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Annual Review of Physiology

Branched Chain Amino Acids
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Michael Neinast,* Danielle Murashige,*

and Zoltan Arany
Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, USA; email: zarany@pennmedicine.upenn.edu

Annu. Rev. Physiol. 2019. 81:139–64 Keywords

First published as a Review in Advance on
branched chain amino acids, catabolism, diabetes, cancer, heart disease
November 28, 2018

The Annual Review of Physiology is online at Abstract

physiol.annualreviews.org
Branched chain amino acids (BCAAs) are building blocks for all life-forms.
https://doi.org/10.1146/annurev-physiol-020518-
We review here the fundamentals of BCAA metabolism in mammalian
114455
physiology. Decades of studies have elicited a deep understanding of bio-
Copyright © 2019 by Annual Reviews.
chemical reactions involved in BCAA catabolism. In addition, BCAAs and
All rights reserved
various catabolic products act as signaling molecules, activating programs
*These authors contributed equally to this article.
ranging from protein synthesis to insulin secretion. How these processes are
integrated at an organismal level is less clear. Inborn errors of metabolism
highlight the importance of organismal regulation of BCAA physiology.
More recently, subtle alterations of BCAA metabolism have been suggested
to contribute to numerous prevalent diseases, including diabetes, cancer,
and heart failure. Understanding the mechanisms underlying altered BCAA
metabolism and how they contribute to disease pathophysiology will keep
researchers busy for the foreseeable future.

139
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THE BIOCHEMISTRY OF BRANCHED CHAIN AMINO ACIDS

Branched chain amino acids (BCAAs) cannot be synthesized by metazoans. Despite this, they
are abundant components of animals, constituting approximately 35% of essential amino acids
in most mammals (1–3). The functional R groups of all three BCAAs are branched (hence their
name), small, and hydrophobic, rendering them critical components of most protein (4, 5). To-
gether, BCAAs account for about 18% of amino acids and 63% of hydrophobic amino acids in
protein across many life-forms (1–3, 6). The molar relative abundance of BCAAs to each other
is nearly always approximately 1.6:2.2:1.0 Val:Leu:Ile, reflecting the linked nature of their syn-
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thesis and oxidation (see below). The three BCAAs are thus almost always eaten and combusted
together (7, 8), and as such are also almost always studied as one entity, despite significant dif-
ferences in their biological effects as outlined below. This tendency has often led to erroneous
assumptions.

Synthesis
BCAAs are synthesized in bacteria, plants, and fungi, but not in animals. The synthesis of valine
and isoleucine is carried out by the same enzymes, and leucine is created from α-ketoisovalerate, a
transamination precursor of valine (Figure 1) (9). The carbons in valine (and leucine) are derived
from the readily available and abundant pyruvate, but isoleucine carbons are derived from the
relatively rare threonine, again reflecting the conserved ratio of abundance in protein. Because
it does not occur in animals, BCAA synthesis has been successfully targeted for antimicrobials,
herbicides, and antifungal agents (10).

Catabolism
All life-forms catabolize BCAAs in a similarly linked process (Figure 1). In mammals, all
three BCAAs are initially transaminated by branched chain amino transferases (BCATs) to
form branched chain α-ketoacids (BCKAs) (11). The most common nitrogen acceptor is α-
ketoglutarate (αKG), yielding glutamate (12). This reaction is rapid with a low free energy change
and is thus likely in equilibrium in most cases. There is, however, a preference for the reverse re-
action because (a) the Km for BCKAs is in the 100-μM range, while that for BCAAs is in the
1-mM range (somewhat higher for valine) (12, 13); and (b) the concentration of intracellular glu-
tamate is typically relatively high (14). Two genes encode BCATs: BCAT1 (or cBCAT) encodes a
cytoplasmic protein and is primarily expressed in the brain, whereas BCAT2 (or mBCAT) encodes
a mitochondrial protein and is ubiquitously expressed (12, 15).
Irreversible initiation of BCKA oxidation occurs in the branched chain amino acid dehydro-
genase (BCKDH) complex. The BCKDH complex is found on the inner surface of the inner
membrane of mitochondria and shares many attributes with the pyruvate dehydrogenase (PDH)
complex (16, 17). Like the PDH complex, BCKDH catalyzes an oxidative decarboxylation, re-
leasing CO2 and covalently adding a coenzyme A (CoA) group to the oxidized BCKA product
(18). CoA, a bulky and hydrophilic prosthetic moiety, traps all subsequent intermediates inside
the mitochondria with one exemption: 3-hydroxyisobutyrate (3-HIB) in the valine catabolic path-
way. The BCKDH complex has three components (19, 20): a thiamin-dependent decarboxylase,
existing as an alpha2/beta2 heterotetramer (21), encoded by the BCKDHA and BCKDHB genes,
respectively; a lipoate-dependent dihydrolipoyl transacylase that transfers the acyl groups to CoA,
encoded by the DBT gene; and a FAD-dependent dihydrolipoyl dehydrogenase that transfers the
released electrons to NAD+ and is encoded by the DLD gene (18). DLD also participates in other

