Branched chain amino acids and their importance in nutrition

Abstract

Branched chain amino acids (BCAA) - leucine, isoleucine and valine are essential amino acids which are metabolized directly in muscles and offer energy fuel to performance of the work. There is lot of evidences supporting the positive effect of BCAA supplementation on muscle growth. The main importance is attached particularly to leucine. There was observed that leucine supplementation increased protein synthesis in skeletal muscles after resistance exercise in young people and in elderly people suffered by sarcopenia as well. There is not exactly clear, what is the reason for the positive effect of BCAA to increase protein synthesis in muscles. Besides the positive effect of BCAA on muscle growth, there was observed their positive effect against fatigue and on a production of endogenous glucose, which is necessary to maintain the glucose balance in body during adaptation to stress. The minimum and maximum dose of BCAA is not established, but the daily recommended amount of leucine : isoleucine : valine is in a ratio 40:20:20 mg.kg body weight -1. It is recommended to use the mixture of BCAA rather than leucine individual, because of depletion other BCAA in body. There was observed no toxicity of BCAA even at high doses. The present review describes the metabolism of action and effect of BCAA on protein synthesis and physiological functions in human.

Full text

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BRANCHED CHAIN AMINO ACIDS AND THEIR IMPORTANCE IN NUTRITION
Matej Brestenský1*, Soňa Nitrayová1, Peter Patráš1, Jaroslav Heger1, Jozef Nitray2
Address(es): Ing. Matej Brestenský, PhD.
1National Agricultural and Food Center, Research Institute of Animal Production Nitra, Institute of Nutrition, Hlohovecká 2, 951 41 Lužianky, Slovakia, +4216546
182.
2Tekmar Slovakia Co. Ltd., Vinárska 26, 951 41 Lužianky, Slovakia.
*Corresponding author: m_brestensky@vuzv.sk
ABSTRACT
Keywords: Branched chain amino acid; protein; leucine; isoleucine; valine
INTRODUCTION
Well balanced amino acids content of protein diet is necessary for lean muscle
growth. Required amount of dietary protein is necessary for protein synthesis.
Not only proteins but also amino acids, constituents that make up proteins, are
important part of nutrition which could not be neglected, especially when
resistance exercise is performed. Besides the supplementation of complex
essential amino acids, that the body is not able to synthesize, supplementation of
branched chain amino acids (BCAA) is important. Leucine, isoleucine and valine
are of the same structure of branched chain and so they are known as branched
chain amino acids - BCAA. They belong among essential amino acids for
humans and animals and have common membrane transport systems and
enzymes for their transamination and decarboxylation (Harper et al., 1984). It
indicates that they are closely connected with their metabolism in a body. BCCA
represent 35 - 40 % of dietary essential amino acids in body proteins and 14-18
% of total amino acids present in muscle proteins (Riazi et al., 2003; Layman
and Baum, 2004).
