R E V I E W Open Access
Branched-chain amino acids in health and
disease: metabolism, alterations in blood
plasma, and as supplements
Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic
properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However,
until today, there is no consensus regarding their therapeutic effectiveness.
In the article is demonstrated that the crucial roles in BCAA metabolism play: (i) skeletal muscle as the initial site of BCAA
catabolism accompanied with the release of alanine and glutamine to the blood; (ii) activity of branched-chain keto acid
dehydrogenase (BCKD); and (iii) amination of branched-chain keto acids (BCKAs) to BCAAs. Enhanced consumption of
BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and
urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure,
trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main
cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in
diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by
amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles.
The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies
should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects
with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation
in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin
resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with
It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful
studies are needed to elucidate their therapeutic effectiveness in most indications.
Keywords: Cachexia, Ammonia, Glutamine, Diabetes, Cirrhosis, Nutrition
The branched-chain amino acids (BCAAs), valine, leucine,
and isoleucine are essential amino acids, which have been
studied in a number of disorders, notably liver cirrhosis,
renal failure, sepsis, trauma, burn injury, and cancer. BCAA
supplementation has been thought to promote anabolic
pathways and therefore mitigate cachexia, prevent or treat
signs of hepatic encephalopathy, attenuate fatigue during
exercise, promote wound healing, and stimulate insulin
production. However, until today, there is not consensus
regarding their use as nutritional supplements [1,2].
The intentions of this article are to: (i) review main
metabolic pathways and supposed effects of BCAAs; (ii)
assess the causes of alterations in metabolism and BCAA
levels in various healthy and pathological conditions;
and (iii) provide current views on their use as nutritional
supplements for the main possible indications. As the
main pathways of all three BCAAs are common and
mixtures of all three BCAAs are used in most indications,
the article does not describe the differences in effects of
Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles
University, Simkova 870, 500 03, Hradec Kralove, Czech Republic
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Holeček Nutrition & Metabolism (2018) 15:33
BCAA catabolism (Fig. 1)
Unlike most amino acids, the initial step of BCAA catabol-
ism does not take place in the liver due to low hepatic ac-
tivity of branched-chain-amino-acid aminotransferase
(BCAT), the first enzyme in the BCAA catabolism path-
way. Therefore, the BCAA increase rapidly in systemic cir-
culation after protein intake and are readily available to
extrahepatic tissues. This phenomenon gives a unique ad-
vantage to the BCAA-based nutritional formulas compared
with others, especially those targeted on muscles and brain.
The initial site of most of the BCAA catabolism is skel-
etal muscle because of the BCAT high activity. The BCAT
reaction involves the reversible transfer of the BCAA
amino group to α-ketoglutarate (α-KG) to form glutamate
and the corresponding branched-chain keto acids (BCKAs)
,α-ketoisocaproate (KIC, ketoleucine), α-keto-β-methylva-
lerate (KMV, ketoisoleucine), and α-ketoisovalerate (KIV,
ketovaline). Glutamate then acts as an amino group source
to form alanine (ALA) from pyruvate or as a substrate for
ammonia detoxification to glutamine (GLN). GLN, ALA,
and a significant portion of the BCKA are released from
muscles to the blood.
The second enzyme of BCAA catabolism, branched-
chain α-keto acid dehydrogenase (BCKD), is a multien-
zyme complex located on the inner surface of the inner
mitochondrial membrane, which catalyzes irreversible
decarboxylation of the BCKA to the corresponding
branched-chain acyl-CoA esters. The BCKD is regulated
by the phosphorylation-dephosphorylation mechanism.
Phosphorylation mediated by a specific kinase results in
inactivation, while dephosphorylation by a specific phos-
phatase activates the enzyme. Changes in kinase activity
may play a main role.
The BCKD activity is highest in the liver, intermediate
in kidneys and heart, and low in muscles, adipose tissue,
and brain . When the weights of individual tissues are
taken into consideration, muscles, which make up 35 to
40% of total body weight, should contribute substantially
to total body BCAA utilization. Thus, BCAA degradation
is under joint control of a number of tissues, among which
the muscle and liver play a dominant role (Fig. 2). Many
influences including cytokines, hormones, nutrients, and
various metabolites affect the activity state of the enzyme
. The remarkable rise in BCKD activity in muscles in-
duces endotoxin or tumor necrosis factor alpha (TNF-α)
Beyond the BCKD reaction, the metabolism of the
BCAA diverges into separate pathways. Catabolism of
KIC leads to acetyl-CoA and acetoacetate (KIC is keto-
genic), KIV is catabolized to succinyl-CoA (KIV is gluco-
genic), and KMV to acetyl-CoA and succinyl-CoA (KMV
is both glycogenic and ketogenic). A special product of
KIC catabolism is β-hydroxy-β-methylbutyrate (HMB)
synthesized in the reaction catalyzed by KIC dioxygenase.
Amination of the BCKA and interorgan cycling of the
BCAA and BCKA (Fig. 3)
As the BCAT reaction is reversible and near equilibrium,
its direction should respond to changes in concentrations
Fig. 1 Main pathways of BCAA catabolism. ALA, alanine; GLU, glutamate; GLN, glutamine; HMB, β-hydroxy-β-methylbutyrate; HMG-CoA, 3-hydroxy-3-methyl-
glutaryl-CoA; KIC, α-ketoisocaproate (ketoleucine); KIV, α-ketoisovalerate (ketovaline); KMV, α-keto-β-methylvalerate (ketoisoleucine); α-KG, α-ketoglutarate. 1,
branched-chain-amino-acid aminotransferase (BCAT); 2, branched-chain α-keto acid dehydrogenase (BCKD); 3, KIC dioxygenase
Holeček Nutrition & Metabolism (2018) 15:33 Page 2 of 12
of BCAA and BCKA, and availability of the donors and
acceptors of nitrogen. In most conditions the majority of
the BCAA uptake and BCKA release occurs in muscles,
while amination of the BCKA to the BCAA may occur in
other tissues, notably in the liver, kidneys and enterocytes.
Direct evidence of the BCKA amination to the BCAAs
the labelled BCAA in proteins . The main sources of
nitrogen for amination of the BCKA are GLN, glutam-
ate, and ALA .
The studies demonstrate that BCAA synthesis from
the BCKA is activated in various muscle wasting dis-
muscles release high amounts of GLN and ALA to
the blood [7–11]. A marked increase in leucine
release was observed by the isolated liver of
endotoxin-treated animals after addition of KIC into
perfusion medium ; higher synthesis of the BCAA
from BCKA was shown in the liver perfused with
medium containing 0.5 mM GLN when compared to
perfusion with medium without GLN . Amination
of the BCKA may have a role in the unique increase
of all three BCAA in blood plasma during a brief
starvation characterized by accelerated release of
ALA, GLN, and BCKA from muscles and augmented
gluconeogenesis in the liver [9,10].