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a Synthesis
Threonine α-ketobutyrate Pyruvate
+ +
pyruvate Pyruvate
AHAS

2(S)-aceto-2-hydroxybutyrate 2(S)-acetolactate

KARI

2,3-dihydroxy-3-methylvalerate 2,3-dihydroxyisovalerate
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IMPI
DHAD 2-isopropylmalate 3-isopropylmalate

IPMS IPMDH
α-KMV α-KIV α-KIC

BCAT

Isoleucine Valine Leucine

b Oxidation
N-acyl-leucine N-acyl-isoleucine N-acyl-valine

Leucine Isoleucine Valine

α-ketoglutarate

BCAT
Glutamate
α-hydroxy-3-methylvalerate,
α-hydroxyisocaproate L-alloisoleucine? α-hydroxyisovalerate BCKDK PP2Cm

α-KIC α-KMV α-KIV

PPP
CoA E1
BCKDH
E2
CO2 C5 acylcarnitine, BCFA BCFA
E3
Isovaleryl-CoA α-methylbutyryl-CoA Isobutyryl-CoA
IVD ACADSB ACAD8
β-hydroxy- β-methylcrotonyl-CoA Tiglyl-CoA Methylacrylyl-CoA
β-methylbutyrate
MCCC HADHA HADHA
β-methylglutaconyl-CoA α-methyl-β-hydroxybutyryl-CoA β-hydroxyisobutyryl-CoA
AUH HSD17B0 HIBCH
CoA
β-hydroxy-β-methylglutaryl-CoA α-methylacetoacetyl-CoA β-hydroxyisobutyrate
C3 acylcarnitine HIBADH
HMGCL ACAT1 OCFA BAIBA
Methylmalonate-
semialdehyde
Acetoacetate CoA
ALDH6A1
Propionyl-CoA
Acetyl-CoA CO2
OXCT1
PCCB
Succinyl-CoA Methylmalonyl-CoA
TCA MUT

(Caption appears on following page)

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Figure 1 (Figure appears on preceding page)

BCAA synthesis and catabolism. Synthesis (a) occurs in plants, bacteria, and fungi. Oxidation (b) occurs in plants, bacteria, fungi, and
animals. All three BCAAs share the BCAT and BCKDH steps, after which catabolism of each BCAA is unique. The BCKDH complex
is composed of a core of 24 E2 subunits, which are docked by E1 heterotetamers and E3 dimers. BCKDK inhibits E1 via
phosphorylation, which is reversed by PP2Cm. Abbreviations: ACAD8, acyl-CoA dehydrogenase family member 8; ACADSB,
short/branched chain acyl-CoA dehydrogenase; ACAT1, acetyl-CoA acetyltransferase 1; AHAS, acetohydroxyacid synthase; α-KIC,
α-ketoisocaproic acid; α-KIV, α-ketoisovaleric acid; α-KMV, α-ketomethylvaleric acid; ALDH6A1, aldehyde dehydrogenase 6 family
member A1; AUH, AU RNA-binding protein/enoyl-coenzyme A hydratase; BAIBA, beta-amino-isobutyric acid; BCAA, branched
chain amino acid; BCAT, branched chain amino transferase; BCFA, branched chain fatty acid; BCKDH, branched chain amino acid
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dehydrogenase; BCKDK, BCKDH kinase; CoA, coenzyme A; DHAD, dihydroxyacid dehydratase; HADHA, hydroxyacyl-CoA
dehydrogenase subunit alpha; HIBADH, 3-hydroxyisobutyrate dehydrogenase; HIBCH, 3-hydroxyisobutyryl-CoA hydrolase;
HMGCL, 3-hydroxymethyl-3-methylglutaryl-CoA lyase; HSD17B0, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase; IPMDH,
isopropylmalate dehydrogenase; IPMI, isopropylmalate isomerase; IPMS, isopropylmalate synthase; IVD, isovaleryl-CoA
dehydrogenase; MCCC, methylcrotonoyl-CoA carboxylase; MUT, methylmalonyl-CoA mutase; OCFA, odd-chain fatty acid; OXCT1,
3-oxoacid CoA transferase; P, phosphorylation; PCCB, propionyl-CoA carboxylase subunit beta.

