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Branched-chain amino acids in health and disease: Metabolism, alterations in blood plasma, and as supplements

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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 type 2 diabetes. 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.
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R E V I E W Open Access
Branched-chain amino acids in health and
disease: metabolism, alterations in blood
plasma, and as supplements
Milan Holeček
Abstract
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
type2diabetes.
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
Background
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
specific BCAAs.
Correspondence: holecek@lfhk.cuni.cz
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
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BCAA metabolism
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 [3]. 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
[3]. The remarkable rise in BCKD activity in muscles in-
duces endotoxin or tumor necrosis factor alpha (TNF-α)
administration [4,5].
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
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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
wasprovidedbystudiesusinglabelledBCKAshowing
the labelled BCAA in proteins [6]. The main sources of
nitrogen for amination of the BCKA are GLN, glutam-
ate, and ALA [3].
The studies demonstrate that BCAA synthesis from
the BCKA is activated in various muscle wasting dis-
orders,e.g.sepsis,trauma,orsurgery,inwhichthe
muscles release high amounts of GLN and ALA to
the blood [711]. A marked increase in leucine
release was observed by the isolated liver of
endotoxin-treated animals after addition of KIC into
perfusion medium [7]; 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 [8]. 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
conditions [11].
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 [11]. ALA, alanine; BCAA, branched-chain amino acids; BCKA,
branched-chain keto acids. GLU, glutamate; GLN, glutamine; PYR, pyruvate; α-KG, α-ketoglutarate
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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 [12].
A role in protein anabolic effect of leucine plays also its
stimulatory effect on insulin secretion [13]. 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 [14].
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 [17].
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
BCAAsandAAAsmayinfluencesynthesisofsome
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 [18]. 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
maydecreasebodyadiposity[19].
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 [24]. Further investi-
gation is needed to understand variable reports ranging
from improving glucose utilization to inducing insulin
resistance.
Effects mediated by ALA and GLN
The rate of BCAA degradation in skeletal muscle is highly
responsive to their availability [25]. 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
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BCKAs, ALA, and GLN in peripheral circulation [26].
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
shock proteins.
Other effects
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
reported [21].
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.
Starvation
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 [26].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 [8]. A role in
theincreaseofBCAAsmayhavealsotheirdecreased
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
blood.
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 [33].
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 [35].
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 [36].
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 [38].
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
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liver cirrhosis, urea cycle disorders, and chronic renal
insufficiency.
Liver cirrhosis
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 [45]. 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 [46].
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 [20,4749].
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
[52]. 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 [52].
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
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GLN and a decline in BCAA levels, notably during acute
metabolic decompensation [53]. 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
cirrhosis [45,54].
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. [57].
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 [58].
Chronic renal failure (CRF)
Most studies of amino acid patterns in CRF reported
decreased BCAA and BCKA levels in the blood plasma
[5961] 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 [61].
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 [67]. Further studies have shown that in addition
to the increase of BCAAs, there is a decrease in levels of
gluconeogenic amino acids, especially ALA [6870]. 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 [71]. 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 [72].
However, unlike brief starvation, the changes in diabetes
are associated with marked increase in proteolysis and
BCKD activity in muscles, resulting in severe cachexia
[73]. 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
diabetes [74].
Obesity and type 2 diabetes
Plasma concentrations of BCAAs are frequently elevated
in obesity and type 2 diabetes [7577]. 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 [24].
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BCAA supplementation
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 [80] and rescued insulin
signaling in adipose tissue obtained from insulin resistant
db/db mice [81]. Arakawa et al. [82] reported that BCAAs
reduced hepatic and triglyceride concentrations in mice
fed a high-fat diet. On the other hand, Newgard et al. [79]
showed that administration of a mixture of BCAA to rats
on a high-fat diet increased insulin resistance. White et al.
[24] 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 supplementation
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 [83]. 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
2
)
for one day [56]. Long-term studies in different MSUD
phenotypes are indicated to verify phenylbutyrate efficacy.
Conditions with enhanced BCAA catabolism and
inconsistent alterations in BCAA levels
Exercise
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 [86]. The plasma BCAA levels during or
after exercise have been reported to be unchanged [87],
to decrease [88], or to increase [89]. 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 [90].
Inadditiontothepositivereports,thereareanumberof
reports showing no benefits of BCAA supplementation
[91]. 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 [97]. 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 [7].
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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
inconsistent.
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 [100102]. 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 [103105]. 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
[106] 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
and mTOR.
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 [107], 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 [110]. 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 [111].
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 [112]. 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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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
disease.
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
that:
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
diabetes.
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
indications.
Abbreviations
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,
α-ketoglutarate
Funding
The author was supported by the program PROGRES Q40/02.
Authorscontributions
MH performed the literature search and wrote the manuscript. The author
read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Competing interests
The author declares that he/she has no competing interests.
PublishersNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Received: 7 March 2018 Accepted: 18 April 2018
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... Branched-chain amino acids-valine, leucine, and isoleucine-are essential amino acids that promote protein anabolism and reduce the severity of cachexia, prevent (or treat) hepatic encephalopathy, promote wound healing, and stimulate insulin production [48]. In addition, leucine also functions as a signaling molecule to stimulate protein synthesis [49]. ...
