Review Article Metabolic and Physiological Roles of Branched-Chain Amino Acids

Abstract

Branch chain amino acids (BCAAs) have unique properties with diverse physiological and metabolic roles. They have functions other than simple nutrition. Different diseases including metabolic disease lead to protein loss, especially muscle protein. Supplementation of BCAAs promotes protein synthesis and reduces break down, as well as improving disease conditions. They are important regulators of mTOR signaling pathway and regulate protein synthesis as well as protein turnover. BCAAs facilitate glucose uptake by liver and SK muscle and also enhance glycogen synthesis. Oxidation of BCAAs seems to be beneficial for metabolic health as their catabolism increases fatty acid oxidation and reduces risk of obesity. BCAAs are also important in immunity, brain function, and other physiological aspects of well-being. All three BCAAs are absolutely required for lymphocyte growth and proliferation. They are also important for proper immune cell function. BCAAs may influence brain protein synthesis, and production of energy and may influence synthesis of different neurotransmitters. BCAAs can be used therapeutically and future studies may be directed to investigating the diverse effects of BCAAs in different tissues and their signaling pathways.

Full text

Review Article
Metabolic and Physiological Roles of
Branched-Chain Amino Acids
Md. Monirujjaman1and Afroza Ferdouse2
1Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada R3E 0M2
2BiochemistryandMolecularBiology,UniversityofDhaka,Dhaka1000,Bangladesh
Correspondence should be addressed to Md. Monirujjaman; monirujjaman108@gmail.com
Received 6 July 2014; Accepted 8 August 2014; Published 19 August 2014
Academic Editor: Haile Yancy
Copyright © 2014 Md. Monirujjaman and A. Ferdouse. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Branch chain amino acids (BCAAs) have unique properties with diverse physiological and metabolic roles. ey have functions
other than simple nutrition. Dierent diseases including metabolic disease lead to protein loss, especially muscle protein.
Supplementation of BCAAs promotes protein synthesis and reduces break down, as well as improving disease conditions. ey are
important regulators ofmTOR signaling pathway and regulate protein synthesis as well as protein turnover. BCAAs facilitate glucose
uptake by liver and SK muscle and also enhance glycogen synthesis. Oxidation of BCAAs seems to be benecial for metabolic health
as their catabolism increases fatty acid oxidation and reduces risk of obesity. BCAAs are also important in immunity, brain function,
and other physiological aspects of well-being. All three BCAAs are absolutely required for lymphocyte growth and proliferation.
ey are also important for proper immune cell function. BCAAs may inuence brain protein synthesis, and production of energy
and may inuence synthesis of dierent neurotransmitters. BCAAs can be used therapeutically and future studies may be directed
to investigating the diverse eects of BCAAs in dierent tissues and their signaling pathways.
1. Introduction
Amino acids (AAs) are biologically important compounds
containing carboxylic and amine moiety as functional groups
and are the building blocks of protein. ey play important
metabolic and physiological roles in all living organisms.
Although more than 300 AAs have been found, only 20
AAsareknownasstandardAAandcontainaspecicside-
chain specic to each AA [1]. ree branch chain amino
acids (BCAAs), including isoleucine, leucine, and valine, have
unique properties with diverse physiological and metabolic
roles. BCAAs are primarily oxidized in the peripheral tissue,
in particular in skeletal (SK) muscle, whereas the other AA
catabolizes in the liver. BCAAs may regulate rate of protein
synthesis and degradation in SK muscle and other organs.
BCAAs and aromatic AA bind to the same carrier proteins to
be transported to brain. ey compete with each other and
their ratio in brain may inuence the synthesis of specic
neurotransmitters, and that may inuence the behavior of an
organism [2,3]. BCAAs have glycogen sparing action and
they have an opposite relation with tryptophan levels of brain,
which is the precursor of serotonin. Serotonin is a mediator
of central fatigue. us supplementation of BCAAs may
prevent fatigue during extensive exercise, and diet enriched
with BCAAs may improve muscle protein metabolism, body
maintenance, and also aerobic exercise [3,4]. BCAAs have
functions other than simple nutrition. AAs supplementation
enriched with BCAAs clinically is used for patients with liver
diseases, renal failure, sepsis, and surgical injury [2,5–7]. It is
also found that BCAAs may aect gene expression, hepato-
cyte apoptosis and regeneration, and insulin resistance. ey
are necessary for lymphocyte proliferation and dendritic cell
maturation, and they also inhibit cancer cell proliferation
[8–13].Inthisreviewwewillprovidesomeinsightsinto
metabolic and physiological roles of BCAAs.
