrient meal: a randomized, crossover study. J Int Soc Sports Nutr 18, 4