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Branch-Chained Amino Acids: More Than Just Amino Acids?

The idea of supplementing with extra branch-chained amino acids (BCAA) in addition to ones protein intake has been around for quite some time. It is time to take an in depth look at BCAA's. Read on to learn more.

By: Derek Beast Charlebois

Part 1 | Part 2

The idea of supplementing with extra branch-chained amino acids (BCAA) in addition to ones protein intake has been around for quite some time. But with all the 'magic elixirs' and 'pump potions' on the market today, BCAA supplementation has never gained popularity outside of the hardcore (as in elite athletes) circles.

One reason for this oversight on BCAA may be that people feel supplementing with additional BCAA on top of an already high protein diet will not be beneficial. Others may simply be uninformed about BCAA.

Whatever the case may be, it is time to take an in depth look at BCAA to see if they have a place in your supplement arsenal. Before you begin reading this article, I recommend you first read my article on "Amino Acid Metabolism", as it will give you the basics to understand the article at hand.


What Are Branch-Chained Amino Acids?

The BCAA Are A Group Of Three Essential Amino Acids:

  1. Leucine
  2. Isoleucine
  3. Valine.

The BCAA are different from the other 17 Amino Acids in that they are primarily metabolized in skeletal muscle (Layman, 2003) and metabolized at a much lower rate in the liver (Norton, 2005). The rate limiting enzyme in BCAA catabolism is Branched Chain Keto Acid Dehydrogenase, which is much more active in skeletal muscle than in the liver (Norton, 2005).

Because BCAA serve as a "fuel" for skeletal muscle, supplementing with additional BCAA to improve sports performance and to treat various diseases and aliments as been suggested. BCAA have many other roles besides being just a fuel for skeletal muscle.

The Metabolic Roles Of The BCAA Include:

  • Substrate for energy production
  • Substrate for protein synthesis
  • Precursor for the formation of other amino acids
    • Primarily Alanine and Glutamine
  • Metabolic signals (Primarily Leucine)
    • Stimulates protein synthesis through insulin secretion/activation of the PI3K pathway
    • Stimulates protein synthesis through activation of mTOR
  • Stimulates leptin expression in adipocytes through activation of mTOR

    We will now examine briefly the BCAA's roles as substrates for energy production and protein synthesis then closely examine their roles in the formation of other amino acids and as metabolic signals.

Substrate For Energy Production

    Point blank, exercise promotes increased BCAA oxidation (Shirmomura et al., 2004). This increased degradation of BCAA helps maintain energy homeostasis by providing carbon as a direct energy source and glucose homeostasis by providing substrates for the citric-acid cycle and gluconeogenesis.

    Amino acids are categorized as glucogenic, ketogenic, or a combination of glucogenic and ketogenic. A glucogenic amino acid when metabolized gives rise to pyruvate or other TCA cycle intermediates that can be used for the production of glucose through gluconeogenesis.

    A ketogenic amino acid is metabolized via the fatty acid pathway and gives rise to actyl-CoA, a fatty acid precursor. Leucine is completely ketogenic, valine is completely glucogenic, and isoleucine is both glucogenic and ketogenic. Valine and isoleucine can both be used to produce intermediates for glucose production via gluconeogenesis.

    Due to leucine's metabolic properties (discussed below), increasing attention is being given to it and its metabolism. Research has shown plasma leucine levels to decrease during both aerobic and anaerobic exercise (Mero, 1999).

    According to Freund and Hanani (2002), "Complete oxidation of leucine in the muscle yields more adenosine triphosphate molecules on a molar basis than complete oxidation of glucose." So leucine can provide skeletal muscle with more ATP than an equal amount of glucose, which is due to leucine being completely ketogenic and metabolized via the fatty acid pathway.

What Is ATP?
A nucleotide, C10H16N5O13P3, that contains high-energy phosphate bonds and is used to transport energy to cells for biochemical processes, including muscle contraction and enzymatic metabolism.

    In order to meet the increased demand for BCAA during exercise the body breaks down muscle tissue to supply additional BCAA. By supplying the body exogenous BCAA during exercise, one can meet the increased demand for BCAA oxidation without breaking down muscle tissue to supply the needed BCAA.