2. Metabolism and Metabolic Roles of BCAAs
For metabolism, AAs are needed to be transported into
the cell. Like glucose, AAs are also transported to the
cell via special carrier mediated pathway. Inside the cell,
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2Advances in Molecular Biology
transamination reaction of BCAAs gives rise to keto acids,
specic to each AA. e keto acids further undergo oxidative
decarboxylation to produce acyl-CoA derivatives and enter
TCA cycle. e enzyme (activity) responsible for BCAA
metabolism is found mostly in SK muscle, heart, and kidney
but to lesser extent in liver [2].
In muscle, BCAAs not only provide nonspecic carbon
source of oxidation for production of energy but also act
as a precursor for muscle protein synthesis. BCAAs are
more energy ecient than glucose. For example, complete
oxidation of leucine in muscle produces more energy than
complete oxidation of glucose in the form of ATP. Oxidation
of BCAAs increases under various physiological conditions
to meet the energy demand including the demand at star-
vation. It is also observed that BCAAs regulate the turnover
of protein in muscles by inhibiting protein degradation and
enhancing protein synthesis [14–16]. Several metabolic and
clinical conditions, such as starvation, surgery, trauma, sepsis,
liver disease, and cancer, lead to protein loss especially muscle
protein and supplementation of BCAAs promotes protein
synthesis and reduces break down as well as improving those
conditions [2,17–22]. ere is an increasing demand for AAs,
alanine, and glutamine in those clinical conditions and they
can be synthesized in SK muscle from BCAAs oxidation.
So, BCAAs can cover the elevated demands for alanine and
glutamine by the body during those clinical conditions [23].
2.1. Protein Synthesis and Turnover. Initiation of mRNA
translation is one of the key steps in protein synthesis.
Amino acids may stimulate protein synthesis by enhancing
this important step of protein synthesis [24]. Deacylated
tRNA reduces or inhibits protein synthesis by aecting the
initiation step. BCAAs may lead to formation of aminoacyl-
tRNA derivatives that enhance initiation of protein synthesis
by minimizing that inhibitory eect. Another possible way
that BCAAs may inuence protein synthesis is the formation
of active metabolic intermediate by the oxidation of BCAAs
[25].BCAAshaveuniqueroleinproteinsynthesisaswell
as in turnover. Buse et al. [26]studiedinvitroeectof
BCAAs on protein synthesis by analyzing polysome struc-
tures. Healthy rats were injected with BCAAs intravenously
aer 48–96 hours of fasting. And they observed that the
number of polysomes (units) decreases during fasting state
and supplementation of BCAAs or leucine alone signicantly
increases the density of polysomes, which was not observed
when rat was fed normal food, which suggests that BCAAs,
in particular leucine, enhances protein synthesis. In another
study, Li and Jeerson [25] examined inuence of BCAAs
supplementation on protein turnover in rat SK muscle. Fast-
ing young rats were supplemented with dierent combina-
tions of BCAAs by perfusion. A signicant increase (25–50%)
of muscle protein synthesis and signicant decrease (30%) in
protein degradation were observed in perfused supplemented
group compared to control. It was also observed that when
the BCAAs were removed from complete mixture of amino
acids, the rest of the amino acids showed no eects on protein
turnover [25]. So, BCAAs not only enhance protein synthesis,
but also inuence protein turnover.
2.2. BCAAs and Signaling. Hypoalbuminemia and muscle
wasting symptoms are quite common in liver cirrhotic
patient. Oral administration of BCAA is found benecial by
increasing plasma albumin and reducing muscle wasting in
both animals and humans. It is proposed that BCAAs acceler-
ate protein synthesis in liver and other tissues via mammalian
target of rapamycin (mTOR) signaling pathways. mTOR
is a serine/threonine protein kinase and its signaling path-
ways may regulate protein synthesis and transcription as
well as other cellular functions [27,28]. BCAA, particularly
leucine, is the potent activator of mTOR signaling and
activates protein synthesis by translational initiation [26]. In
astudy[29], rat hepatocytes in culture were incubated with
dierent combinations of BCAAs and secretion of albumin
was observed. It was found that mixture of BCAAs promotes
albumin production in dose dependent manner and they
were the key eectors. Rapamycin, which is the potent
inhibitorofmTOR,reducesmorethanhalfofthisproduction
of albumin promoted by leucine. It was also observed that
activation of downstream translational eector proteins of
mTOR, elF4E-BP1, and p70 S6 kinase is induced by leucine
only. And rapamycin completely inhibits those proteins.
ese observations suggest that synthesis of albumin in rat
hepatocytes via mTOR signaling is promoted by BCAAs,
particularly by leucine. In another study [30]starvingmale
rats were orally administered either saline or each BCAA
separately. Also, starved rats were injected intravenously with
rapamycinbeforeleucineadministration.Itwasfoundthat
only leucine stimulated signicant protein synthesis in SK
muscle compared to controls. Moreover, leucine eectively
enhanced phosphorylation and activation of elF4E-BP1 and
p70 S6 kinase. Both in leucine-treated and starved rats,
rapamycin inhibited protein synthesis.
