A Closer Look at Branched Chain Amino Acids;
        Leucine, Isoleucine and Valine

As an important essential nutrient, protein performs a wide array of physiological functions that range from, use in the formation of almost all enzymes and hormones to regulating our metabolisms.³ Proteins consist of a complex structure made up of elements of carbon, hydrogen, oxygen, nitrogen, and sometimes sulfur, which combine into various structures called amino acids.³ There are a total of twenty amino acids that link together to form the proteins necessary for the structure and functions of the human body.³ Amongst themselves, these twenty amino acids can then be further separated into two groups: essential amino acids and non-essential amino acids.³

The difference between essential and non-essential amino acids is that the human body is unable to synthesize, or manufacture, the essential amino acids itself. This means that they must be acquired through an outside source obtained from the diet.³ Of the twenty total amino acids occurring in proteins, nine of them are essential and include: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.³ The ten non-essential amino acids, which can be formed within the body, include: alanine, arginine, asparagine, aspartic acid, cystine, glutamic acid, glutamine, glycine, proline, and serine.³Of the ten non-essential amino acids, six of them are termed to be conditionally essential.³ This classification is used because, in some conditions, such as during times of endogenous synthesis (like during exercise), these amino acids may have to be acquired via the diet.³

Particular attention is directed towards three specific amino acids: leucine, isoleucine, and valine. Collectively, these amino acids are referred to as the “branched chain amino acids”, or BCAA's. The importance of BCAA's is due to their ability to take on roles in anabolism,^2-8 anti-catabolism,^2-8 and their ability to serve as a substrate during exercise. Due to these important properties, BCAA's are advertised extensively by the supplement industry and by reviewing current literature on these matters, healthcare professionals can validate an accurate reading on this topic.

The branched chain amino acids, or BCAA's, consist of the amino acids leucine, isoleucine, and valine. BCAA's are unique from the other amino acids due to the way that they are metabolized in the body. Of the other, both essential and non-essential, amino acids, catabolism occurs primarily in the liver.⁷ As for the BCAA's, after ingestion they are passed through the hepatic bed and enter into the bloodstream where more than 60% undergo metabolism extrahepatically in the skeletal muscle.

“The first step in the BCAA's metabolism in peripheral tissues occurs via deamination by the enzyme branched chain amino acid aminotransferase (BCAT) to produce branched chain keto-acids.”⁶ “The branched chain keto-acids are then incorporated into protein, or circulate the body and serve as an important energy substrate in not only skeletal muscle, but also in the brain, the kidneys, liver, and the heart.”^6-7 In skeletal muscle, as well as in the aforementioned organs, the branched chain keto-acids then undergo oxidative decarboxylation via branched chain keto-acid dehydrogenase with the subsequent generation of substrates for the citric acid cycle.^6-8 This final step, after a series of further reactions, results in the formation of a derivative of coenzyme A (CoA; e.g. acetyl-CoA forms from leucine).⁶

The BCAA's, in addition to being available as a source of cellular energy in the forms of ATP and phosphocreatine, can stimulate the synthesis of other amino acids. For example, the amino acid alanine can be exported into the liver to form glucose and the amino acid glutamine can be sent to the gut, allowing both to serve as energy substrates.⁶ Endogenous BCAA's provide a major source of nitrogen for use in the synthesis of alanine.⁶ Only 40% of circulating plasma alanine is produced from protein breakdown, while the remaining 60% is derived from de novo synthesis.⁶ After an overnight fast, at least 20% of alanine synthesis is derived solely from leucine. Therefore, if the contribution of nitrogen from isoleucine and valine is similar to that of leucine, the BCAA's may also contribute to at least 60%of the nitrogen required for alanine synthesis.⁶

During a fasted state, the endogenous BCAA's that are released by protein breakdown, become the prime precursors for glutamine synthesis.⁶ The carbon chains of the BCAA's that enter the citric acid cycle in muscle are not used for oxidation nor for alanine synthesis.⁶ Instead, these carbon chains are solely converted into glutamine.⁶ This process is especially critical during periods of starvation because the BCAA's cause a reduction in the rate of glutamine breakdown.⁶ The significance of this effect is that an increase of intracellular glutamine levels causes an increase in the muscle nitrogen balance.⁶ In turn, this is a protective mechanism that ensures preservation of the BCAA's for protein synthesis when dietary protein is insufficient, allowing lean tissues to be spared from catabolism.⁵

A study performed by Johnson et al.¹² demonstrated that an infusion of BCAA's, in both stressed and normal human models, decreased muscle amino acid release and maintained whole blood and muscle nitrogen pools.¹² Another study, done by Abumrad et al.¹³, showed that “an infusion of the BCAA's leucine elicited a reduction in muscle glucose uptake, stimulated muscle ketone-body synthesis, and increased plasma insulin levels.” With muscle glucose uptake levels reduced, leucine then caused a decrease in muscle glycogen storage, thus serving as a substrate during times of stress.^12-13

Exercise produces diverse changes in amino acid metabolism and in protein turnover in skeletal muscle.⁵ The changes seen in amino acid metabolism can be either acute or long-term. Acute changes concern meeting energy needs and amino acid availability, while long term changes effect the adaptation of proteins for structure and performance.¹⁴ Since BCAA administration regarding both resistance and endurance exercises has not been researched for its long-term effects, the current research is focused solely on the acute changes.