complexes, including the PDH complex, and may have moonlighting proteolytic functions (22).
The rate of oxidation by the BCKDH complex is thought to be largely proportional to intracellu-
lar concentrations of BCKAs, as these are typically well below their Km for the BCKDH complex
(∼15–30 μM). Also similar to PDH, the BCKDH complex is tightly regulated by phosphory-
lation/dephosphorylation (16, 19). BCKDH kinase (BCKDK) adds phosphate on three residues
of BCKDHA, thereby suppressing BCKDH activity (23–27). The complementary activating de-
phosphorylation is carried out by the recently identified phosphatase, PP2Cm (28, 29). BCKDK
is allosterically suppressed by BCKAs [its greatest affinity is for α-ketoisocaproic acid (α-KIC)],
thus allowing elevations in BCKAs to promote their own oxidation (30–33). Efficient product
inhibition of BCKDH also occurs by nicotinamide adenine dinucleotide hydrate (NADH) and
acyl-CoAs.
Like many sequential metabolic enzymes, BCAT2 and the BCKDH complex can be found
physically associated in organized supramolecular complexes, often termed metabolons, allowing
for substrate channeling from one enzyme to another. The association of BCKDHA with BCAT2
and the phosphorylation by BCKDK compete for the same loop on BCKDHA, such that BCAT2
binding increases BCKDH activity, while conversely, phosphorylation of BCKDHA destabilizes
the interaction with BCAT2 (34).
After BCKDH decarboxylation, subsequent catabolism of BCAAs resembles fatty acid oxida-
tion, and indeed, these two processes share a number of enzymatic subunits. Each set of reactions
is mostly unique to each BCAA, and all occur inside the mitochondrial matrix. Ultimately,
BCAA carbons are either lost as CO2 or enter the tricarboxylic acid (TCA) cycle. Specifically,
valine (5C) loses 2 carbons to CO2 and contributes 3 carbons to the TCA as succinyl-CoA;
leucine (6C) loses 1 carbon to CO2 and contributes 5 to the TCA in acetyl-CoAs; and isoleucine
(6C) loses 1 carbon to CO2 and contributes 5 to the TCA as acetyl-CoA and succinyl-CoA
(see 35 for a carbon tracing diagram). As a consequence, valine is considered glucogenic
(i.e., succinyl-CoA is anaplerotic), whereas leucine is considered ketogenic, and isoleucine is
mixed.

Catabolic Intermediates and By-Products

As noted above, all of these reactions occur in the mitochondrial matrix, and essentially all
intermediate metabolites are trapped within the matrix by the CoA adduct. The main exception
is 3-HIB, an intermediate in the valine catabolic pathway. The CoA adduct is removed in the