Substrate For Protein Synthesis

    I am going to give a very brief overview of protein synthesis. A person's genetic code is contained in DNA, which is held in the nucleus of cells. DNA contains information that specifies the amino acid sequence for the synthesis of various proteins. Without going into detail, the process of creating a protein from DNA is as follows:

      DNA-Transcription --> RNA-Translation --> Protein

    During translation, amino acids from the intracellular amino acid pool are added to a growing protein chain. All three of the BCAA are essential amino acids, meaning the body cannot create them and they must be acquired from the diet. Simply put, adequate levels of all essential amino acids (and all amino acids for that matter, but the non-essential amino acids can be created by the body) are needed for protein synthesis to occur uninterrupted. An athlete should follow a diet with a sufficient protein intake for their needs.

Precursor For The Formation Of Alanine & Glutamine

    The BCAA's are involved in maintaining glucose homeostasis through the glucose-alanine cycle (see figure 1). The glucose-alanine cycle involves pyruvate (derived from glucose) being transaminated in muscle to form alanine, with the BCAA serving as the main nitrogen source (donors) for the synthesis of alanine (Holecek, 2002).

    The newly synthesized alanine is released in the blood stream and sent to the liver where it is converted into glucose through gluconeogenesis. This glucose can then be sent from the liver back to the working muscle to be used as fuel.


Click To Enlarge.
Interorgan movement of branched-chain amino acids (BCAA), ALA, alanine; GIN, glutamine; Glu, glutamate; áKG, alpha-keto-glutarate.

Figure 2 - Adapted from: Layman, DK (2003). The role of leucine in weight loss diets and glucose homeostasis. J. Nutr. 133: 261S-267S.

    The amino acid glutamine has multiple roles in the body. According to Houston (2001), "Glutamine content in skeletal muscle and other tissues appears to have a regulatory role in whole body protein synthesis." Glutamine levels inside muscle govern protein synthesis and nitrogen balance and therefore muscle gain (VanAcker et al. 1999).

    Glutamine is also a powerful cell volumizer (Haussinger et al. 1993). An increase in cell volume, also called cell swelling, stimulates many anabolic pathways (synthesis of protein and glycogen) and inhibits catabolic pathways (protein degradation) (Haussinger, 1996). Glutamine is a "nitrogen shuttle" between organs, a fuel for cells of the immune system and intestines, and a precursor for nucleotide synthesis (Holecek, 2002).

    Ingestion of supplemental free-form glutamine or glutamine peptides is oxidized by the intestinal tract or taken up by the liver and kidney, all of which is beneficial but supplementing with BCAA can cause de novo synthesis of glutamine inside skeletal muscle (Houston, 2001).

    The body's need for alanine and glutamine is increased during exercise is met by BCAA from muscle protein breakdown (Holecek, 2002). Increased muscle protein breakdown equates to muscle loss, which no athlete wants. By supplementing with BCAA, one can deliver the needed building blocks for both alanine and glutamine and spare muscle tissue.

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If you're an athlete then you probably already know that glutamine can benefit your training and muscle building efforts.
[ Click here to learn more. ]

Stimulation Of Insulin Secretion, PI3K, & Protein Synthesis By Leucine

    One pathway through which protein synthesis can be increased is the phosphatodyl-inositol-3-kinase pathway (PI3K). PI3K regulates glucose uptake through GLUT4 translocation and also increases amino acid uptake. Insulin, the body's "storage" hormone, works by activating the PI3K pathway.

    Interestingly, leucine ingestion causes insulin secretion, but leucine can also directly activate PI3K in the absence insulin (Nishitani et al. 2002), suggesting leucine to have a synergistic role with insulin as a PI3K activator (Layman, 2002). So not only can leucine increase glucose uptake, it can also increase it's own and other amino acids' uptake into cells.

    These facts suggest that taking additional BCAA with carbohydrates around ones workout will lead to a synergistic increase in glucose and amino acid uptake into skeletal muscle. Leucine can stimulate protein synthesis through insulin secretion and the activation of the PI3K pathway, but can also stimulate protein synthesis through other pathways.

Activation Of mTOR By Leucine

    The Mammalian Target of Rapamycin (mTOR) is one of the body's protein synthesis regulators. MTOR functions as an energy sensor; it is activated when ATP levels are high and blocked when ATP levels are decreased (AMPK is activated when ATP decreases, which works antagonistically to mTOR).

