Lowdown on BCAA Supplements

How to Use Them for Optimum Gains

The branched-chain amino acid (BCAA) is an amino acid with a side-chain consisting of covalently linked carbon atoms that form a branch-like structure, thus eliciting their name. There are the three BCAAs found in the body: leucine, isoleucine and valine. Supplementation with BCAAs has been very popular, primarily because of the apparent ability of BCAAs to increase muscle growth. The problem is that all three BCAAs do not equally promote muscle growth. In fact, it’s not even close as leucine is, by far, the most potent stimulator of muscle growth, while isoleucine and valine come in a very distant second and third place, respectively.^1,2

That said, isoleucine and valine do provide some performance-enhancing effects. However, the simultaneous consumption of all three BCAAs should be avoided, as many of the performance-enhancing effects caused from the independent ingestion of a particular BCAA can be diminished by the simultaneous ingestion of all three BCAAs. Furthermore, the counterproductive influence caused by taking all three BCAAs at the same time likely increases the amount of BCAA required to produce the desired performance-enhancing effect, and greater BCAA intake further depletes the positive influence from BCAA consumption— as too much BCAA intake promotes insulin resistance³, stunting muscle growth and thus performance.

Leucine: the Most Potent Muscle-building BCAA

Out of all three BCAAs, leucine elicits the strongest anabolic response by potently activating the nutrient-sensing enzyme mTOR, which directly enhances muscle protein synthesis while preventing muscle protein breakdown, resulting in muscle growth. Several scientific studies highlight potent mTOR activation by the amino acid leucine. One study by Walker et al.⁴ showed that leucine consumption shortly after working out increased mTOR activity, leading to greater post-workout muscle protein synthesis, compared to an exercised group that was not fed leucine. Another scientific inquiry by Pasiakos et al.⁵ demonstrated that consumption of leucine immediately after exercise specifically enhanced muscle protein synthesis by as much as 33 percent.

Leucine consumption has also been shown to decrease muscle protein breakdown, once again by activating mTOR⁶, which has the capacity to turn off the energy-sensing enzyme AMPK. Inactivation of AMPK prevents its normal function of initiating the breakdown of protein into amino acids for energy, in order to restore energy levels within the cell when cellular energy is low. Altogether, the ability of leucine to robustly increase muscle protein production while decreasing protein degradation increases muscle protein levels, resulting in considerable muscle hypertrophy.

Antagonistic Effects of Isoleucine and Leucine

Despite the limited capacity of isoleucine to trigger muscle protein synthesis and therefore muscle growth relative to leucine^1,2, isoleucine outperforms leucine when it comes to supplying the muscle cell with energy from glucose. This occurs because isoleucine intake increases the influx of glucose into the muscle cell and increases the rate at which glucose is converted into energy within muscle.⁷ In contrast, leucine consumption only increases glucose influx into the muscle cell. After that, glucose is then converted into glycogen for energy storage, instead of being immediately burned for energy.⁸

The antagonistic effects of isoleucine and leucine on glucose metabolism within the muscle cell indicates that co-consumption of these two BCAAs is likely unproductive and should be avoided. On the other hand, the use of isoleucine and leucine at different times should generate superior performance enhancement— particularly if isoleucine use occurs before training to maximize energy production, and leucine use takes place post-workout to increase the anabolic response to training. 

Furthermore, the ability of isoleucine to convert glucose into energy within the muscle cell plausibly contributes to the inhibitory effect that isoleucine has on insulin function, as higher energy levels from isoleucine consumption tend to inactivate certain isoforms of the energy-sensing enzyme AMPK.⁹ Inactivation of AMPK lowers the capacity that AMPK has to augment the insulin-signaling pathway, resulting in a weaker overall insulin response that reduces the capacity to pack on muscle mass.