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preceding reaction and re-added after the generation of methylmalonic semialdehyde. As a

result, 3-HIB can be secreted and is detected in plasma at 10–40-μM concentrations. An-
other possible exception is the last step of leucine oxidation, which yields acetyl-CoA plus
acetoacetate, the latter of which could escape the matrix prior to ketone oxidation. In addition,
some alternative metabolites can emanate from BCAA catabolism, although they are poorly
studied and likely represent a small fraction of overall BCAA catabolic flux. Prior to oxidation
by BCKDH, α-ketoacids can be reduced at the α-carbon to form branched chain α-hydroxy
ketoacids (36, 37). These are present in healthy adult urine at very low levels (often below
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detection) and are directly degraded by α-hydroxyacid oxidases, probably in the liver (38).
Additionally, a cytosolic dioxygenase converts a small percentage of α-KIC to beta-hydroxy-
beta-methylbutyrate (HMB), which is present in human serum at approximately 2 μM (39). After
oxidation by BCKDH, and prior to entry into propionyl-CoA or HMG-CoA, species that are
normally bound to CoA can be released as 3-hydroxy acids (3-hydroxy-2-methylbutyric acid,
3-hydroxy-2-ethylpropionic acid, and 3-hydroxyisovaleric acid) (36). In healthy adults, keto-
genesis is associated with urinary excretion of these 3-hydroxy acids, although in small amounts.
Several intermediates of BCAA oxidation may also contribute to acylation of mitochondrial
enzymes, but the biological significance of these side products of BCAA catabolism remains
unclear (37).
BCAAs also contribute to the synthesis of several unique lipid species, broadly categorized
as N-acyl amino acids, branched chain fatty acids, and odd-chain fatty acids. Mammals appear
to be capable of synthesizing all three types. In mammals, at least some N-acyl amino acids are
synthesized by the secreted enzyme PM20D1, which covalently couples fatty acids to amino acids
by an amide bond (40). Adipocytes and perhaps other cell types can synthesize odd-chain fatty
acids by combining propionyl-CoA (with carbons derived from valine or isoleucine) and malonyl-
CoA, followed by fatty acid chain extension via fatty acid synthase (35, 41). Fatty acid synthase can
also elongate isobutyryl-CoA, isovaleryl-CoA, or 2-methylbutyryl-CoA to form branched chain
fatty acids (42). These unique fatty acids are mostly synthesized in brown adipocytes, but their
role remains unclear. All of these particular lipid species are present in normal serum but at low
concentrations (43). Strikingly, branched chain fatty acids are found at very high levels in vernix
caseosa, the white waxy substance found on newborn human skin, constituting 30% of fatty acid
content (44).

SIGNALING BY BRANCHED CHAIN AMINO ACIDS

AND THEIR CATABOLITES
mTOR
In addition to their structural and metabolic roles, BCAAs and many of their metabolites also have
important allosteric regulatory and signaling effects. The best studied of these is the regulation of
the mechanistic target of rapamycin (mTOR) pathway by leucine. Numerous cellular processes,
including most notably protein synthesis and cellular growth, are controlled by the ubiquitous
multiunit mTORC1 complex, and leucine is a potent activator of mTORC1 activity. The role
of leucine as a growth-regulatory signal was first established in early experiments demonstrating
that leucine stimulates muscle protein synthesis in vitro (45–47) and in perfused skeletal muscle
preparations (47). Leucine (but not valine, isoleucine, or the BCKAs) promotes mTORC1
activation by directly binding Sestrin2 a negative regulator of mTORC1 activity (48) (Figure 2a).
In the absence of leucine, Sestrin2 binds and inhibits GATOR2, a positive regulator of mTORC1
activity. When leucine is available at physiologically relevant concentrations, Sestrin2 releases

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a b
Leu ADP
α-KIC GTP
Leu
Sestrin
GDH
TCA cycle αKG
Insulin GATOR2
Leu
granules V-ATPase LeuRS
NADH GATOR1
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Pyruvate RagA/B
ATP
ADP Ca2+ RagC/D mTORC1 Rheb
Ca2+
K+ K+ K+
K+ K+ Opened Ragulator
Glucose Ca2+ Lysosome