Table 1 Content of BCAA in different foods, feeds and protein sources (g.kg-1 DM)*
CP
Leu
Ile
Val
Total
BCAA
BCAA expressed as %
of CP
Ratio of
Leu : Ile : Val
Foods and feeds
Rye1
153.1
10.0
4.4
6.5
20.8
13.6
2 : 0.9 : 1.3
Barley1
141.3
9.1
4.3
6.2
19.6
13.9
2 : 0.9 : 1.4
Soybean meal1
490.2
39.8
21.5
24.0
85.3
17.4
2 : 1.1 : 1.2
Malting sprouts1
204.4
15.0
8.8
12.6
36.5
17.8
2 : 1.2 : 1.7
Sorghum1
105.1
15.1
4.9
6.3
26.3
25.0
2 : 0.6 : 0.8
Wheat germs1
201.3
21.4
11.8
17.4
50.6
25.1
2 : 1.1 : 1.6
Broken rice1
89.6
6.2
3.3
5.2
14.8
16.5
2 : 1.1 : 1.7
Protein sources
Pea protein concentrate2
878.2
69.7
39.6
43.0
152.3
17.3
2 : 1.1 : 1.2
Soy protein concentrate2
703.8
55.7
32.3
33.9
121.9
17.3
2 : 1.2 : 1.2
Casein2
969.8
89.8
49.0
63.3
202.1
20.8
2 : 1.1 : 1.4
Whey protein concentrate2
808.5
89.3
50.2
48.1
187.6
23.2
2 : 1.1 : 1.1
Rice protein concentrate3
728.4
57.3
31.4
44.6
133.3
18.3
2 : 1.1 : 1.6
* BCAA - branched chain amino acids; CP – crude protein; Leu –leucine; Ile – isoleucine; Val – valine
1 Brestenský et al., (2013), 2 NRC (2012), 3 Gottlob et al., (2012)
Branched chain amino acids (BCAA) - leucine, isoleucine and valine are essential amino acids which are metabolized directly in
muscles and offer energy fuel to performance of the work. There is lot of evidences supporting the positive effect of BCAA
supplementation on muscle growth. The main importance is attached particularly to leucine. There was observed that leucine
supplementation increased protein synthesis in skeletal muscles after resistance exercise in young people and in elderly people suffered
by sarcopenia as well. There is not exactly clear, what is the reason for the positive effect of BCAA to increase protein synthesis in
muscles. Besides the positive effect of BCAA on muscle growth, there was observed their positive effect against fatigue and on a
production of endogenous glucose, which is necessary to maintain the glucose balance in body during adaptation to stress. The
minimum and maximum dose of BCAA is not established, but the daily recommended amount of leucine : isoleucine : valine is in a
ratio 40:20:20 mg.kg body weight -1. It is recommended to use the mixture of BCAA rather than leucine individual, because of depletion
other BCAA in body. There was observed no toxicity of BCAA even at high doses. The present review describes the metabolism of
action and effect of BCAA on protein synthesis and physiological functions in human.
ARTICLE INFO
Received 24. 3. 2015
Revised 13. 7. 2015
Accepted 17. 8. 2015
Published 1. 10. 2015
Review
doi: 10.15414/jmbfs.2015.5.2.197-202

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198
Human musculature represents 40 % of total body weight of a man, and so
muscle proteins "pool" represents very large reservoir of BCAA in the body. But
the content of free BCAA in skeletal muscle of human is low; only 0.1 g (0.6-1.2
mmol)/muscle kg (Rennie, 1996). Total concentration of BCAA in human blood
(0.3-0.4 mmol/l) is relatively high when compared with other amino acids
(except for glutamine) (Ahlborg et al., 1974; Wahren et al., 1976). However, in
comparison with content of BCAA in muscle, total amount of BCAA in human
blood is low.
Content of individual and total BCAA among various feeds and protein sources is
different (Table 1). The higher content is in protein sources compared to foods
and feeds. Leucine content is between 41 - 58 % of total BCAA and the ratio of
leucine : isoleucine : valine is similar within the foods and protein sources as
well, but is not completely identical to recommended ratio 2:1:1 (Kurpad et al.,
2006), and is slightly higher, regarding isoleucine and valine. The content of
BCAA corresponds to the content of crude protein (Fig. 1).
Figure 1 The ratio of total content BCAA to crude protein in foods, feeds and
protein sources
BCAA metabolism in the body
In contrast to other amino acids, BCAA are metabolized directly in the muscles
and their catabolic pathways are located in the mitochondria. The first step in
BCAA metabolism in tissues is production of branched chain keto acids that are
incorporated into proteins or circulate in the body and serve as an energy
substrate for skeletal muscle, brain, liver and heart (Abumrad et al., 2001).
Branched chain amino acid aminotransferase (BCAT) enzyme is responsible for
change of BCAA into keto acids. Another enzyme - branched-chain α-keto acid
dehydrogenase (BCKDH) causes decarboxylation of keto acids in the tissues and
organs with generation of substrates entering the citrate cycle (Darner and
Elsas, 1989). BCAA catabolism is carried out in two steps (Fig. 2): 1) reversible
transamination of α-keto acids in presence of BCAT (Bixel et al., 1997); 2); the
second step is catalyzed by BCKDH and it is irreversible (Harris et al., 1997).