All of these studies suggest that BCAAs, particularly,
leucine, promote protein synthesis in SK muscle as well as in
theliverbythesamemechanismviamTOR.
2.3. Glucose Metabolism. Cirrhotic patients also suer from
impaired glucose metabolism and many of them develop
diabetes mellitus. Synthesis of glycogen takes place in liver
and SK muscles; they are the main reservoir of glycogen too.
is glycogen store is very important in controlling blood
glucose level. Cirrhotic patients have low level of glycogen
store in their liver and SK muscle compared to healthy
individuals [31]. BCAAs facilitate glucose uptake by liver and
SK muscle as well as enhancing glycogen synthesis. Nishitani
et al. [32] collected soleus muscles from healthy rats and incu-
bated them with leucine in insulin-free conditions to test the
eect of leucine on glucose uptake. ey found that leucine
promotes glucose uptake; moreover, 𝛼-ketoisocaproic acid,
a metabolic product of leucine, showed similar stimulatory
eect. ey observed that inhibition of phosphatidylinositol
3-kinase (PI3-kinase) or protein kinase C (PKC) by selective
inhibitors leads to complete loss of stimulatory eect of
leucine. However, rapamycin treatment showed no eect.
ese observations indicate that leucine stimulates glucose
transport in SK muscle by insulin-independent manner
through PKC and PI3-kinase pathways rather than mTOR
pathway. In another study Peyrollier et al. [33] deprived

Advances in Molecular Biology 3
myoblast L6 cells ∼1hforAAsandaerthatincubatedthem
with leucine. ey observed a signicant increase of PI3-
kinase and p70 S6 kinase activity. ey also found that glyco-
gen synthase kinase-3 (GSK-3) is inactivated by leucine. GSK-
3isanenzymethatinactivatesglycogensynthase(GS)activity
and stops glycogen synthesis. ese results suggest that
BCAA supplementation may enhance glycogen synthesis by
activating GS.
2.4. Energy Metabolism. ere is an inverse relationship
between physical activity and obesity. Obesity on the other
hand is associated with dierent types of complications,
including metabolic diseases. Regular physical activities keep
a person t with reducing risks of those diseases. It is
benecial and important for us to know how the energy
metabolism is regulated and coordinated. BCAAs oxidation
seems to be benecial for our metabolic health as their
catabolism increases fatty acid oxidation as well as reducing
riskofobesity.erearehigherlevelsofplasmaBCAAsfound
in obese animals and humans; on the other hand, lower levels
ofplasmaBCAAsarefoundinleanandexercisedanimals
and humans. It is also found that supplementation of BCAAs
enriched protein is benecial in animals and humans by
increasing exercise performance, composition of body pro-
tein and properties, and better glucose tolerance and control;
all of these are related to better health and tness [4].
Nishimura et al. [34] fed mice with high fat diet and sup-
plemented isoleucine to test the eect of isoleucine supple-
mentation on obesity condition, glucose, and fat homeostasis.
ey observed that isoleucine supplementation leads to a
decrease in weight gain and reduced lipid mass in isoleucine
supplemental group compared to control. Triglyceride con-
centrations and degree of hyperinsulinemia were also lower
in hepatic and SK muscle of isoleucine supplemented group.
In a double-blind, placebo-control, cross-over study [35],
human volunteers were supplemented with either the BCAA
ortheplacebofor3days.eirexercisecapacityandlipid
oxidation were measured. It was found that BCAA supple-
mentation increases lipid oxidation during exercise and helps
to overcome fatigue condition. e glucose metabolism of
the volunteer also improved. Qin et al. [36]showedthat
there is an inverse relation between BCAA intake and obesity.
Apparent middle aged healthy adults from China, Japan, UK,
and USA, who consumed higher amount of BCAAs, had
low incidence of obesity and overweight status. All of these
evidences suggest that BCAAs have large inuence on energy
metabolism as well as reducing risks of obesity.
3. Physiological Roles of BCAAs
3.1. BCAAs in Immunity. e immune system is important in
protecting host from pathogens (including bacteria, viruses,
fungi, parasites, etc.), existing in surrounding environments,
and also protects from other notorious threats. Immune cells
(i.e., lymphocytes, neutrophils, etc.) express dehydrogenase
and decarboxylase enzyme and can eectively oxidize BCAAs
[37–39]. All three BCAAs are absolutely required for lympho-
cytes growth and proliferation. BCAAs are also important for
cytotoxic T lymphocyte and natural killer cell activity [40].