Closed

c
Val
BAIBA OH
H2N O
O
HO OH β-oxidation
3-HIB
FFAs

ROS
immobilization
Thermogenesis

Osteocyte
death

Figure 2
(a) Leucine and α-KIC promote insulin release from pancreatic B cells via activation of glutamate dehydrogenase. (b) Leucine
promotes mTORC1 activity by relieving Sestrin2-mediated inhibition and promoting LeuRS-mediated pathway activation.
(c) Skeletal muscle secretes valine catabolites BAIBA and 3-HIB. BAIBA promotes hepatic B oxidation, adipocyte thermogenesis, and
osteocyte survival; 3-HIB induces fatty acid transport across the endothelium and into skeletal muscle. Abbreviations: 3-HIB,
3-hydroxyisobutyrate; ADP, adenosine 5 -diphosphate; αKG, α-ketoglutarate; ATP, adenosine 5 -triphosphate; BAIBA,
beta-amino-isobutyric acid; FFA, free fatty acid; GATOR1, GAP activity toward the Rag GTPases 1; GATOR2, GAP activity toward
the Rag GTPases 2; GDH, glutamate dehydrogenase; GTP, guanosine triphosphate; Leu, leucine; LeuRS, leucyl tRNA synthetase;
mTORC1, mechanistic target of rapamycin complex 1; NADH, nicotinamide adenine dinucleotide; TCA, tricarboxylic acid; ROS,
reactive oxygen species; Val, valine; v-ATPase, vacuolar H+-adenosine triphosphatase ATPase.

GATOR2, promoting full mTORC1 activation (49). Upon activation, mTORC1 promotes
protein synthesis and inhibits autophagy by phosphorylating several targets, including S6K,
4E-BP1, Ulk1, and TFEB/3. Leucine likely activates mTORC1 via other mechanisms as well,
including via loaded leucyl tRNA synthetase (50–52). For a full discussion of mTOR signaling,
we refer the reader to a number of excellent reviews (53–56).

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Glutamate Dehydrogenase
Leucine also directly regulates protein-mediated insulin secretion in pancreatic islet beta cells.
Leucine and α-KIC are strong insulin secretagogues in low-glucose states. The secretogenic ac-
tivity is direct and not dependent on leucine oxidation because nonhydrolyzable analogs of leucine
are equally secretogenic (57, 58). Instead, leucine promotes insulin release via activation of gluta-
mate dehydrogenase (GDH), which catalyzes the oxidative deamination of glutamate to αKG (59).
Under high-glucose states, GDH is inactive and suppressed by high GTP levels. When glucose
drops below 5 mM, adenosine 5 -diphosphate (ADP) levels rise and can activate GDH, thereby
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providing reducing equivalents and promoting αKG entry into the TCA cycle. Both of these
promote adenosine 5 -triphosphate (ATP) production, subsequent inhibition of KATP channels,
depolarization of plasma membrane, and vesicular release of insulin (59–61). Leucine allosterically
activates GDH under these conditions by increasing its affinity for ADP, thus further increasing
the ATP energy charge, and consequently, insulin secretion. How leucine allosterically activates
GDH is not known. Leucine can be a low-affinity substrate for GDH, so the catalytic may also
be a site of allosteric activation (GDH functions as a homohexamer). Patients with mutations in
GDH that cause hyperactivation in response to leucine (via loss of inhibition by GTP) lead to
protein meal–induced hypoglycemia and hyperinsulinemia-hyperammonia syndrome (62). αKIC
is also a strong insulin secretagogue, in part via its transamination, which yields both leucine to ac-
tivate GDH and αKG to enter the TCA cycle (63). In addition, αKIC may directly inhibit KATP
channels (64).