Alpha-keto acids generated during this step are subject to oxidative
decarboxylation from which derivatives of coenzyme A are generated (Platell et
al., 2000). Intensity of BCAA oxidation is different in individual tissues and it
depends on the activity of transaminase and dehydrogenase. BCKDH exists both
in active form (dephosphorylated) and in non-active form (phosphorylated).
Enzyme that is responsible for activation and inactivation of BCKDH is
BCKDH-kinase which occurs particularly in mitochondria (Anderson and
Hanson, 1983; Harris et al., 1997). BCKDH is activated during training by
dephosphorylation of BCKDH-kinase. It was found that activity of BCKDH in
the muscles is increased 10-times during training (Kasperek et al., 1985).
Increased activity of BCKDH was also observed during starvation (Kasparek,
1989). Dephosphorylation is connected with decrease of ATP level in the
muscles (Shimomura et al., 1995). BCAT concentrations are the highest in the
skeletal muscle, and so muscles are the main place of BCAA transamination
(Harper et al., 1984). During increased physical activity or during the stress and
infection periods (when there is increased consumption and lack of energy in the
body), BCAA metabolism in the skeletal muscle is increased. When catabolism
of proteins is increased, flow of BCAA is also increased.
Figure 2 Degradation pathway for branched-chain amino acids (BCAA); BCAT:
branched-chain amino acid transaminase; BCKDH: branched-chain α-keto acid
dehydrogenase; KIV: α-ketoisovalerate; KMV: α- keto-beta-mehylvalerate; KIC:
α-ketoisocaproate; CoA-SH: coenzyme A reduced form; IV-CoA: isovaleryl
CoA; R-CoA: acyl CoA; Pase: phosphatase (Shimomura et al., 2004).
Catabolic state of the body and BCAA
Catabolic state of the body is characterized by increased proteolysis,
gluconeogenesis, decreased proteosynthesis and negative nitrogen balance. These
states can be observed most often during infections, diseases and nutritional
deficiencies. Therefore, it is very important to protect muscle mass during
catabolic states, particularly during periods with increased occurrence of
infections.
BCAA oxidation is increased during catabolic state of the body. In this time,
BCAA represent important source of energy for skeletal muscle (Platell et al.,
2000). Changes in BCAA metabolism during catabolic states are influenced by
long-term activity of BCKDH (Garcia-Martinez et al., 1985) what explains
increased oxidation of BCAA. Several studies reported that administration of
BCAA to people in catabolic states (postoperative, multiple trauma, severe burns
and sepsis) improved nitrogen balance, increased concentration of amino acids in
the plasma, increased protein synthesis and decreased catabolism in the skeletal
muscle (Echenique et al., 1984). Based on this information it is evident that
BCAA protect muscles when the body is in catabolic state caused by insufficient
nutrition or diseases.
Fatigue and brain function
It is assumed that BCAA concentration in plasma affects brain functions,
appetite, as well as physical and mental fatigue. BCAA influence brain functions
by changing of utilization of the aromatic amino acids. Leucine, isoleucine and
valine directly or indirectly participate on different bio-chemical reactions in the
brain (Fernstrom, 1990), such as protein synthesis, energy production,
compartmentalization of glutamate, neurotrasmitter serotonin synthesis
(Suryawan et al., 1998; Daikhin and Yudkoff, 2000).
BCAA are transferred by blood to the brain via blood brain barrier transport
system and they are the main source of nitrogen for production of glutamate and
glutamine in the brain (Chuang et al., 1995) and serve as energy substrate for the
brain. They are swiftly metabolized in the neurons also despite the fact that there
is sufficient amount of other energy substrates, such as glucose. BCAA and
particularly leucine provide amino group necessary for glutamate synthesis
(Kanamori et al., 1998; Hutson et al., 2001) and they are a source of nitrogen
for peripheral tissues in the amount of 30-50 % (Yudkoff et al., 2005). Leucine
crosses rapidly into the brain, first passing into astrocytes, where it is swiftly
transaminated. Glutamate and branched chain keto acids are products of
transamination, and keto isocapronate (KIC) is a product of leucine (Fig. 2).