The above-mentioned findings indicate the existence
of an interorgan cycle (Fig. 3) that attenuates the loss of
essential BCAA in various physiological and pathological
Fig. 2 Cooperation of the muscles and the liver in BCAA catabolism. BCAA, branched-chain amino acids; BCKA, branched-chain keto acids
Fig. 3 The schemes of the BCAT reactions (BCAA deamination and BCKA amination) and supposed cycling of the BCAA and BCKA among
organs, which may in various conditions attenuate the loss of essential BCAA . ALA, alanine; BCAA, branched-chain amino acids; BCKA,
branched-chain keto acids. GLU, glutamate; GLN, glutamine; PYR, pyruvate; α-KG, α-ketoglutarate
Holeček Nutrition & Metabolism (2018) 15:33 Page 3 of 12
Functions of the BCAA
The BCAAs serve as substrates for protein synthesis or
energy production and perform several metabolic and
signaling functions, particularly via activation of the
mammalian target of rapamycin (mTOR) signaling
pathway. The following roles of the BCAA should be
considered as crucial for their use as nutritional supple-
ments (Fig. 4).
Effects on protein metabolism
BCAAs not only serve as substrates for protein synthesis,
but also exert stimulatory effect on protein synthesis and
an inhibitory effect on proteolysis. The effects are realized
by the BCAAs themselves, especially by leucine, and their
metabolites. Leucine stimulates protein synthesis through
the mTOR signaling pathway and phosphorylation of
translation initiation factors and ribosomal proteins .
A role in protein anabolic effect of leucine plays also its
stimulatory effect on insulin secretion . The inhibitory
effect of the BCAA on proteolysis is mediated mainly by
BCKAs and HMB. BCKAs have been shown to prevent
proteolysis in muscles under in vitro conditions .
Infusions of KIC were more effective than leucine in
maintaining nitrogen balance in fasted subjects and in
patients undergoing major abdominal surgery [15,16].
HMB decreases the activity of the ubiquitin-proteasome
proteolytic pathway and exerts beneficial effects on muscle
in various conditions of health and disease .
Effects on neurotransmission
BCAAs are transported into the brain via the same
carrier that transports aromatic amino acids (AAA; phenyl-
alanine, tyrosine, tryptophan), and competition between
neurotransmitters, notably dopamine, norepinephrine,
and 5-hydroxytryptamine (serotonin). Therefore, elevation
of the BCAA in blood plasma is able to influence neuro-
transmitter levels in the brain with effects on behavior and
brain function. This phenomenon is the rationale for use
of the BCAAs in patients with liver cirrhosis, in which a
decreased ratio of BCAAs to AAAs plays a role in patho-
genesis of hepatic encephalopathy . It is believed that
BCAA supplementation attenuates production of sero-
tonin, which is responsible for fatigue during exercise.
Furthermore, BCAA transamination in the brain plays a
role in the synthesis of glutamate and gamma-aminobutyric
acid, and in ammonia detoxification to GLN in astrocytes.
The studies have shown that leucine decreases appetite and
Effects on glucose metabolism
There are close associations between BCAAs and plasma
glucose levels. The fact that BCAAs upregulate glucose
transporters and activate insulin secretion has been widely
demonstrated [13,20,21]. However, several researchers
have suggested that excessive intake of amino acids could
lead to inhibition of insulin signaling [22,23]. Recent
studies have suggested differential effects of each BCAA
on glucose utilization and that BCAAs may induce insulin
resistance through mTOR activation . Further investi-
gation is needed to understand variable reports ranging
from improving glucose utilization to inducing insulin
Effects mediated by ALA and GLN
The rate of BCAA degradation in skeletal muscle is highly
responsive to their availability . The consequences of
this phenomenon are that the primary effects of the
consumption of a BCAA-enriched diet are activated
catabolism of the BCAAs and enhanced levels of the
Fig. 4 Supposed effects of BCAA supplementation. ALA, alanine; BCAA, branched-chain amino acids; GLN, glutamine; ↑, increase; ↓, decrease
Holeček Nutrition & Metabolism (2018) 15:33 Page 4 of 12
BCKAs, ALA, and GLN in peripheral circulation .
Therefore, a number of effects of BCAA supplementation
are mediated by ALA and GLN. ALA is the main gluco-
neogenic amino acid, and GLN availability is essential for
immune system, glutathione production, maintenance of
acid-base balance by the kidneys, and expression of heat
During recent years, a number of novel functions of
BCAAs, including benefits for mammary health and
milk quality, intestinal development, immune response,
mitochondrial biogenesis and oxidative stress have been
Effects of starvation and diets with a different
protein content on metabolism and BCAA levels
BCAA metabolism is very sensitive to changes in the
amount and composition of the food, which may occur in
both healthy and disease states. Here, I have attempted to
explain the effects of starvation and diets with low and
high protein contents.
Brief starvation uniquely increases BCAA concentrations
in plasma. In humans, the increase is evident within a day,
and reaches maximum by the second or third day [27,28].
Both increased proteolysis and reduced protein synthe-
sis in muscles have been reported during brief starvation
and may explain the enhanced availability of BCAAs for
muscles [10,29,30]. In this condition, BCAAs in muscles
act as a source of nitrogen for synthesis of ALA and GLN,
which are released into the blood and used in visceral
tissues, especially as gluconeogenic substrates. Increased
BCAT activity in muscles during starvation has been
reported by several laboratories [31,32].
Together with ALA and GLN, the BCKAs generated
in BCAT reaction are released into circulation and their
concentration in the blood increases .Itmaybesup-
posed that a portion of nitrogen released during catabolism
of GLN and ALA in visceral tissues escapes utilization in
the urea cycle and is used for amination of BCKAs. Higher
rates of BCAA synthesis from the BCKAs were observed
by the liver perfused with GLN-containing medium than
that perfused with GLN-deficient medium . A role in
uptake from the blood due to the decreased levels of
insulin. An unresolved possibility is the activated break-
down of proteins in the liver, which may, due to low activity
of hepatic BCAT, result in the release of the BCAA into the
Prolonged starvation lowers the BCAA concentration
to basal levels and gradually increases the activity of the
BCKD complex. Marked increase in BCKD activity in
muscles and heart occurs in the terminal phase of
starvation, when amino acids replace fatty acids and ketone
bodies as the predominant energy substrate .
Effects of a low-protein diet
Feeding healthy human volunteers or animals a diet devoid
of protein, but adequate in caloric content, lowered the
plasma BCAA concentrations below basal levels [27,34].
The amino acid pattern of children with severe kwashiorkor
shows severe decrease of BCAAs .
It is believed that the principal factors in the decrease
of BCAAs during protein deprivation are the absence of
exogenous amino acids as well as curtailed muscle protein
breakdown. Lowered BCKD activities in muscles and liver
of protein-depleted rats indicate the effort of the body to
conserve BCAAs .
BCAA or BCKA supplementation should be recom-
mended when a low-protein diet is prescribed to patients
with chronic renal failure or urea cycle disorders.
Effects of a high-protein diet
Increased intake of protein may increase protein synthesis,
decrease protein breakdown, reduce fat accumulation, and
increase fat-free mass. Therefore protein supplementation
or a high-protein diet is recommended to build the
muscles in athletes, to prevent muscle wasting in severe
illness, and to lose fat in the treatment of obesity.
High concentrations of BCAAs and urea are found in
the postprandial state in the peripheral blood and muscles
after intake of a protein meal and in subjects consum-
ing a high-protein diet. In contrast to increased BCAA
levels, the increments in arterial concentrations of most
remaining amino acids of the ingested protein are small
or insignificant [37,38].
The main cause of the specific BCAA increase is the
unique distribution of the enzymes, which control BCAA
catabolism. While complete oxidation of most individual
amino acids occurs in the liver, the initial site of BCAA
catabolism is skeletal muscle. Therefore, a significant
portion of ingested BCAA escapes hepatic uptake and
appears in peripheral circulation. The effects of protein
ingestion on BCAA levels are not observed in a postab-
sorptive state .