Valine Catabolites
Metazoans likely evolved to use leucine as a sensor for activation of mTOR signaling and insulin
secretion because leucine is the most abundant essential amino acid; it thus serves well as an indica-
tor of access to protein-derived amino acids. Nevertheless, other BCAA metabolites can also serve
as signaling molecules. Two salient examples are 3-HIB and beta-amino-isobutyric acid (BAIBA),
both related to valine catabolism (Figure 2c). As noted above, 3-HIB is the only intermediate
metabolite of BCAAs that is separated from its covalent attachment to CoA; consequently, it is the
only such metabolite that can easily leave the mitochondrial matrix. 3-HIB is thus in a position
to report on rates of mitochondrial BCAA catabolic flux. 3-HIB is secreted by muscle and likely
other tissues and is present in plasma in 30–50-μM concentrations (65). In muscle, secreted 3-HIB
acts, in a paracrine fashion, on surrounding microvascular endothelial cells, where it promotes the
transport of fatty acids out of the circulation, across the endothelial capillary wall, and to the my-
ofibers. The pathway thus provides an important cross-regulatory link between BCAA and fatty
acid consumptions, which represent two dominant fuel sources. Much remains to be learned about
this pathway, including the receptor (if any) for 3-HIB and the mechanisms of transendothelial
fatty acid transport.
BAIBA (technically also a BCAA) is not a direct intermediate of valine catabolism, but rather a
potential side product, derived from methylmalonic semialdehyde, itself in rapid equilibrium with
3-HIB. Importantly, BAIBA can also be derived from thymine breakdown, and it is not always
clear which source of BAIBA, thymine, or valine predominates under various studied conditions.
Secretion of BAIBA, probably from muscle, has both paracrine and endocrine effects on muscle
adipocytes and distal fat tissues, respectively (66). In these cells, BAIBA induces expression of the
uncoupling protein UCP1, likely in part via activation of the nuclear receptor PPARα. BAIBA
has also been reported to promote osteocyte survival, prevent bone loss (67), suppress renal
fibroblast proliferation, prevent endoplasmic reticulum stress in hepatocytes (68), and suppress

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inflammation in adipocytes (69). Similar to 3-HIB, how BAIBA signals to its target cells remains
ill defined, although in the case of osteocytes, the Mas-related G protein–coupled receptor type D
appears to be directly targeted by BAIBA, preventing apoptosis in osteocytes (67). Both the 3-HIB
and BAIBA pathways thus uncover novel extracellular metabolites with paracrine or endocrine
signaling functions. They also underscore the important concept that the three BCAAs should
not always be freely interchanged, conceptually or experimentally. Only valine oxidation can yield
3-HIB and BAIBA, whereas only leucine powerfully activates mTOR and GDH, for example.
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ORGANISMAL PHYSIOLOGY
As noted, BCAAs are essential amino acids and cannot be synthesized by animals. Therefore,
under homeostatic conditions, animals must maintain a precise balance between intake and loss
of BCAAs. The diet is likely the only significant source of BCAAs; synthesis of BCAAs by gut
microbiota has also been proposed, but it likely contributes a minor component. In terms of
losses, oxidative catabolism of BCAAs dominates, as no appreciable amounts of BCAAs are lost
in the urine. Circulating levels of BCAAs (approximately 200 μM of valine, 100 μM of leucine,
and 60 μM of isoleucine) are maintained in the fasted state and return to these levels within
hours after feeding; thus, the balance of BCAA intake/loss is under homeostatic control (70–72).
Broadly, whole-animal BCAA physiology can be divided into a circulating pool and a tissue pool
(Figure 3). BCAAs derived from the diet or released from protein breakdown appear in circula-
tion. BCAAs are then disposed from circulation into tissues where they can be oxidized or incor-
porated into newly synthesized protein.

Dietary Intake
Dietary BCAA uptake is generally very efficient. Ingested BCAAs are usually derived from protein
and are absorbed in the gut predominantly by short peptide carriers rather than by single amino
acid carriers (73). After a protein-rich meal, circulating BCAA levels rise about 2–3 fold and decline
back to baseline within 3 h, and the uptake kinetics differ depending on the protein source (74,
75). The classic recommended protein intake to maintain minimal muscle mass is 0.8 g/kg/day,
but modern recommendations for a healthy diet are higher (76). The range of protein intake
in the United States varies widely from 0.9 g/kg/day in the fifth percentile to 2.2 g/kg/day in
the ninety-fifth percentile for young adult males (77), perhaps reflecting the variety of popular
diets. The average protein intake in males of 1.7 g/kg/day translates to approximately 88, 145, and
66 mg/kg/day of valine, leucine, and isoleucine. Protein intake varies by age and sex: It is on average
higher in males than females and declines with age but comprises close to 15% of calories in all
groups (77). Notably, typical laboratory rodent diets used for research contain 30% protein by
calories, although the typical Western diet contains about 20%. BCAAs account for only 2–5% of
dietary energy sources.