Glutamate is neurotransmitter which acts as a stimulator that increases neuron
activity in the brain. The brain can oxidize KIC and leucine to CO2 (Auestad et
al., 1991), but degree of this oxidation is lower than the degree of transamination
(Shambaugh and Koehler, 1983).
Blood brain barrier transport system is the same for both BCAA and tryptophan.
Since this transport system has limited capacity, BCAA and tryptophan compete
to transfer also through this transport system. When BCAA concentration in the
blood increases, transport of tryptophan to the brain is decreased (Fernstrom

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2005). Due to the fact that tryptophan is metabolized in the brain to 5
hydroxytryptamine (5-HT; serotonin), reduced transfer of tryptophan into the
brain will result to reduce the amount of metabolized 5-HT, which has slightly
sedative effects and is responsible for fatigue (Struder et al., 1998; Blomstrand,
2006).
Increased BCAA concentrations in the blood suppress fatigue by blocking the
entry of tryptophan into the brain. This is also confirmed by several works
dealing with effect of BCAA on fatigue. When a mixture of BCAA was
administered to people during training, they stated reduction of exertion and
mental fatigue (Blomstrand et al., 1997). Similarly, also physical performance
measured as a time to exhaustion was improved from 137 minutes to 153
minutes. (Mittleman et al., 1998).
BCAA and glucose metabolism
Due to increased degradation of BCAA in peripheral tissues, increasing the
concentration of BCAA occurs in cells. Decomposition of BCAA in the skeletal
muscle results in increased production of alanine and glutamine and maintenance
of glucose equilibrium in the body (Layman 2003). The relationship between
BCAA and the glucose level is related to glucose-alanine cycle (Ahlborg et al.,
1974), within which BCAA are released from the liver. Subsequently, released
BCAA are transmitted by blood to the muscles. Uptake of BCAA in the skeletal
muscles increases concentration and transamination of BCAA in the cells and
incorporation of amino nitrogen into pyruvate from which alanine is produced.
Alanine is transmitted from the muscles to the liver by blood, where it is changed
to pyruvate from which glucose is produced. Amino acids serve as a primary
source of carbon necessary for gluconeogenesis (Jungas et al., 1992). Production
of endogenous glucose is a crucial factor for maintaining the balance of glucose
in the body (Balasubramanyam et al., 1999). BCAA provide 25-30 % of
nitrogen necessary for formation of alanine (Haymond et al., 1978), from which
glucose is produced. Glucose is important in the process of adaptation to stress
and starvation.
BCAA and protein metabolism
Recent studies showed that free BCAA, particularly leucine, play important role
in protein metabolism. Leucine stimulates protein synthesis and prevents
breakdown of proteins by a mechanism containing so called mammalian target of
rapamycin - mTOR (serine - threonine - protein kinase regulating growth,
proliferation, motility, and survival of cells and synthesis and transcription of
proteins) (Mordier et al., 2000; Bolster et al., 2004). Leucine is not only a
structural part of proteins, but it also forms protein metabolism. BCAA are
metabolized out of liver in the skeletal muscle (Buse and Reid, 1975; Shinnick
and Harper, 1976). They are important source of energy in the muscles during
training and in stress periods, as well as precursors of other amino acids and
proteins (Ferrando et al., 1995). The main source of energy for muscles is
oxidation of BCAA (Shinnick and Harper, 1976; Harper et al., 1984). The
oxidation is controlled by by-products of leucine transamination for short time
(Parker and Randle, 1978) and by many physiological and pathological
conditions for long time period, such as starvation, diabetes, inflammation
processes, cancer illnesses and infections (Harris et al., 1985; Argiles and
Lopez-Soriano, 1990; Nawabi et al., 1990; Hayashi et al., 1996; Lombardo et
al., 1998; Price et al., 1998).