    The main energy-consuming process in the cell is protein synthesis. When mTOR is activated (high ATP levels sensed) protein synthesis is increased and when mTOR is suppressed (low ATP levels are sensed) protein synthesis is blunted. MTOR activation is vital for skeletal muscle hypertrophy.

    Interestingly, mTOR is also a nutrient sensor of amino acid availability, specifically of leucine availability. Research has shown that regulation of mTOR by ATP and amino acids act independently through separate mechanisms (Dennis et al., 2001).

    Leucine is the key regulator of the mTOR-signaling pathway (Anthony et al. 2001 & Lynch et al. 2002). According to Laymen (2003), "The increase in leucine concentration is sensed by an element of the insulin-signaling pathway and triggers a phosphorylation cascade that stimulates the translational initiation factors eIF4 and p70S6K." (See figure 2)

    Activation of these initiation factors initiates the translation of muscle mRNA components and are vital for skeletal muscle protein synthesis and creation of new contractile proteins (muscle). Leucine directly signals and primes your muscles to grow through the activation of mTOR.


Click To Enlarge.
Insulin signaling cascade [adapted from Laymen (17) amd Anthony et at. (39)]. IRS-1, Insulin receptor substrate 1; Pß-K, phosphatidylinostitol-3 kinase; GLUT4, Insulin-dependent glucose transporter; PKC, proteinkinase C; mTOR, mammial target of rapamycin; el F4, translational factor 4.

Figure 3 - Adapted from: Layman, DK (2003). The role of leucine in weight loss diets and glucose homeostasis. J. Nutr. 133: 261S-267S.

    We see that leucine stimulates protein synthesis through both insulin secretion/activation of PI3K pathway and activation of the mTOR pathway, but there is still a third pathway through which leucine stimulates protein synthesis; a mTOR-independent pathway that not much is known about (and hence will not be discussed in this article). Sign up for article updates here.

Stimulation of Leptin Expression through mTOR activation in Adipocytes

    Intake of leucine stimulates expression of the hormone leptin in adipocytes (the primary site of leptin secretion) through activation of the mTOR pathway (Meijer and Dubbelhuis, 2003). Leptin is a very complicated hormone; the gist of it is involved in the regulation of metabolism, body weight, and appetite.

    Leptin secretion is linked with body fat levels; higher body fat is associated with higher leptin secretion and lower body fat is associated with lower leptin levels. When you diet and lose fat, the amount of leptin you secrete decreases, which makes your body "crave" food in an attempt to bring your body fat level back up to where the body is comfortable (known as the body fat "set point").

    Leucine has the ability to activate leptin expression and will cause the body to think it is "fed" or receiving "adequate" calories, which will keep things running (specifically your metabolism) smoothly.


Supplementing With BCAA

What is interesting about the BCAA is their ability to participate in the above metabolic processes, energy substrates, substrates for protein synthesis, precursors for alanine and glutamine, and modulators of protein synthesis, is governed by their availability. Research suggests that first and foremost the BCAA are used for the synthesis of protein structures (Layman, 2003).

Xtreme Formulations ICE.
As a serious athlete you know just how much intense weight training can break down muscle tissue. This is evidenced through the muscle soreness which is felt in the days following your grueling workouts.

Research on leucine shows that once the minimum requirement of leucine for protein synthesis is met leucine can then be used as a precursor for alanine and glutamine or to activate various signaling pathways (Layman, 2003), such as the mTOR pathway. It may sound like leucine is free to exert its powerful effect of mTOR activation, but one must remember that protein breakdown and synthesis is occurring throughout the entire body; the body's protein stores are in a constant state of flux.

The constant body protein flux plus the increased leucine oxidation caused by exercise means that leucine is in high demand and therefore may not be able to participate in muscle growth at its full potential. This is where supplementing with additional BCAA comes into play and importance.

Due to leucine's metabolic properties, many people focus solely on leucine and not the other two BCAAs valine and isoleucine.

Research has shown that leucine-rich diets or administration of leucine alone lead to decreases in valine and isoleucine plasma concentrations and a BCAA imbalance (Shirmomura et al., 2004). While it may be cheaper to supplement with leucine alone instead of all three BCAA, one should supplement with all three BCAA so not to create a BCAA imbalance.