Valine and Leucine Together Can Promote Sluggishness and Fatigue

Although the BCAA valine doesn’t effectively drive muscle growth^1,2, it can improve exercise performance by lowering production of the neurotransmitter serotonin during exercise by directly inhibiting transport of the serotonin-precursor tryptophan, resulting in a diminished conversion of tryptophan into serotonin.¹⁰ Since serotonin tends to bring about sluggishness and fatigue in the gym, the reduction in serotonin levels from valine intake enhances performance. So, it seems pretty simple— take a handful of BCAAs containing valine before your workout to lower serotonin levels and reduce fatigue, and you’ll be good to go.

Well, unfortunately it’s not that simple. As it turns out, greater fatigue from exercise is actually influenced more heavily by the ratio of serotonin to another neurotransmitter, dopamine¹¹, where higher serotonin to dopamine ratios increase fatigue. Thus, simply taking BCAAs isn’t going to effectively reduce tiredness, because BCAAs do more than simply lower serotonin. In fact, the BCAA leucine also prevents the uptake of the dopamine-precursor tyrosine into the brain, ultimately reducing dopamine production.¹² Of course, this would counteract any positive effect that valine might have by reducing serotonin levels, as the simultaneous reduction in dopamine levels would reestablish a serotonin to dopamine ratio that promotes fatigue. So, once again, the antagonistic functions of BCAAs— in this case, valine and leucine— reveals that co-ingesting them is unproductive. BCAAs should be consumed separately, with valine intake before exercise to optimally hinder pre-workout fatigue— and leucine after training, to induce relaxation that promotes full recuperation.

Too Much BCAA Intake Can Reduce Muscle Growth

Insulin is one of the most potent muscle-building hormones in the human body, possessing the ability to drastically increase muscle protein synthesis and enhance muscle growth.¹³ Insulin achieves this muscle-building effect by binding to the insulin receptor and setting off a cascade of signaling events that eventually activates the enzyme mTOR, triggering muscle growth.¹⁴ Because of its potency, the insulin-signaling cascade is very sensitive to overstimulation, where extraneous activation of the insulin-signaling pathway rapidly triggers negative feedback mechanisms— ultimately resulting in diminished muscle growth.

Interestingly, several studies have shown that BCAAs can overstimulate the insulin-signaling machinery, resulting in reduced insulin signaling^15,16 and ultimately insulin resistance.³On the contrary, leucine consumption alone has been shown to actually rescue insulin-signaling deficiency¹⁷, despite the strong influence that leucine has on insulin secretion and signaling activity which, in theory, should have a propensity to decrease insulin function via the previously mentioned negative feedback mechanism that occurs with too much insulin signaling. Although the exact mechanism by which leucine improves insulin function is not completely understood, it appears that leucine’s strong influence on muscle growth generates a large demand for energy as muscle tissue is very active metabolically, thus requiring considerable energy. As a result, leucine intake also triggers the production of energy, primarily by burning fat.^18,19 The loss of body fat augments the response to insulin signaling thus overcoming, to some degree, the negative influence that leucine can have on insulin signaling via overstimulation. 

In summary, the optimal use of BCAAs for performance enhancement involves more than just simply consuming BCAAs before and after working out to boost muscle growth. The correct use requires the proper timing of leucine, isoleucine and valine intake to prevent their antagonistic effects on each other, thus maximizing the performance-enhancing effects of BCAA consumption. Moreover, the removal of any counteracting effects from proper timing of BCAA intake further enhances the muscle-building effect by lowering the effective dosage required for each BCAA, which reduces the negative impact that extraneous BCAA consumption can have on insulin-driven muscle growth.

For most of Michael Rudolph’s career he has been engrossed in the exercise world as either an athlete (he played college football at Hofstra University), personal trainer or as a research scientist (he earned a B.Sc. in Exercise Science at Hofstra University and a Ph.D. in Biochemistry and Molecular Biology from Stony Brook University). After earning his Ph.D., Michael investigated the molecular biology of exercise as a fellow at Harvard Medical School and Columbia University for over eight years. That research contributed seminally to understanding the function of the incredibly important cellular energy sensor AMPK— leading to numerous publications in peer-reviewed journals including the journal Nature. Michael is currently a scientist working at the New York Structural Biology Center doing contract work for the Department of Defense on a project involving national security.

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