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... Finally, branched-chain AAs (Leu, Ile, and Val) are essential for protein synthesis and energy metabolism. Under postoperative stress, shifts in the metabolism of these AAs likely reflect the body's adaptation to surgical trauma and its increased metabolic demands during recovery [24]. ...
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... Beyond that, a similar trend was also observed in Ala and Tyr levels. Branched-chain amino acids (BCAAs) are essential amino acids whose catabolism, conversely to most others, does not take place in the liver due to low hepatic activity of branched-chain-aminoacid aminotransferase (BCAT), the first enzyme involved in their catabolic pathway, but in skeletal muscle [28]. BCAAs are principally involved in protein synthesis as well as energy production in addition to performing several important metabolic and signaling functions. ...
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Beta‐hydroxy‐beta‐methylbutyrate (HMB) is a metabolite of the essential amino acid leucine that has been reported to have anabolic effects on protein metabolism. The aims of this article were to summarize the results of studies of the effects of HMB on skeletal muscle and to examine the evidence for the rationale to use HMB as a nutritional supplement to exert beneficial effects on muscle mass and function in various conditions of health and disease. The data presented here indicate that the beneficial effects of HMB have been well characterized in strength‐power and endurance exercise. HMB attenuates exercise‐induced muscle damage and enhances muscle hypertrophy and strength, aerobic performance, resistance to fatigue, and regenerative capacity. HMB is particularly effective in untrained individuals who are exposed to strenuous exercise and in trained individuals who are exposed to periods of high physical stress. The low effectiveness of HMB in strength‐trained athletes could be due to the suppression of the proteolysis that is induced by the adaptation to training, which may blunt the effects of HMB. Studies performed with older people have demonstrated that HMB can attenuate the development of sarcopenia in elderly subjects and that the optimal effects of HMB on muscle growth and strength occur when it is combined with exercise. Studies performed under in vitro conditions and in various animal models suggest that HMB may be effective in treatment of muscle wasting in various forms of cachexia. However, there are few clinical reports of the effects of HMB on muscle wasting in cachexia; in addition, most of these studies evaluated the therapeutic potential of combinations of various agents. Therefore, it has not been possible to determine whether HMB was effective or if there was a synergistic effect. Although most of the endogenous HMB is produced in the liver, there are no reports regarding the levels and the effects of HMB supplementation in subjects with liver disease. Several studies have suggested that anabolic effects of HMB supplementation on skeletal muscle do not occur in healthy, non‐exercising subjects. It is concluded that (i) HMB may be applied to enhance increases in the mass and strength of skeletal muscles in subjects who exercise and in the elderly and (ii) studies examining the effects of HMB administered alone are needed to obtain conclusions regarding the specific effectiveness in attenuating muscle wasting in various muscle‐wasting disorders.
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It is widely known that branched chain amino acids (BCAA) are not only elementary components for building muscle tissue but also participate in increasing protein synthesis in animals and humans. BCAA (isoleucine, leucine and valine) regulate many key signaling pathways, the most classic of which is the activation of the mTOR signaling pathway. This signaling pathway connects many diverse physiological and metabolic roles. Recent years have witnessed many striking developments in determining the novel functions of BCAA including: (1) Insufficient or excessive levels of BCAA in the diet enhances lipolysis. (2) BCAA, especially isoleucine, play a major role in enhancing glucose consumption and utilization by up-regulating intestinal and muscular glucose transporters. (3) Supplementation of leucine in the diet enhances meat quality in finishing pigs. (4) BCAA are beneficial for mammary health, milk quality and embryo growth. (5) BCAA enhance intestinal development, intestinal amino acid transportation and mucin production. (6) BCAA participate in up-regulating innate and adaptive immune responses. In addition, abnormally elevated BCAA levels in the blood (decreased BCAA catabolism) are a good biomarker for the early detection of obesity, diabetes and other metabolic diseases. This review will provide some insights into these novel metabolic and physiological functions of BCAA.
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Insulin-dependent diabetes mellitus (IDDM) induces plasma amino acid (AA) abnormalities, including low alanine and high branched-chain (BCAA). While insulin treatment restores plasma AA pattern, proline, methionine, valine, isoleucine, and total BCAA remain elevated in skeletal muscle intracellular water. This suggests that the restoration of plasma AA concentrations is not a satisfactory index of recovered AA metabolism in IDDM.