Disorders with decreased BCAA levels
The studies have shown that BCAA deficiency impairs
mRNA translation and dietary inadequacies of BCAA
result in impaired growth and protein wasting [12,39,40].
In addition, studies in human subjects have shown that
decreased BCAA level may influence synthesis of neuro-
transmitters and adversely affect brain function [18,41].
Therefore, BCAA supplementation seems rational in
disorders with decreased BCAA levels, which occur in
Holeček Nutrition & Metabolism (2018) 15:33 Page 5 of 12
liver cirrhosis, urea cycle disorders, and chronic renal
The decrease in BCAAs and an increase in AAAs are
characteristic alterations in the blood of subjects with
liver cirrhosis, which play a role in pathogenesis of hep-
atic encephalopathy and muscle wasting [18,42]. Several
studies have shown an inverse relationship between
plasma ammonia and BCAA concentrations in patients
with cirrhosis and that ammonia infusion decreases BCAA
levels [43,44]. BCAAs decrease because they are rapidly
consumed to form glutamate from α-KG as a pivotal step
in ammonia detoxification to GLN in muscles and in the
brain . Accelerated consumption of α-KG (cataplerosis)
may disturb the function of the tricarboxylic acid (TCA)
cycle (Fig. 5). The AAA increase is due to the decreased
ability of the diseased liver to metabolize these amino
acids. The BCAA levels do not decrease in acute liver in-
jury due the leaking of amino acids from dying hepatocytes
into the circulatory system .
Effects of BCAA supplementation
BCAAs are recommended to ameliorate cachexia and the
decreased ratio of BCAAs to AAAs, which plays a role in
the pathogenesis of hepatic encephalopathy. Potential bene-
fits also include positive effects of the BCAA on ammonia
detoxification to GLN in muscles, liver regeneration,
albumin synthesis, immune and hepatic function, glucose
metabolism, and physical and mental fatigue [20,47–49].
Unfortunately, the results from clinical trials do not
provide strong evidence of their beneficial effects [50,51]
and adverse effects of BCAA supplementation, which may
compete with their benefits, have also been suggested
. The positive effects of BCAAs in subjects with liver
cirrhosis may be blunted by enhanced catabolism of GLN
produced in muscles to ammonia in visceral tissues, espe-
cially in the gut and kidneys. The draining of α-KG from
TCA cycle may also be detrimental (Fig. 5). Therefore,
therapeutic strategies are needed to avoid potential adverse
effects of BCAAs on ammonia production and cataplerosis.
Options include substitution of α-KG, glutamate related
substrates (e.g. L-ornithine-L-aspartate), GLN elimination
from the body by phenylbutyrate, replacement of BCAAs
by BCKAs, and optimizing dose, proportions, and timing of
BCAA supplementation .
Urea cycle disorders (UCD) and phenylbutyrate
UCD result from inherited enzymatic defects in the
ammonia detoxification pathway in the liver, leading to
low levels of urea and high levels of ammonia in the
blood. The disorders are characterized by seizures, lethargy,
coma, and death in the neonatal period or severe long-
term neurological impairment.
In addition to altered levels of ammonia and urea,
common finding in patients with UCD is an increase in
Fig. 5 Pathways of ammonia detoxification to GLN in muscles associated with enhanced consumption of the BCAA and α-KG (cataplerosis) and
suggested effects of BCAA and phenylbutyrate in subjects with liver cirrhosis or UCD. Positive effect of BCAA on ammonia detoxification to GLN may be
blunted by GLN degradation to ammonia in enterocytes and kidneys. Phenylbutyrate decreases ammonia via enhanced excretion of GLN by urine. An
adverse side effect of phenylbutyrate is activation of BCKD resulting in the decrease of the BCAA. ALA, alanine; BCAA, branched-chain amino acids; BCKA,
branched-chain keto acids. GLU, glutamate; GLN, glutamine; PYR, pyruvate; TCA cycle, tricarboxylic acid cycle; UCD, urea cycle disorders; α-KG,
α-ketoglutarate. 1, branched-chain-amino-acid aminotransferase; 2, branched-chain α-keto acid dehydrogenase; 3, GLN synthetase
Holeček Nutrition & Metabolism (2018) 15:33 Page 6 of 12
GLN and a decline in BCAA levels, notably during acute
metabolic decompensation . These alterations support
the theory that BCAAs play a unique role in ammonia
detoxification to GLN and that hyperammonemia is the
cause of decreased BCAA levels in subject with liver
At present, the management of UCD is achieved by
dietary protein restriction and the use of compounds that
remove nitrogen, notably benzoate and phenylbutyrate.
Benzoate conjugates glycine to promote the synthesis of
hippuric acid that is eliminated in urine and thus attenu-
ates catabolism of glycine to ammonia. Phenylbutyrate is
converted by β-oxidation into phenylacetate that is conju-
gated with GLN to form phenacetylglutamine, which is
excreted in the urine (Fig. 4). Unfortunately, it has been
shown that phenylbutyrate activates the BCKD, resulting
in decreases in BCAA and BCKA levels in blood plasma
[55,56]. Marked decrease of BCAAs in UCD after phenyl-
butyrate treatment has been reported by Scaglia et al. .
Effects of BCAA supplementation
Low BCAA levels in subjects with UCD, especially those
treated by phenylbutyrate, indicate the rationale to use
BCAAs as a therapeutic agent. Unfortunately, the reports of
attempts to use BCAAs in UCD are unique. Cross-sectional
data from 41 European Inherited Metabolic Disorder
centers reported that only 16 (3%) patients (from 8 centers
in 5 countries) received BCAA supplements. The two most
common conditions were ornithine transcarbamylase
deficiency and citrullinaemia .
Chronic renal failure (CRF)
Most studies of amino acid patterns in CRF reported
decreased BCAA and BCKA levels in the blood plasma
[59–61] and reduced concentrations of valine in muscles
[61,62]. The derangements are caused by the action of
multiple factors, notably acidosis and glucocorticoids.
Decreased intake of proteins and hemodialysis, resulting in
low concentrations of most essential and nonessential amino
acids, is also a factor. In contrast to CRF, inconsistent alter-
ations have been reported in acute renal failure.
Several articles have suggested that metabolic acidosis
is responsible for accelerated proteolysis and enhanced
activity of the BCKD in muscles and liver [63,64]. More
significant increases in proteolysis and leucine oxidation
were reported in rats with chronic uremia and acidosis
when compared with uremic rats without acidosis. A signifi-
cant decrease in valine concentration in the gastrocnemius
muscle was found only in rats with acidosis .
Effects of BCAA supplementation
BCAAs and BCKAs are supplied to patients with CRF
together with other essential amino acids and their ketoana-
logues to decrease protein intake as much as possible to
maintain protein balance and avoid its deleterious effects
on urea levels [65,66].
Disorders with enhanced BCAA levels
Increased BCAA concentrations are found in various
insulin-deficient and -resistant states, especially diabetes
and obesity. Very high BCAA and BCKA concentrations
are found in maple syrup urine disease (MSUD).
Type 1 diabetes
High BCAA levels in subjects with defective insulin
secretion were first described in dogs with experimental
diabetes . Further studies have shown that in addition
to the increase of BCAAs, there is a decrease in levels of
gluconeogenic amino acids, especially ALA [68–70]. Most
data on pathogenesis of high levels of the BCAA in
diabetes type 1 originate from studies using animals with
diabetes induced by streptozotocin or alloxan.