The main question or argument with BCAA supplementation people have is whether additional BCAA supplementation on top of an already high protein intake will produce any benefits, specifically enough benefits justify to the cost of the BCAA. Research and anecdotal findings would definitely suggest yes.

I feel that the benefits of free-form BCAA lie in their ability to quickly flood the blood stream and amino acid pools with high amounts of BCAA, specifically leucine. While whey protein is absorbed quickly, ingestion of 10 grams of BCAA from whey does not create the same metabolic response as the ingestion of 10 grams of free-form BCAA.

Once whey protein reaches the gut, it takes about 45 minutes before the amino acids start to be extracted and are absorbed and can be used. This lower absorption means the amino acid pools are not "flooded" with large amounts of BCAA.

Remember, the BCAA ability to be utilized in various pathways is governed by their availability. It is my belief that delivering large amounts of BCAA to muscle and keeping BCAA levels elevated will cause a strong and sustained activation of mTOR, leading to skeletal muscle hypertrophy.

The current research available clearly displays that the BCAA (specifically leucine) are very potent stimulators of protein synthesis and have many other beneficial effects to athletes.

In Summary, The Metabolic Roles Of The BCAA Include:

  • Substrate for energy production
  • Substrate for protein synthesis
  • Precursor for the formation of other amino acids
    • Primarily Alanine and Glutamine
  • Metabolic signals (Primarily Leucine)
    • Stimulates protein synthesis through insulin secretion/activation of the PI3K pathway
    • Stimulates protein synthesis through activation of mTOR
    • Stimulates leptin expression in adipocytes through activation of mTOR

What all this means is ingesting BCAA primes your body for growth (protein synthesis). All of these actions are beneficial to an athlete and should not be overlooked. There is endless research backing BCAA supplementation. I feel it would be much more beneficial, both performance/results wise and money wise, to go "old school" and supplement with BCAA than to buy into all the current hype supplements on the market today.

This concludes the first installment on BCAA. In part II, I will talk about BCAA dosing and what supplements can be stacked with BCAA to create a synergistic effect on your progress and growth.

Part 1 | Part 2

References:

  1. Anthony JC, Anthony TG, Kimball SR, Jefferson LS. Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine. J Nutr. 2001 Mar;131(3):856S-860S.
  2. Dennis, PB. Jaescke, A., Saitoh, M., Fowler, B., Kozma, SC., Thomas, G. (2001). Mammalian TOR: A homeostatic ATP sensor. Science. 294: 1102-1105.
  3. Haussinger D et al. Cellular hydration state: An important determinant of protein catabolism in health and disease. Lancet 341:1330-1332.1993.
  4. Houston, Michael (2001). Biochemistry Primer for Exercise Science (2nd Ed.). Illinois: Human Kinetics
  5. Layman DK (2002). Role of leucine in protein metabolism during exercise and recovery. Can J Appl Physiol. Dec;27(6):646-63.
  6. Layman, DK (2003). The role of leucine in weight loss diets and glucose homeostasis. J. Nutr. 133: 261S-267S.
  7. Lynch CJ, Patson BJ, Anthony J, Vaval A, Jefferson LS, Vary TC. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Am J Physiol Endocrinol Metab. 2002 Sep;283(3):E503-13.
  8. Mero A. (1999) Leucine supplementation and intensive training. Sports Med. 1999 Jun;27(6):347-58.
  9. Nishitani S, Matsumura T, Fujitani S, Sonaka I, Miura Y, Yagasaki K. (2002). Leucine promotes glucose uptake in skeletal muscles of rats. Biochem Biophys Res Commun. Dec 20;299(5):693-6.
  10. Norton, L. (2005) Soon to be published data, will add reference when the journal article is published.
  11. Shimomura, Y. Murakami, T.Nakai, N. Nagasaki, M. Harri, R.A. (2004). Exercise Promotes BCAA Catabolism: Effects of BCAA Supplementation on Skeletal Muscle during Exercise J. Nutri. 134: 1583S-1587S.
  12. VanAcker BA,.et al. (1999) Glutamine:the pivot of our nitrogen economy? JPEN, 23:S45-8.

Branch-Chained Amino Acids: More Than Just Amino Acids?
derek@scivation.com

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