“Acute changes in amino acid metabolism caused by exercise are largely catabolic, with a net balance between the rates of protein synthesis and breakdown, while also increasing the rate of amino acid oxidation.”⁵ It has been shown that BCAA's have anabolic effects on protein metabolism by increasing protein synthesis and decreasing protein degradation.⁸ These constant changing and remodeling processes, through both the synthesis of new proteins and the breakdown of existing proteins, are referred to as “the rate of protein turnover”.⁸

“Regular resistance exercise increases muscle mass due to a higher rate of protein synthesis in relation to protein breakdown.”⁸ The BCAA's are able to serve as an oxidative substrate for skeletal muscle during intense exercise, however, recent studies suggest that there is an anabolic effect on muscle when BCAA's are administered before and during exercise, due to an increase of protein synthesis.^6,8,15 Current studies have confirmed that BCAA's administered during a fasted state increase nitrogen retention (i.e. protein synthesis) in skeletal muscle.^6,12,13 New studies have also been conducted to research the effects of BCAA's when administered both during and after exercise.

When 10 grams of BCAA's were ingested during and after one session of quadriceps resistance training, an increase was observed in mTOR (mammalian target of repaying), p70 S6 kinase, and S6 phosphorylation in the recovery period.⁸ In the subjects who did not receive the BCAA’s during and after the same exercise regiment, there was no noted rise in mTOR.⁸ Although the activation of the mTOR signaling pathway is not fully understood, it was stated in the study that mTOR does contribute to increasing protein synthesis, thereby leading to cell growth, cell proliferation, and cell survival under times of stress, such as during exercise.⁸

This study also illustrated that, without protein and/or BCAA administration pre and/or post exercise, a net gain in protein could not be achieved. Conclusively meaning that protein and/or BCAA administration both during and after exercise causes a stimulation in protein synthesis and a reversal of protein degradation.⁸ The research did not, however, acquire any other potential benefits (such as muscular hypertrophy) due to the short time frame in which the study was conducted.

A study performed by Baylor University drew the conclusion that protein supplementation did, in fact, increase total body mass, fat free mass, thigh mass, and muscular strength in human subjects.¹⁶ During 10 weeks of resistance training, one group of males was given 20 grams of whey protein enriched with 6 grams of BCAA’s, while a placebo group was given 20 grams of dextrose. Both groups were given their products one hour prior to and one hour after exercise. At the end of the study, the subjects who received the BCAA enriched whey protein gained an average of 5 kg of lean body mass, lost 2% body fat, and were able to increase their bench press by 30% and their parallel squat by 50%.¹⁶

The thigh mass of the subjects was, on average, increased by 1 inch. These were incredible gains since chronic resistance training typically only promotes gains in fat-free mass between 0-1 kg per month.¹⁷ This study demonstrated that a 10 week resistance training program, in combination with the ingestion of a blend of whey protein and BCAA’s, improved overall muscle strength and mass better than carbohydrate ingestion alone.¹⁶

In a study involving untrained athletes, it was demonstrated that ingesting 6 grams of BCAA's one hour prior to and after exercise during a 14-week resistance training program, was more effective than administering 20 grams of carbohydrates when trying to improve muscular power in the vertical jump.¹⁸ A study conducted by Byrd¹⁹, took 10 untrained males through a 12-week resistance training program and administered either 6 grams of BCAA’s or a 6% carbohydrate solution. At the end of the 12 weeks, the group using the BCAA's displayed greater improvements in increased muscle strength and fat-free mass when compared to the group taking only the carbohydrates.¹⁸

An evaluation of BCAA supplementation and its effects on muscle soreness has also conducted. A study involving 20 subjects, 16 female and 14 male, were administered either 5 grams of a BCAA solution or 5 grams of a placebo solution. The subjects were then asked to perform a squat exercise to induce delayed-onset muscle soreness.⁷ The experiment was done with a crossover design where each subject was tested with both the placebo and the BCAA's.⁷ In the placebo group, muscle soreness was experienced on the second day and continually increased in severity into the third day, indicating that DOMS had occurred.⁷ As for the BCAA group, peak soreness was reached on the second day, however, a significantly lower level of soreness was displayed on the third day. This indicated that BCAA's may potentially play a role in reducing DOMS.⁷

Conclusions suggest that protein and BCAA supplementation during and after exercise increase protein synthesis and decrease the rate of protein breakdown for up to 48 hours.⁸ Current research today also suggests that protein and/or BCAA administration pre and post resistance exercise causes an increase in muscle hypertrophy, muscular strength, and a reduction in body fat percentage.^16,18,19 Research regarding BCAA supplementation and its role in reducing delayed-onset muscle soreness is limited, but the available studies have demonstrated a reduction in DOMS when taken prior to and during exercise.⁷