There are some similarities in the pathogenesis of the
increased BCAAs in diabetes and short-term starvation,
which is also an insulin deficient state. As in starvation,
a role play activated amination of the BCKAs in the liver
and impaired uptake of the BCAA by muscles. The
BCKA levels increase in blood plasma and muscles of
rats with chemically-induced diabetes, but decline in the
liver . The role of the liver as a source of BCAAs is
supported by observations of reduced activity of hepatic
BCKD in rats with severe ketotic diabetes .
However, unlike brief starvation, the changes in diabetes
are associated with marked increase in proteolysis and
BCKD activity in muscles, resulting in severe cachexia
. While muscle nitrogen repletion occurs and BCAA
levels are normalized after feeding of previously starving
subjects, the BCAAs accumulate and diminished nitrogen
repletion remains after feeding in subjects with type 1
Obesity and type 2 diabetes
Plasma concentrations of BCAAs are frequently elevated
in obesity and type 2 diabetes [75–77]. The mechanism
responsible for the increased BCAAs in these insulin-
resistant states is not completely clear. A major cause
might be reduced activity of the BCKA dehydrogenase,
which was reported in the liver and adipose tissue in
genetically obese ob/ob mice, Zucker rats and spontan-
eous type 2 diabetes Otsuka Long-Evans Tokushima Fatty
(OLETF) rats [76,77].
The studies have shown that the BCAA levels in obesity
correlate with insulin resistance and are a sensitive pre-
dictor of diabetes in the future [78,79]. Recent studies
have suggested that high levels of the BCAA interfere with
oxidation of fatty acids in muscles, leading to accumula-
tion of various acylcarnitines and insulin resistance .
Holeček Nutrition & Metabolism (2018) 15:33 Page 7 of 12
Conflicting results have been reported concerning the
effects of BCAA supplementation in subjects with insulin
resistance. Leucine improved glucose tolerance, decreased
hepatic steatosis, and decreased inflammation in adipose
tissue in mice fad a high-fat diet  and rescued insulin
signaling in adipose tissue obtained from insulin resistant
db/db mice . Arakawa et al.  reported that BCAAs
reduced hepatic and triglyceride concentrations in mice
fed a high-fat diet. On the other hand, Newgard et al. 
showed that administration of a mixture of BCAA to rats
on a high-fat diet increased insulin resistance. White et al.
 demonstrated that the BCAA-restricted diet improved
muscle insulin sensitivity in Zucker-fatty rats.
Maple syrup urine disease (MSUD)
MSUD is recessive disorder caused by a severe defi-
ciency of BCKD activity. All three BCAAs, as well as the
corresponding BCKAs, are elevated in blood, tissues,
and urine. High BCAA and BCKA levels are related to
excitotoxicity, energy deficit, and oxidative stress in the
brain, resulting in severe neurological symptoms.
BCAA administration to subjects with MSUD is inappro-
priate. DNA damage in the hippocampus and the striatum
was demonstrated after administration of BCAAs in an
animal model of MSUD . Current treatment of MSUD
is based on protein restriction and synthetic formulas with
reduced BCAA content. Perspective may be phenylbuty-
rate, which activates BCKD and decreases BCAA and
BCKA levels [55,56]. Unfortunately, studies examining
phenylbutyrate in MSUD patients are unique. Decreased
BCAA and BCKA levels were reported in three out of the
five MSUD patients treated by phenylbutyrate (10 g/m
for one day . Long-term studies in different MSUD
phenotypes are indicated to verify phenylbutyrate efficacy.
Conditions with enhanced BCAA catabolism and
inconsistent alterations in BCAA levels
Physical exercise is associated with enhanced BCAA oxi-
dation and GLN release from muscles [84,85]. Evidence
suggests that BCKD is activated by dephosphorylation
mediated by falling ATP levels within the muscles during
exercise. Training appears to increase mRNA expression
of this enzyme . The plasma BCAA levels during or
after exercise have been reported to be unchanged ,
to decrease , or to increase . The cause of incon-
sistent response can be explained by different work load
and duration of exercise.
Effects of BCAA supplementation
BCAAs are recognized as supplements for athletes with a
number of benefits, notably on muscle protein synthesis,
fatigue recovery, and exercise-induced muscle damage .
reports showing no benefits of BCAA supplementation
. Of special interest should be findings of enhanced
blood ammonia levels after BCAA administration during
exercise suggesting that exogenous BCAA may exert
negative effects on muscle performance via ammonia
[92,93]. Additional studies are needed to assess the true
efficacy of BCAA supplementation on muscle perform-
ance and fatigue.
Hypermetabolic states accompanied by systemic
inflammatory response syndrome
There are several hypermetabolic states (e.g. sepsis, burn
injury, trauma, and cancer) in which alterations in BCAA
levels are not consistent, with increased, unchanged, and
decreased levels being reported. Present in all of these
conditions is systemic inflammatory response syndrome
(SIRS) characterized by a wide range of neuro-humoral
abnormalities, including enhanced production of cyto-
kines, sympathetic nervous system activation, and cortisol
production. These events cause several alterations in
metabolism, including insulin resistance and enhanced
myofibrillar protein degradation, resulting in severe
depletion of lean body mass. If the hypermetabolic state
persists, multisystem organ failure and eventually death
may occur (Fig. 6).
In this situation, BCAAs act as a significant energy
substrate for muscles [4,5,94]. Increased BCAA oxidation
is coupled with increased synthesis of GLN, which is
released from muscles and utilized, preferably by the
immune system. Utilization of GLN often exceeds its
synthesis, leading to a lack of GLN in blood and tissues
[95,96]. Decreased GLN availability can become rate-
limiting for key functions of immune cells, such as
phagocytosis and antibody production. Decreased GLN
levels have been shown to act as a driving force for
BCAA utilization in muscles . Studies have also
indicated that inflammatory signals decrease BCAA
absorption from the gut and inhibit BCAA transport from
the blood to muscles, while promoting transport into the
liver [98,99]. The BCAA synthesis from the BCKA in
visceral tissues is probably activated. A marked increase in
leucine release was observed by the isolated liver of
endotoxin-treated animals after the addition of KIC into
perfusion medium .
The cause of inconsistent alterations in BCAA levels
although their oxidation is remarkably activated are different
influences of individual metabolic changes occurring in the
SIRS. Increased protein breakdown or decreased protein
synthesis in muscles and insulin resistance may enhance the
Holeček Nutrition & Metabolism (2018) 15:33 Page 8 of 12
BCAA levels. Activation of BCAA catabolism associated
with enhanced ALA and GLN production in muscles
and protein synthesis in visceral tissues decrease the
BCAA levels. Therefore, alterations in BCAA levels are
BCAA supplementation in burn, trauma, and sepsis
Rationales for the use of BCAA supplements in conditions
with SIRS are their enhanced oxidation, which may limit
their availability in tissues and their protein anabolic prop-
erties. Benefits of BCAAs may also be related to their role
as a precursor of GLN, which is a key factor in maintaining
immune functions and gut integrity, and has a favorable
influence on protein balance.