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Purpose of review: Skeletal muscle loss or sarcopenia is a frequent complication of cirrhosis that adversely affects clinical outcomes. As skeletal muscle is the largest store of proteins in the body, proteostasis or protein homeostasis is required for maintenance of muscle mass. This review will focus on disordered skeletal muscle proteostasis in liver disease. Recent findings: Increased skeletal muscle uptake of ammonia initiates responses that result in disordered proteostasis including impaired protein synthesis and increased autophagy. The cellular response to the stress of hyperammonemia (hyperammonemic stress response, HASR) involves the coordinated action of diverse signaling pathways targeting the molecular mechanisms of regulation of protein synthesis. Transcriptional upregulation of myostatin, a TGFβ superfamily member, results in impaired mTORC1 signaling. Phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) also relates to decreased global protein synthesis rates and mTORC1 signaling. Ammonia also causes mitochondrial and bioenergetic dysfunction because of cataplerosis of α-ketoglutarate. Lowering ammonia, targeting components of HASR and regulating cellular amino acid levels can potentially restore proteostasis. Summary: Signaling via myostatin and eIF2α phosphorylation causes decreases in protein synthesis and mTORC1 activity with a parallel mitochondrial dysfunction and increased autophagy contributing to proteostasis perturbations during skeletal muscle hyperammonemia of liver disease.
Article
We have investigated amino acid concentrations and protein metabolism in musculus extensor digitorum longus (EDL, fast-twitch, white muscle) and musculus soleus (SOL, slow-twitch, red muscle) of rats sacrificed in the fed state or after one day of starvation. Fractional protein synthesis rates (FRPS) were measured using the flooding dose method (L-[3,4,5-3H]phenylalanine). Activities of two major proteolytic systems in muscle (the ubiquitin-proteasome and lysosomal) were examined by measurement of chymotrypsin like activity of proteasome (CTLA), expression of ubiquitin ligases atrogin-1 and muscle-ring-finger-1 (MuRF-1), and cathepsin B and L activities. Intramuscular concentrations of the most of non-essential amino acids, FRPS, CTLA and cathepsin B and L activities were in postprandial state higher in SOL when compared with EDL. The differences in atrogin-1 and MuRF-1 expression were insignificant. Starvation decreased concentrations of a number of amino acids and increased concentrations of valine, leucine, and isoleucine in blood plasma. Starvation also decreased intramuscular concentrations of a number of amino acids differently in EDL and SOL, decreased protein synthesis (by 31 % in SOL and 47 % in EDL), and increased expression of atrogin-1 and MuRF-1 in EDL. The effect of starvation on CTLA and cathepsin B and L activities was insignificant. It is concluded that slow-twitch (red) muscles have higher rates of protein turnover and may adapt better to brief starvation when compared to fast-twitch (white) muscles. This phenomenon may play a role in more pronounced atrophy of white muscles in aging and muscle wasting disorders.
Article
Phenylbutyrate (PB) acts as chemical chaperone and histone deacetylase inhibitor, which is used to decrease ammonia in urea cycle disorders and has been investigated for use in the treatment of a number of lethal illnesses. We performed in vivo and in vitro experiments to examine the effects of PB on glutamine (GLN), branched-chain amino acid (BCAA; valine, leucine and isoleucine) and protein metabolism in rats. In the first study, animals were sacrificed one hour after three injections of PB (300mg/kg b.w.) or saline. In the second study, soleus (SOL, slow twitch) and extensor digitorum longus (EDL, fast twitch) muscles were incubated in a medium with or without PB (5 mM). L-[1-(14) C] leucine was used to estimate protein synthesis and leucine oxidation, and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. PB treatment decreased GLN, BCAA and branched-chain keto acids (BCKAs) in blood plasma, decreased BCAA and increased GLN concentrations in muscles, and increased GLN synthetase activities in muscles. Addition of PB to incubation medium increased leucine oxidation (55% in EDL, 29% in SOL), decreased BCKA and increased GLN in medium of both muscles, increased GLN in muscles, decreased protein synthesis in SOL and increased proteolysis in EDL. It is concluded that PB decreases BCAA, BCKA and GLN in blood plasma, activates BCAA catabolism and GLN synthesis in muscle and exerts adverse effects on protein metabolism. The results indicate that BCAA and GLN supplementation is needed when PB is used therapeutically and that PB may be a useful prospective agent which could be effective in management of maple syrup urine disease.
Article
The main rationale for branched-chain amino acid (BCAA; valine, leucine, and isoleucine) supplementation to patients with liver cirrhosis are their decreased levels in blood plasma, which play a role in pathogenesis of hepatic encephalopathy and cachexia, and their unique pharmacologic properties. In the article is shown that the BCAA provides nitrogen to alpha-ketoglutarate (α-KG) for synthesis of glutamate, which is a substrate for ammonia detoxification to glutamine (GLN) in the brain and muscles, and that the favourable effects of the BCAA supplementation might be associated with three adverse effects: (i) the draining of α-KG from tricarboxylic acid cycle (cataplerosis), (ii) increased GLN content and altered glutamatergic neurotransmission in the brain, and (iii) activated GLN catabolism to ammonia in the gut and kidneys. Cataplerosis of α-KG can be attenuated by dimethyl-α-ketoglutarate, L-ornithine-L-aspartate, and ornithine salt of α-KG. Examined should be pros and cons of GLN elimination from the body using phenylbutyrate (phenylacetate), which may impair liver regeneration and decrease the BCAA levels. Therapeutic potential of the BCAA might be enhanced also by optimizing the BCAA supplementation protocol. It is concluded that search for strategies attenuating adverse and increasing positive effects of the BCAA is needed to include the BCAA among standard medications for liver cirrhosis.