“There is a significant activation of BCAA metabolism with prolonged exercise, and studies indicate that this is more pronounced in endurance subjects, with plasma concentrations of BCAA's being more affected than any other amino acid.”⁸ “During endurance exercise, BCAA’s are taken up by skeletal muscle and the resultant decline in plasma BCAA's can lead to an increase in the ratio of free tryptophan to BCAA's.”²

Since tryptophan and BCAA's compete for the same mechanism of transport across the blood-brain barrier, an increase in the ratio of plasma free tryptophan to BCAA's would promote the formation of the neurotransmitter 5-hydroxytryptamine (5-HT).¹⁹ 5-hydroxytryptamine, more commonly known as serotonin, causes drowsiness, depresses motor neuron excitability, and influences autonomic and endocrine functions; which all contribute to the development of central fatigue.¹⁹ Theoretically, by ingesting the BCAA’s during exercise, the plasma concentrations of the BCAA's should increase and thereby balance the increase in free tryptophan, thus off-setting central fatigue.¹⁹

A study performed by Blomstrand, took seven male cyclists and had them perform on a cycle ergometer for 60 minutes at 70% of their maximal oxygen uptake.²⁰ One group was given a beverage enriched with 7 grams of BCAA’s while the other group received a placebo.²⁰ Every 10 minutes, their perceived exertion and level of mental fatigue were measured and recorded through an RPE scale.²⁰ At the end of the test, the group taking BCAA's had a 7% lower perceived exertion rate than the group given the placebo, as well as, a 15% lower rate of mental fatigue.²⁰ The plasma concentration ratio between free tryptophan and BCAA's was either decreased or unchanged in the BCAA group, while the placebo group experienced and increase in the ratio.²⁰

Another similar study was done involving endurance runners who were administered either a drink enhanced with 7.5 grams of BCAA's or a placebo drink during a 30 km marathon. The runners mental and physical performances were measured utilizing the Stroop Colour and Word Test, or the CWT, both before and after completion of the 30 km run.²¹ After measuring and analyzing the test scores, improvements were only seen in runners who received BCAA's.²¹ “Slower runners”, or runners who completed the run in 3-3.5 hours, showed improvements in their physical performance scores, whereas, runners that completed the 30 km in under 3 hours showed no improvements.²¹ The methodology of this study was later questioned because of the way the “slower” and “faster” runners were separated by an arbitrary time point, and has been criticized on statistical grounds.

When 7 moderately trained males and 6 moderately trained females were given 15.8 grams and 9.4 grams of BCAA's, respectively, while cycling until exhaustion at 40% VO2max, both sexes displayed improved times to exhaustion, as well as, a decrease in central fatigue.²² Coinciding with results from the prior studies, BCAA administration during endurance exercise promoted a decrease in fatigue along with improving the subject’s overall performance.

From this research, it has been shown that using BCAA supplementation can significantly alter the balance between BCAA's and tryptophan, leading to a decrease in central fatigue. BCAA supplementation also displayed an improvement in cognitive function after the 30 km run when training the endurance athletes.²¹ The information regarding BCAA supplementation among researchers is not controversial due to the fact that BCAA’s can provide benefits in regards to central fatigue and cognitive functioning. Controversy does, however, lie in whether or not BCAA's aid in physical performance among endurance athletes.

While the study performed by Blomstrand displayed improvements in two groups of subjects, other researchers have found no benefits in BCAA supplementation.²³ Modern researchers have complained of disruptions in methodology while testing for physical performance benefits. These disruptions ranged from administering carbohydrates with the BCAA's during endurance tests to the separation methods used during the Blomstrand²¹ study. Current literature suggests that more studies are required to accurately conclude any ergogenic effects from using BCAA supplementation through better testing methods.^19-22

With resistance training, literature suggests that BCAA administration both during and after exercise increased protein synthesis and decreased protein degradation. The studies have also suggested that this response may be equally as likely to occur via the ingestion of foods containing BCAA's.¹⁸ Furthermore, protein synthesis is naturally increased after weight training, however, without using BCAA supplementation during and after exercising, protein degradation will continue to increase.⁸

Endurance exercise and BCAA ingestion does off-set the ratio between plasma free tryptophan and the BCAA’s, thus slowing down the on-set of central fatigue. In that respect, BCAA's do improve cognitive performance, however, research is controversial to whether or not BCAA's actually improve physical performance. The studies mentioned within this review, although limited, demonstrated that BCAA’s improved time to exhaustion, which, in turn, could represent an improvement in physical performance.

In the study involving the endurance runners, previous 30 km times improved for the athletes that were less experience (i.e. slower runners), but were not improved for the experienced or faster runners.²¹ Recent literature states that issues with methodologies used in the studies may be flawed,²³ thus explaining the differing opinions among researchers. An important point made in literature on BCAA supplementation, is that there are no known side-effects from their use.

There are still many controversial opinions concerning BCAA supplementation and, as literature suggests, additional studies are necessary to determine their use in improving athletic performance.^23,25 Since protein and BCAA supplementation have become so popular among the American population, researchers suggest that more studies be conducted on BCAA's to help further substantiate the benefits of their use. This concludes my article on BCAA's. In next month’s article, I will be discussing creatine monohydrate.