Various solutions containing different amounts and
proportions of individual BCAA have been used to exam-
ine their effects in trauma, burn, or sepsis. A number of
investigators have reported that BCAA ameliorate negative
nitrogen balance [100–102]. However, the results of other
investigators have not been impressive, and there is no
scientific consensus regarding the effect BCAA-enriched
formulas on protein balance, length of hospital stay, and
mortality [103–105]. A serious shortcoming of most of the
studies is the lack of information regarding BCAA concen-
trations in blood and tissues, which may be suggested as a
possible criterion of eligibility of the indication.
The low effectiveness of the BCAA in disorders with
the presence of SIRS may be related to insulin resistance
and metabolic alteration associated with inflammation.
Studies have shown that inflammatory response blunts the
anabolic response to BCAA administration. Lang and Frost
 demonstrated that leucine induced activation of
eukaryotic initiation factor eIF4E is abrogated in endotoxin-
treated rats and that endotoxin treatment antagonized the
leucine-induced phosphorylation of ribosomal protein S6
In recent years articles have emerged suggesting positive
effects of BCAA in traumatic brain injury. In rodents,
BCAAs have demonstrated to ameliorate injury-induced
cognitive impairment , and clinical studies have
demonstrated that BCAAs enhance the cognitive recovery
in patients with severe traumatic brain injury [108,109].
BCAA supplementation in cancer
Unlike other states accompanied by SIRS, muscle wasting
and amino acid mobilization from muscles in subjects
with cancer may be driven by secretion of different
tumor-derived mediators. Therefore, progressive depletion
of muscle mass may be observed in some cancer patients.
Also high rates of BCAA oxidation in muscles of subjects
with cancer have been reported . Increasing evidence
demonstrates that BCAAs are essential nutrients for can-
cer growth and are used as a source of energy by tumors.
Expression of the cytosolic type of BCAT has been shown
to correlate with more aggressive cancer growth .
The findings of clinical trials examining the effects of
BCAA-enriched nutritional support to cancer patients are
inconsistent. Some showed improved nitrogen balance and
reduced skeletal muscle catabolism whereas others show
no significant improvement . A concern in the
tumor-bearing state is that provision of the BCAA will
promote tumor growth.
Summary and conclusions
The studies indicate that important role in pathogenesis
of alterations in BCAA metabolism play: (i) skeletal
muscle as initial site of BCAA catabolism accompanied
by the release of GLN, ALA, and BCKA to the blood; (ii)
activity of BCKD in muscles and liver, and (iii) amination
Fig. 6 Main alterations in protein and BCAA metabolism in disorders accompanied by SIRS. AA, amino acids; BCAA, branched-chain amino acids;
BCKA, branched-chain keto acids; GLN, glutamine; SIRS, systemic inflammatory response syndrome; ↑, increase; ↓, decrease
Holeček Nutrition & Metabolism (2018) 15:33 Page 9 of 12
of BCKA to corresponding BCAA, especially by nitrogen
of ALA and GLN released from muscles. Here are exam-
ples of importance of these metabolic steps:
ad (i) Because the muscle is the initial site of BCAA
catabolism, marked rise of BCAA is observed after a
meal while the rise of other amino acids is small. En-
hanced consumption of the BCAA for ammonia de-
toxification to GLN in muscles is the main cause of
the decrease of the BCAA in hyperammonemic con-
ditions (liver cirrhosis, UCD). Increased production of
GLN after BCAA intake in muscles may lead to en-
hanced production of ammonia in enterocytes and
kidneys with deleterious effect in subjects with liver
ad (ii) Decreased BCKD activity is the main cause of
increased BCAA and BCKA levels in MSUD and may
play a role in increased BCAA levels in obesity and type
2 diabetes. Increased BCKD activity is responsible for
the decrease of BCAAs in CRF and enhanced oxidation
of BCAAs during exercise and in various hypermeta-
bolic conditions (burn, sepsis, trauma, cancer).
ad (iii) BCKA amination partially explains the in-
creased BCAA concentrations during brief starvation
and in type 1 diabetes, and is the basis of rationale to
use BCKA-enriched supplements in CRF therapy.
Although amino acid concentrations in the plasma
pool are poor indicators of their requirements, it may
be suggested that under conditions of good understand-
ing of the BCAA metabolism in specific disorder, the
BCAA levels would conceptually be an acceptable argu-
ment for their supplementation. It may be supposed
1. Together with requirements to decrease protein
content in a diet, increased oxidation and low
BCAA levels are a clear rationale to use the BCAA
together with other essential amino acids and their
ketoanalogues in CRF therapy.
2. Although BCAA decrease in blood plasma is a
rationale to use the BCAA supplements in patients
with liver cirrhosis and UCD, therapeutic strategies
are needed to avoid detrimental effects of BCAA
supplementation on ammonia production.
3. Further studies are necessary to conclude the
question of the effects of BCAA supplementation in
burn, trauma, sepsis, cancer, and exercise. A very
small number of clinical studies have reported the
effects of BCAA supplementation in relation to
amino acid concentrations in blood and tissues.
4. Whether increased BCAA levels only markers are
or also contribute to insulin resistance should be
known before the decision is taken regarding their
suitability in obese subjects and patients with type 2
In conclusion, alterations in BCAA metabolism are com-
mon in a number of disease states and the BCAA have
therapeutic potential due to their proven protein anabolic
effects. However, many controversies about the use of
BCAAs in clinical practice still exist, and careful studies
are needed to elucidate the effectiveness of BCAAs in most
KIC: α-ketoisocaproate (ketoleucine); KIV: α-ketoisovalerate (ketovaline);
KMV: α-keto-β-methylvalerate (ketoisoleucine); ALA: Alanine;
BCAA: Branched-chain amino acids; BCAT: Branched-chain-amino-acid
aminotransferase; BCKA: Branched-chain keto acids; BCKD: Branched-chain
α-keto acid dehydrogenase; CRF: Chronic renal failure; GLN: Glutamine;
MSUD: Maple syrup urine disease; SIRS: Systemic inflammatory response
syndrome; TCA cycle: Tricarboxylic acid cycle; UCD: Urea cycle disorders; α-KG,
The author was supported by the program PROGRES Q40/02.
MH performed the literature search and wrote the manuscript. The author
read and approved the final manuscript.
Ethics approval and consent to participate
The author declares that he/she has no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Received: 7 March 2018 Accepted: 18 April 2018
1. Chen L, Chen Y, Wang X, Li H, Zhang H, Gong J, Shen S, Yin W, Hu H.
Efficacy and safety of oral branched-chain amino acid supplementation in
patients undergoing interventions for hepatocellular carcinoma: a meta-
analysis. Nutr J. 2015;14:67.
2. Bifari F, Nisoli E. Branched-chain amino acids differently modulate catabolic
and anabolic states in mammals: a pharmacological point of view. Br J
3. Harper AE, Miller RH, Block KP. Branched-chain amino acid metabolism.
Annu Rev Nutr. 1984;4:409–54.
4. Holecek M. Leucine metabolism in fasted and tumor necrosis factor-treated
rats. Clin Nutr. 1996;15:91–3.
5. Holecek M, Sprongl L, Skopec F, Andrýs C, Pecka M. Leucine metabolism in
TNF-α- and endotoxin-treated rats: contribution of hepatic tissue Am J Phys
6. Swain LM, Shiota T, Walser M. Utilization for protein synthesis of leucine and
valine compared with their keto analogues. Am J Clin Nutr. 1990;51:411–5.
7. Holeček M, Šprongl L, Tichý M, Pecka M. Leucine metabolism in rat liver
after a bolus injection of endotoxin. Metabolism. 1998;47:681–5.
