Download What is Xtend

Scivation Xtend Write-Up
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 Branched-Chain 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
o Primarily Alanine and Glutamine
Metabolic signals (Primarily Leucine)
o Stimulates protein synthesis through insulin secretion/activation of the
PI3K pathway
o 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.
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 nonessential 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.
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 its 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)]. IRS1, 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 mTORindependent 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).
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
o Primarily Alanine and Glutamine
Metabolic signals (Primarily Leucine)
o Stimulates protein synthesis through insulin secretion/activation of the
PI3K pathway
o Stimulates protein synthesis through activation of mTOR
o 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.
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. Holecek M. Relation between glutamine, branched-chain amino acids, and protein
metabolism. Nutrition. 2002 Feb;18(2):130-3. Review.
5. Houston, Michael (2001). Biochemistry Primer for Exercise Science (2nd Ed.).
Illinois: Human Kinetics
6. Layman DK (2002). Role of leucine in protein metabolism during exercise and
recovery. Can J Appl Physiol. Dec;27(6):646-63.
7. Layman, DK (2003). The role of leucine in weight loss diets and glucose
homeostasis. J. Nutr. 133: 261S-267S.
8. 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.
9. Mero A. (1999) Leucine supplementation and intensive training. Sports Med.
1999 Jun;27(6):347-58.
10. 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.
11. Norton, L. Leucine regulates translation initiation of protein synthesis in skeletal
muscle after exercise. J Nutr. 2006 Feb;136(2):533S-537S.
12. 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.
13. VanAcker BA,.et al. (1999) Glutamine:the pivot of our nitrogen economy? JPEN,
23:S45-8.