Moreover, BCAA significantly affect glutamine metabolism (Darmaun and
Dechelotte, 1991). Glutamine is important nutrient for rapidly growing cells in
the body, particularly in intestine and immune system. BCAA are transferred
from food through the liver to the system circulation of the body, where more
than 60 % of them are processed by metabolism in the muscles (Gelfand et al.,
1986). They are used as oxidative source of energy in the muscles. They
stimulate glutamine and alanine synthesis, which are exported to the liver. Here,
they form glucose that is a source of energy. There is so called liver-muscle
metabolic pathway in the body. This pathway is particularly important during
starvation, because alanine, which is synthesized in the muscles de novo,
becomes a main precursor for the liver gluconeogenesis. Alanine carbon is
mostly created by BCAA, particularly by valine (Freund et al., 1979).
Increased availability of amino acids and resistance training directly increase
synthesis of proteins in the skeleton musculature. BCAA, particularly leucine,
have anabolic effect on protein metabolism in such a way that they increase
degree of protein synthesis and decrease degree of proteolysis in the skeletal
musculature of people staying in rest (Louard et al., 1990; Nair et al., 1992).
BCAA have anabolic effect in the skeletal muscle also during recovery period
after the training (Blomstrand and Saltin, 2001). The administration of BCAA
increases phosphorylation of proteins that participate on regulation of protein
synthesis, including p70S6K in human skeletal musculature (Liu et al., 2001).
The p70S6k a serine threonine kinase is an enzyme, which goal is S6 ribosome
protein. Its phosphorylation indicates protein synthesis in ribosome. The p70S6k
activity induced by training correlates with growth of skeletal musculature
observed after six weeks of resistance training and with increased degree of
protein synthesis (Baar and Esser, 1999). Changes in p70S6k phosphorylation in
skeletal musculature after the training can reflect activation of so called signal
pathways that can be responsible for growth of protein synthesis during early
recovery period after the training. It is assumed that BCAA increase protein
synthesis in the skeletal musculature during recovery after resistance training by
p70S6k signaling cascade (Karlsson et al., 2004).
Resistance training increases musculature due to higher degree of protein
synthesis compared to protein breakdown, but the net protein increase was
achieved only in combination with a nutritional supplement (Biolo et al., 1997;
Tipton et al., 1999). Synthesis of myofibril proteins increases, and because these
proteins form 80 % of skeletal proteins, the effect of resistance training can be
measured as an increase of muscles volume or a cross-section of muscle fiber
after the training (Tesch, 1988).
Importance of leucine for protein synthesis
Studies carried out with people in rest showed that the BCAA administration,
particularly leucine, has anabolic effect on protein metabolism what is reflected
either with increased protein synthesis or decreased protein breakdown
(Alvestrand et al., 1990; Louard et al., 1990; Nair et al., 1992). In spite of the
fact that relatively quick response on increase of efficiency of amino acids in the
body was observed, time necessary for stimulation effect of the amino acids on
protein metabolism is not known (Bohé et al., 2001). The BCAA mixture
infusion stimulated the protein synthesis for 30 minutes after the infusion and it
also increased the degree of synthesis for another 90 minutes (Bohé et al., 2001).
The infusion of BCAA or pure leucine increased phosphorylation of p70S6k
kinase and 4E-BP1 in the skeletal musculature for 2 to 6 hours (Greiwe et al.,
2001; Liu et al., 2001). Increase of phosphorylation of p70S6k kinase was
confirmed 6 hours after taking the infusion consisting of amino acids mixture.