8. Holecek M, Rysava R, Safranek R, Kadlcikova J, Sprongl L. Acute effects of
decreased glutamine supply on protein and amino acid metabolism in hepatic
tissue: a study using isolated perfused rat liver. Metabolism. 2003;52:1062–7.
9. Adibi SA. Influence of dietary deprivations on plasma concentration of free
amino acids of man. J Appl Physiol. 1968;25:52–7.
10. Holeček M, Mičuda S. Amino acid concentrations and protein metabolism
of two types of rat skeletal muscle in postprandial state and after brief
starvation. Physiol Res. 2017;66:959–67.
11. Holecek M. The BCAA-BCKA cycle: its relation to alanine and glutamine
synthesis and protein balance. Nutrition. 2001;17:70.
12. Nair KS, Short KR. Hormonal and signaling role of branched-chain amino
acids. J Nutr. 2005;135:1547S–52S.
Holeček Nutrition & Metabolism (2018) 15:33 Page 10 of 12
13. Floyd JC Jr, Fajans SS, Conn JW, Knopf RF, Rull J. Stimulation of insulin
secretion by amino acids. J Clin Invest. 1966;45:1487–502.
14. Tischler ME, Desautels M, Goldberg AL. Does leucine, leucyl-tRNA, or some
metabolite of leucine regulate protein synthesis and degradation in skeletal
and cardiac muscle? J Biol Chem. 1982;257:1613–21.
15. Mitch WE, Walser M, Sapir DG. Nitrogen sparing induced by leucine
compared with that induced by its keto analogue, alpha-ketoisocaproate, in
fasting obese man. J Clin Invest. 1981;67:553–62.
16. Sapir DG, Stewart PM, Walser M, Moreadith C, Moyer ED, Imbembo AL, et al.
Effects of alpha-ketoisocaproate and of leucine on nitrogen metabolism in
postoperative patients. Lancet. 1983;1(8332):1010–4.
17. Holeček M. Beta-hydroxy-beta-methylbutyrate supplementation and skeletal
muscle in healthy and muscle-wasting conditions. J Cachexia Sarcopenia
18. Fischer JE, Funovics JM, Aguirre A, James JH, Keane JM, Wesdorp RI, et al.
The role of plasma amino acids in hepatic encephalopathy. Surgery. 1975;
19. Pedroso JA, Zampieri TT, Donato J. Reviewing the effects of L-leucine
supplementation in the regulation of food intake, energy balance, and
glucose homeostasis. Nutrients. 2015;7:3914–37.
20. Nishitani S, Takehana K, Fujitani S, Sonaka I. Branched-chain amino acids
improve glucose metabolism in rats with liver cirrhosis. Am J Physiol
Gastrointest Liver Physiol. 2005;288:G1292–300.
21. Zhang S, Zeng X, Ren M, Mao X, Qiao S. Novel metabolic and physiological
functions of branched chain amino acids: a review. J Anim Sci Biotechnol.
22. Um SH, D'Alessio D, Thomas G. Nutrient overload, insulin resistance, and
ribosomal protein S6 kinase 1, S6K1. Cell Metab. 2006;3:393–402.
23. Tremblay F, Lavigne C, Jacques H, Marette A. Role of dietary proteins and
amino acids in the pathogenesis of insulin resistance. Annu Rev Nutr. 2007;
24. White PJ, Lapworth AL, An J, Wang L, McGarrah RW, Stevens RD, et al.
Branched-chain amino acid restriction in Zucker-fatty rats improves muscle
insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-
glycine export. Mol Metab. 2016;5:538–51.
25. Manchester KL. Oxidation of amino acids by isolated rat diaphragm and the
influence of insulin. Biochim Biophys Acta. 1965;100:295–8.
26. Holecek M, Siman P, Vodenicarovova M, Kandar R. Alterations in protein and
amino acid metabolism in rats fed a branched-chain amino acid- or
leucine-enriched diet during postprandial and postabsorptive states. Nutr
Metab (Lond). 2016;13:12.
27. Adibi SA. Metabolism of branched-chain amino acids in altered nutrition.
28. Schauder P, Herbertz L, Langenbeck U. Serum branched chain amino and
keto acid response to fasting in humans. Metabolism. 1985;34:58–61.
29. Fryburg DA, Barrett EJ, Louard RJ, Gelfand RA. Effect of starvation on human
muscle protein metabolism and its response to insulin. Am J Phys. 1990;259:
30. Holecek M, Sprongl L, Tilser I. Metabolism of branched-chain amino acids in
starved rats: the role of hepatic tissue. Physiol Res. 2001;50:25–33.
31. Adibi SA, Peterson JA, Krzysik BA. Modulation of leucine transaminase
activity by dietary means. Am J Phys. 1975;228:432–5.
32. Sketcher RD, Fern EB, James WP. The adaptation in muscle oxidation of
leucine to dietary protein and energy intake. Br J Nutr. 1974;31:333–42.
33. Holecek M. Effect of starvation on branched-chain alpha-keto acid
dehydrogenase activity in rat heart and skeletal muscle. Physiol Res. 2001;
34. Grimble RF, Whitehead RG. Changes in the concentration of specific amino acids
in the serum of experimentally malnourished pigs. Br J Nutr. 1970;24:557–64.
35. Holt LE, Snyderman SE, Norton PM, Roitman E, Finch J. The plasma
aminogram in kwashiorkor. Lancet. 1963;2(7322):1342–8.
36. Reeds PJ. The catabolism of valine in the malnourished rat. Studies in vivo and
in vitro with different labelled forms of valine. Br J Nutr. 1974;31:259–70.
37. Wahren J, Felig P, Hagenfeldt L. Effect of protein ingestion on splanchnic
and leg metabolism in normal man and in patients with diabetes mellitus. J
Clin Invest. 1976;57:987–99.
38. Holecek M, Kovarik M. Alterations in protein metabolism and amino acid
concentrations in rats fed by a high-protein (casein-enriched) diet - effect of
starvation. Food Chem Toxicol. 2011;49:3336–42.
39. Watford M. Lowered concentrations of branched-chain amino acids result in
impaired growth and neurological problems: insights from a branched-
chain alpha-keto acid dehydrogenase complex kinase-deficient mouse
model. Nutr Rev. 2007;65:167–72.
40. Anthony TG, Reiter AK, Anthony JC, Kimball SR, Jefferson LS. Deficiency of
dietary EAA preferentially inhibits mRNA translation of ribosomal proteins in
liver of meal-fed rats. Am J Physiol Endocrinol Metab. 2001;281:E430–9.
41. Blomstrand E. Amino acids and central fatigue. Amino Acids. 2001;20:25–34.
42. Dasarathy S, Hatzoglou M. Hyperammonemia and proteostasis in cirrhosis.
Curr Opin Clin Nutr Metab Care. 2018;21:30–6.
43. Leweling H, Breitkreutz R, Behne F, Staedt U, Striebel JP, Holm E.
Hyperammonemia-induced depletion of glutamate and branched-chain
amino acids in muscle and plasma. J Hepatol. 1996;25:756–62.
44. Holeček M, Šprongl L, Tichý M. Effect of hyperammonemia on leucine and
protein metabolism in rats. Metabolism. 2000;49:1330–4.