In a study [41] mice were supplemented with diet containing
optimal level of protein or diet containing individual AA,
except for limited amount of BCAAs. e susceptibility
to Salmonella typhimurium infection and immune activity
were measured. ey found a higher mortality rate to S.
typhimurium when mice were fed diet containing restricted
amount of BCAAs (any). e liver and spleen were also
colonizedwithhighernumberofS. typhimurium in that
group of mice. BCAA restriction also leads to lower number
of spleen cells and less antibody titer against S. typhimurium
in the serum. ese results suggest that restriction of any
BCAA may impair host defense system. Human study [42]
with surgery patients shows that higher BCAA supplementa-
tion leads to higher postsurgery blood lymphocytes, higher
immune parameters, and better recovery. Bassit et al. [43]
supplemented BCAAs to male elite triathletes to measure
the eects of that supplementation on immunity parameters.
ey observed that BCAAs supplementation increased lym-
phocyte proliferation and modied the pattern of cytokine
production and shi of the immune response from 2 to
1, which is benecial for the athletes.
3.2. BCAAs in Sepsis. Sepsis is a physiological condition
in which severe inammation occurs in whole body due
to infection and it may be life threatening [44]. Potential
benecial roles of BCAAs in sepsis have been studied. Mori
et al. [5] supplemented total parenteral nutrition (TPN)
enriched with branched-chain amino acids (BCAAs) to
septic rats. ey found that BCAA-enriched TPN leads to
signicant improvement of nitrogen balance and decreases
mortality compared to conventional TPN in septic rats. In
a randomized, multicenter study [45] sepsis patients were
supplemented TPN, enriched with BCAAs or conventional
TPN only. ere was signicant decrease in mortality and
improvements of visceral proteins half-life were observed in
the BCAA-supplemental group. ese studies suggest that
BCAAs have a benecial eect in septic patients.
3.3. BCAAs and Diabetes. Diabetes is one of the most
prevalent diseases worldwide and is associated with several
factors such as age, race, body weight, and food habit. ere is
a strong correlation between circulating BCAAs and diabetes
prediction [46]. In a recent study it was found that patients
with type 2 diabetes, who had impaired fasting glucose,
also had elevated levels of BCAAs compared to healthy
individuals [47]. Mammalian target of rapamycin complex
1 (mTORC1) is a nutrient-sensitive kinase, important for
growth and proliferation of beta cell as well as insulin secre-
tion. BCAAs are important regulators of mTORC1 signaling
and elevated levels of plasma BCAAs for a longer period can
cause hyperactivation of mTOR signaling. And that may lead
to early beta cell dysfunction and destruction [48]. So, it is
important to maintain normal plasma levels of BCAA.
3.4. BCAAs in Brain Functions. BCAAs may also play impor-
tant roles in brain function. BCAAs may inuence brain pro-
tein synthesis and production of energy and may inuence
synthesis of dierent neurotransmitters, that is, serotonin,

4Advances in Molecular Biology
dopamine, norepinephrine, and so forth, directly or indi-
rectly. Major portion of dietary BCAAs is not metabolized by
liver and comes into systemic circulation aer a meal. BCAAs
and aromatic AA, such as tryptophan (Trp), tyrosine (Tyr),
and phenylalanine (Phe), share the same transporter protein
to transport into brain. Trp is the precursor of neurotransmit-
ter serotonin; Tyr and Phe are precursors of catecholamines
(dopamine, norepinephrine, and epinephrine). When plasma
concentration of BCAAs increases, the brain absorption of
BCAAs also increases with subsequent reduction of aromatic
AAabsorption.atmayleadtodecreaseinsynthesis
of these related neurotransmitters [3]. Catecholamines are
important in lowering blood pressure. When hypertensive
rats were injected with Tyr, their blood pressure dropped
markedly and injection with equimolar amount of valine
blocks that action [49]. In vigorous working persons, such as
in athletes, depletion of muscle and plasma BCAAs is normal.
And that depletion of muscle and plasma BCAAs may lead
to increase in Trp uptake by brain and release of serotonin.
Serotonin on the other hand leads to central fatigue. So,
supplementation of BCAAs to vigorously working person
may be benecial for their performance and body mainte-
nance [3].
4. Conclusions
BCAAs have unique characteristics as they are not primarily
oxidized in liver and they regulate protein synthesis and
degradation in muscle as well as other tissues. In addition,
BCAAs compete with aromatic AA to enter into brain. ey
have diverse metabolic and physiological roles. BCAAs are
also important regulators of mTOR signaling that regulates
protein and glycogen metabolism in liver and SK muscles.
ese eects in liver and SK muscles are important in
maintaining body composition and glucose balance. ey are
also important regulators of neurotransmitters in brain. So,
BCAAs may be therapeutically useable in various neurologi-
cal disorders. However, more research is needed in this eld.
In vitro and in vivo studies of BCAAs suggest that they might
have benecial eects in various disorders. It is important and
necessary to explore whether BCAAs have other therapeutic
eects on other tissues. Future investigations may be directed
to fully understand the diverse eects of BCAA in dierent
tissues and associated signaling pathways.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
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