In relation to resistance training, intake of amino acids or protein hydrolyzate
after the training stimulates the degree of protein synthesis in the muscles and
causes positive nitrogen balance (degree of protein synthesis is higher than
degree of protein breakdown) (Rasmussen et al., 2000; Børsheim et al., 2002;
Tipton et al., 2004). There are different theories explaining this effect: 1)
Increased efficiency of amino acids increases their transport to the muscles. It is
assumed that it stimulates degree of protein synthesis in the muscles (Wolfe,
2001), 2) Another possibility is that the stimulation effect of one amino acid or a
group of several amino acids occurs, e.g. BCAA - particularly leucine. High
concentrations of leucine are related to protein synthesis of proteins (Ferrando et
al., 1995; Louard et al., 1995). Approximately 40 % of leucine transported to
muscles passes to amino acids pool, 40 % is oxidized and 20 % of leucine
becomes part of proteins (Alvestrand et al., 1990). An addition of leucine to
protein hydrolyzate leads to higher stimulation of protein synthesis after the
resistance training, in comparison if only hydrolyzate without addition of leucine
is used (Koopman et al., 2005). It is documented that leucine causes release of
insulin from the pancreas and it is assumed that the anabolic effect of leucine is
connected with insulin. When BCAA had been administered during endurance
training (running, cycling), their positive effect was observed during the recovery
period, as well as during the training (Blomstrand and Newsholme, 1992;
Blomstrand and Saltin, 2001).
Moreover, leucine as the main regulator of protein synthesis in the muscles plays
an important role in reduction of sarcopenia - loss of muscle mass associated with
aging. With aging, the muscles do not response to anabolic effect of amino acids
(Cuthbertson et al., 2005) and antiproteolytic effect of insulin (Wilkes et al.,
2009) and the degree of protein synthesis in muscles is decreased. Studies
carried out on rats (Rieu et al., 2003) and men (Kastanos et al., 2006; Rieu et
al., 2006) showed that leucine is able to restore the degree of protein synthesis in
old muscles. In case of consumption of essential amino acids in the amount of 6.7
g (of which 26 % is leucine) the degree of protein synthesis in the muscles of
elderly people was not increased; it was increased only in the muscles of young
people. But after increasing the content of leucine to 41 %, the degree of protein
synthesis in the muscles was equally increased both in case of young and old
people (Katsanos et al., 2006). This effect was not observed, when the leucine
was consumed together with common meal. When the leucine is administered
separately in the form of a dietary supplement, a level of other BCAA in plasma
can be depleted (Dardevet et al., 2000). Therefore, more efficient and suitable is
to use balanced mixtures of BCAA than free leucine (Balage and Dardevet,
2010). Supplementation by leucine is more effective, when it is combined with
resistance training, because synthesis of myofibril proteins is stimulated after the
training. Beside this fact, both forms - either training or nutrition are effective
strategies for increasing of muscle mass of elderly people (Churchward-Venne
et al., 2012). There is not well established daily recommended dose of BCAA,
but only mutual ratio of leucine : isoleucine : valine, in proportion of 2:1:1. Some
studies recommended dose of leucine : isoleucine : valine in a daily amount of
40: 17-20 : 20 mg.kg body weight -1 (Kurpad et al., 2006), but some studies
reported beneficial effect of BCAA at minimum dose in a daily amount higher
than 5 g (Shimomura et al., 2004). Despite this fact, EFSA (2012) reported that
there is no evidence that leucine supplementation in daily dose higher than 39
mg.kg body weight-1, would be effective in promoting of muscle growth.
Supplementation of BCAA is safe. In animal studies, there was demonstrated no
toxicity even at doses exceeding 10 g.kg body weight -1 (Okazaki et al., 1989).

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CONCLUSION
It was well documented the positive effect of BCAA supplementation to the diets
on protein synthesis. Especially when resistance training is performed, in order to
stimulate muscle growth, BCAA play important role as an energy fuel and
constituent stimulating protein synthesis. More over BCAA have positive effect
against sarcopenia in elderly people. Based on this information, BCAA
supplements are important part of protein nutrition but minimal dose for their
beneficial effect is not clearly established. In conclusion, it is necessary to note
that to achieve positive effect of BCAA on muscle mass formation of people
taking BCAA mixtures, these people should also take sufficient amount of other,
particularly essential amino acids, especially in the form of different proteins
directly from meal or in the form of dietary supplements.
Acknowledgments: This article was written during realization of the project
"ZDRAVIE no. 26220220176" supported by the Operational Programme
Research and Development funded from the European Regional Development
Fund.
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