45. Holecek M, Kandar R, Sispera L, Kovarik M. Acute hyperammonemia
activates branched-chain amino acid catabolism and decreases their
extracellular concentrations: different sensitivity of red and white muscle.
Amino Acids. 2011;40:575–84.
46. Holeček M, Mráz J, Tilšer I. Plasma amino acids in four models of
experimental liver injury in rats. Amino Acids. 1996;10:229–41.
47. Davis JM, Alderson NL, Welsh RS. Serotonin and central nervous system
fatigue: nutritional considerations. Am J Clin Nutr. 2000;72:573S–8S.
48. Holecek M. Three targets of branched-chain amino acid supplementation in
the treatment of liver disease. Nutrition. 2010;26:482–90.
49. Holecek M, Simek J, Palicka V, Zadák Z. Effect of glucose and branched chain
amino acid (BCAA) infusion on onset of liver regeneration and plasma amino
acid pattern in partially hepatectomized rats. J Hepatol. 1991;13:14–20.
50. Als-Nielsen B, Koretz RL, Kjaergard LL, Gluud C. Branched-chain amino acids
for hepatic encephalopathy. Cochrane Database Syst Rev. 2003;2:CD001939.
51. Gluud LL, Dam G, Les I, Córdoba J, Marchesini G, Borre M, et al. Branched-
chain amino acids for people with hepatic encephalopathy. Cochrane
Database Syst Rev. 2015;9:CD001939.
52. Holeček M. Branched-chain amino acid supplementation in treatment of
liver cirrhosis: updated views on how to attenuate their harmful effects on
cataplerosis and ammonia formation. Nutrition. 2017;41:80–5.
53. Rodney S, Boneh A. Amino acid profiles in patients with urea cycle disorders at
admission to hospital due to metabolic decompensation. JIMD Rep. 2013;9:97–104.
54. Holecek M. Evidence of a vicious cycle in glutamine synthesis and
breakdown in pathogenesis of hepatic encephalopathy-therapeutic
perspectives. Metab Brain Dis. 2014;29:9–17.
55. Holecek M, Vodenicarovova M, Siman P. Acute effects of phenylbutyrate on
glutamine, branched-chain amino acid and protein metabolism in skeletal
muscles of rats. Int J Exp Pathol. 2017;98:127–33.
56. Brunetti-Pierri N, Lanpher B, Erez A, Ananieva EA, Islam M, Marini JC, et al.
Phenylbutyrate therapy for maple syrup urine disease. Hum Mol Genet.
57. Scaglia F, Carter S, O'Brien WE, Lee B. Effect of alternative pathway therapy
on branched chain amino acid metabolism in urea cycle disorder patients.
Mol Genet Metab. 2004;81:S79–85.
58. Adam S, Almeida MF, Assoun M, Baruteau J, Bernabei SM, Bigot S, et al.
Dietary management of urea cycle disorders: European practice. Mol Genet
59. Schauder P, Matthaei D, Henning HV, Scheler F, Langenbeck U. Blood levels of
branched-chain amino acids and alpha-ketoacids in uremic patients given keto
analogues of essential amino acids. Am J Clin Nutr. 1980;33:1660–6.
60. Garibotto G, Paoletti E, Fiorini F, Russo R, Robaudo C, Deferrari G, Tizianello
A. Peripheral metabolism of branched-chain keto acids in patients with
chronic renal failure. Miner Electrolyte Metab. 1993;19:25–31.
61. Holecek M, Sprongl L, Tilser I, Tichý M. Leucine and protein metabolism in
rats with chronic renal insufficiency. Exp Toxicol Pathol. 2001;53:71–6.
62. Alvestrand A, Fürst P, Bergström J. Plasma and muscle free amino acids in
uremia: influence of nutrition with amino acids. Clin Nephrol. 1982;18:297–305.
63. Hara Y, May RC, Kelly RA, Mitch WE. Acidosis, not azotemia, stimulates
branched-chain, amino acid catabolism in uremic rats. Kidney Int. 1987;32:
64. May RC, Masud T, Logue B, Bailey J, England BK. Metabolic acidosis accelerates
whole body protein degradation and leucine oxidation by a glucocorticoid-
dependent mechanism. Miner Electrolyte Metab. 1992;18:245–9.
65. Teplan V, Schück O, Horácková M, Skibová J, Holecek M. Effect of a keto
acid-amino acid supplement on the metabolism and renal elimination of
branched-chain amino acids in patients with chronic renal insufficiency on
a low protein diet. Wien Klin Wochenschr. 2000;112:876–81.
Holeček Nutrition & Metabolism (2018) 15:33 Page 11 of 12
66. Kovesdy CP, Kopple JD, Kalantar-Zadeh K. Management of protein-energy
wasting in non-dialysis-dependent chronic kidney disease: reconciling low
protein intake with nutritional therapy. Am J Clin Nutr. 2013;97:1163–77.
67. Ivy JH, Svec M, Freeman S. Free plasma levels and urinary excretion of eighteen
amino acids in normal and diabetic dogs. Am J Phys. 1951;167:182–92.
68. Borghi L, Lugari R, Montanari A, Dall'Argine P, Elia GF, Nicolotti V, et al.
Plasma and skeletal muscle free amino acids in type I, insulin-treated
diabetic subjects. Diabetes. 1985;34:812–5.
69. Rodríguez T, Alvarez B, Busquets S, Carbó N, López-Soriano FJ, Argilés JM.
The increased skeletal muscle protein turnover of the streptozotocin
diabetic rat is associated with high concentrations of branched-chain amino
acids. Biochem Mol Med. 1997;61:87–94.
70. Jensen-Waern M, Andersson M, Kruse R, Nilsson B, Larsson R, Korsgren O,
Essén-Gustavsson B. Effects of streptozotocin-induced diabetes in domestic
pigs with focus on the amino acid metabolism. Lab Anim. 2009;43:249–54.
71. Hutson SM, Harper AE. Blood and tissue branched-chain amino and alpha-
keto acid concentrations: effect of diet, starvation, and disease. Am J Clin
72. Gibson R, Zhao Y, Jaskiewicz J, Fineberg SE, Harris RA. Effects of diabetes on
the activity and content of the branched-chain alpha-ketoacid
dehydrogenase complex in liver. Arch Biochem Biophys. 1993;306:22–8.
73. Aftring RP, Miller WJ, Buse MG. Effects of diabetes and starvation on skeletal
muscle branched-chain alpha-keto acid dehydrogenase activity. Am J Phys.
74. Felig P, Wahren J, Sherwin R, Palaiologos G. Amino acid and protein
metabolism in diabetes mellitus. Arch Intern Med. 1977;137:507–13.
75. Carlsten A, Hallgren B, Jagenburg R, Svanborg A, Werkö L. Amino acids and
free fatty acids in plasma in diabetes. I. The effect of insulin on the arterial
levels. Acta Med Scand. 1966;179:361–70.
76. She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related
elevations in plasma leucine are associated with alterations in enzymes
involved in branched-chain amino acid metabolism. Am J Physiol
Endocrinol Metab. 2007;293:E1552–63.
77. Kuzuya T, Katano Y, Nakano I, Hirooka Y, Itoh A, Ishigami M, et al. Regulation
of branched-chain amino acid catabolism in rat models for spontaneous
type 2 diabetes mellitus. Biochem Biophys Res Commun. 2008;373:94–8.
78. Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, et al. Metabolite
profiles and the risk of developing diabetes. Nat Med. 2011;17:448–53.
79. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, et al. A
branched-chain amino acid-related metabolic signature that differentiates
obese and lean humans and contributes to insulin resistance. Cell Metab.
80. Macotela Y, Emanuelli B, Bång AM, Espinoza DO, Boucher J, Beebe K, et al.
Dietary leucine - an environmental modifier of insulin resistance acting on
multiple levels of metabolism. PLoS One. 2011;6:e21187.
81. Hinault C, Mothe-Satney I, Gautier N, Lawrence JC Jr, Van Obberghen E.
Amino acids and leucine allow insulin activation of the PKB/mTOR pathway
in normal adipocytes treated with wortmannin and in adipocytes from db/
db mice. FASEB J. 2004;18:1894–6.
82. Arakawa M, Masaki T, Nishimura J, Seike M, Yoshimatsu H. The effects of
branched-chain amino acid granules on the accumulation of tissue
triglycerides and uncoupling proteins in diet-induced obese mice. Endocr J.
83. Scaini G, Jeremias IC, Morais MO, Borges GD, Munhoz BP, Leffa DD, et al.
DNA damage in an animal model of maple syrup urine disease. Mol Genet
84. Kasperek GJ, Dohm GL, Snider RD. Activation of branched-chain keto acid
dehydrogenase by exercise. Am J Phys. 1985;248:R166–71.
85. dos Santos RV, Caperuto EC, de Mello MT, Batista ML Jr, Rosa LF. Effect of
exercise on glutamine synthesis and transport in skeletal muscle from rats.
Clin Exp Pharmacol Physiol. 2009;36:770–5.
86. Shimomura Y, Fujii H, Suzuki M, Murakami T, Fujitsuka N, Nakai N. Branched-
chain alpha-keto acid dehydrogenase complex in rat skeletal muscle:
regulation of the activity and gene expression by nutrition and physical
exercise. J Nutr. 1995;125:1762S–5S.
87. Poortmans JR, Siest G, Galteau MM, Houot O. Distribution of plasma amino
acids in humans during submaximal prolonged exercise. Eur J Appl Physiol
Occup Physiol. 1974;32:143–7.
88. Refsum HE, Gjessing LR, Strømme SB. Changes in plasma amino acid
distribution and urine amino acids excretion during prolonged heavy
exercise. Scand J Clin Lab Invest. 1979;39:407–13.
89. Ahlborg G, Felig P, Hagenfeldt L, Hendler R, Wahren J. Substrate turnover
during prolonged exercise in man. Splanchnic and leg metabolism of
glucose, free fatty acids, and amino acids. J Clin Invest. 1974;53:1080–90.
90. Shimomura Y, Murakami T, Nakai N, Nagasaki M, Harris RA. Exercise
promotes BCAA catabolism: effects of BCAA supplementation on skeletal
muscle during exercise. J Nutr. 2004;134:1583S–7S.
91. Spillane M, Emerson C, Willoughby DS. The effects of 8 weeks of heavy
resistance training and branched-chain amino acid supplementation on
body composition and muscle performance. Nutr Health. 2012;21:263–73.
92. Watson P, Shirreffs SM, Maughan RJ. The effect of acute branched-chain
amino acid supplementation on prolonged exercise capacity in a warm
environment. Eur J Appl Physiol. 2004;93:306–14.
93. Falavigna G, de Araújo AJ, Rogero MM, Pires IS, Pedrosa RG, Martins E, et al.
Effects of diets supplemented with branched-chain amino acids on the
performance and fatigue mechanisms of rats submitted to prolonged
physical exercise. Nutrients. 2012;4:1767–80.
94. Nawabi MD, Block KP, Chakrabarti MC, Buse MG. Administration of endotoxin,
tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle
branched-chain α-keto acid dehydrogenase. J Clin Invest. 1990;85:256–63.
95. Fürst P, Albers S, Stehle P. Stress-induced intracellular glutamine depletion.
The potential use of glutamine-containing peptides in parenteral nutrition.
Beitr Infusionther Klin Ernahr. 1987;17:117–36.
96. Hardy G, Hardy IJ. Can glutamine enable the critically ill to cope better with
infection? JPEN J Parenter Enteral Nutr. 2008;32:489–91.
97. Holecek M, Sispera L. Glutamine deficiency in extracellular fluid exerts
adverse effects on protein and amino acid metabolism in skeletal muscle of
healthy, laparotomized, and septic rats. Amino Acids. 2014;46:1377–84.
98. Hasselgren PO, Pedersen P, Sax HC, Warner BW, Fischer JE. Current concepts
of protein turnover and amino acid transport in liver and skeletal muscle
during sepsis. Arch Surg. 1988;123:992–9.
99. Gardiner K, Barbul A. Intestinal amino acid absorption during sepsis. JPEN J
Parenter Enteral Nutr. 1993;17:277–83.
100. Bower RH, Kern KA, Fischer JE. Use of a branched chain amino acid enriched
solution in patients under metabolic stress. Am J Surg. 1985;149:266–70.
101. Oki JC, Cuddy PG. Branched-chain amino acid support of stressed patients.
102. Jiménez Jiménez FJ, Ortiz Leyba C, Morales Ménedez S, Barros Pérez M,
Muñoz GJ. Prospective study on the efficacy of branched-chain amino acids
in septic patients. J Parenter Enter Nutr. 1991;15:252–61.
103. De Bandt JP, Cynober L. Therapeutic use of branched-chain amino acids in
burn, trauma, and sepsis. J Nutr. 2006;136:308S–13S.
104. Platell C, Kong SE, McCauley R, Hall JC. Branched-chain amino acids. J
Gastroenterol Hepatol. 2000;15:706–17.
105. Mattick JSA, Kamisoglu K, Ierapetritou MG, Androulakis IP, Berthiaume F.
Branched-chain amino acid supplementation: impact on signaling and
relevance to critical illness. Wiley Interdiscip Rev Syst Biol Med. 2013;5:449–60.
106. Lang CH, Frost RA. Endotoxin disrupts the leucine-signaling pathway
involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle. J
Cell Physiol. 2005;203:144–55.
107. Cole JT, Mitala CM, Kundu S, Verma A, Elkind JA, Nissim I, Cohen AS. Dietary
branched chain amino acids ameliorate injury-induced cognitive
impairment. Proc Natl Acad Sci U S A. 2010;107:366–71.
108. Jeter CB, Hergenroeder GW, Ward NH, Moore AN, Dash PK. Human mild
traumatic brain injury decreases circulating branched-chain amino acids and
their metabolite levels. J Neurotrauma. 2013;30:671–9.
109. Aquilani R, Iadarola P, Contardi A, Boselli M, Verri M, Pastoris O, et al.
Branched-chain amino acids enhance the cognitive recovery of patients
with severe traumatic brain injury. Arch Phys Med Rehabil. 2005;86:1729–35.
110. Baracos VE, Mackenzie ML. Investigations of branched-chain amino acids and
their metabolites in animal models of cancer. J Nutr. 2006;136:237S–42S.
111. Ananieva EA, Wilkinson AC. Branched-chain amino acid metabolism in
cancer. Curr Opin Clin Nutr Metab Care. 2018;21:64–70.
112. Choudry HA, Pan M, Karinch AM, Souba WW. Branched-chain amino
acid-enriched nutritional support in surgical and cancer patients. J Nutr.
Holeček Nutrition & Metabolism (2018) 15:33 Page 12 of 12
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at