Protein Breakdown
Isotope tracing studies in the fasted state have consistently demonstrated that BCAAs and other
essential amino acids appear in circulation at rates proportional to their concentration in protein
(78, 79), consistent with protein breakdown being the primary source of BCAA in the circulation.
Typically, the combined rate of appearance of BCAAs from normal protein breakdown is approx-
imately 0.76 g/kg/day in overnight fasted adults, which is more than double the average intake of
0.35 g/kg/day, reflecting significant cycling in and out of the protein pool. Most of the BCAAs

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Dietary protein
(microbiome?)

Exercise recovery,
insulin and leucine

Circulation
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Insulin Protein
pool Aging starvation

Acute exercise,
BCKA, injury
acute exercise, Starvation
insulin,
inflammation

Oxidation
Oxidatio
Ox dation
d
Others

Figure 3
Two-compartment model of whole-organism branched chain amino acid (BCAA) physiology. BCAAs appear
in circulation when released from protein, from either the diet or tissues. BCAAs can leave the circulation to
be deposited into new protein. All BCAAs are ultimately cleared from the system when oxidized in tissues.
Many factors promote or inhibit each of these processes (grey arrows). The tissue-specific regulation of
protein turnover and oxidation is poorly understood.

that appear in circulation are reincorporated into newly synthesized protein, typically accounting
for 70–90% of disposal in the fasted state (80–82). Which tissues serve as the source of BCAAs
is difficult to measure directly, and it likely differs under different conditions. However, current
estimates suggest that skeletal muscle, the liver, and the gut account for most protein breakdown,
reflecting both the large mass of skeletal muscle protein (about 38% of whole-body protein) and
the fast turnover in the liver and gut (83).

Protein Synthesis
In the absence of significant secretion or absorption of protein, rates of protein synthesis and
breakdown in each tissue must be equal under homeostatic conditions. Most studies aimed at
measuring protein synthesis in vivo have focused on skeletal muscle. A summary of these collec-
tive findings establishes that protein synthesis requires both an anabolic signal and the amino acid
building blocks to make new protein. Importantly, BCAAs, and specifically leucine, contribute
to the anabolic signal. Perfusion of isolated skeletal muscle with BCAAs stimulates protein syn-
thesis as efficiently as a complete amino acid mixture, and conversely, perfusion of muscle with an
amino acid mixture lacking BCAAs fails to promote synthesis (84). Leucine exerts the most potent

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BCAA
Workout
100

Relative frequency (% max)

New Year resolution

80

60
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Figure 4
The graph illustrates increasing public interest in branched chain amino acids (BCAAs) since 2004. The
relative frequency of Google searches for the indicated keyword is shown, revealing the rising cyclical
interest in “BCAA” in close correlation with the term “workout” and rising each year in January, coincident
with the term “New Year resolution.”

growth-promoting effect as evidenced by the fact that oral gavage with leucine, but not isoleucine
or valine, stimulates protein synthesis in skeletal muscle (85). Incubation of skeletal muscle with
leucine, but not isoleucine or valine, stimulates protein synthesis nearly as well as a complete BCAA
mixture (85). Importantly, in vivo, other anabolic signals such as insulin must accompany leucine in
order to promote protein synthesis. For example, oral administration of leucine leads to increased
plasma insulin and stimulates protein synthesis, but when plasma insulin levels are maintained at
fasting levels by somatostatin infusion, protein synthesis is inhibited (86). Many of these effects are
likely mediated by mTOR, whose maximal activation requires both hormonal signals (e.g., insulin,
or insulin-like growth factor) and amino acid signals (e.g., leucine via Sestrin2) (55, 56, 87). Inter-
estingly, the relative importance of insulin versus amino acid is likely different in the splanchnic
bed or viscera, where insulin has little effect while amino acids powerfully inhibit breakdown and
activate synthesis (88). More detail can be found in the extensive literature on protein synthesis
(83, 89, 90). The potent anabolic effects of BCAAs have led to growing interest in their use as a
supplement to exercise (Figure 4), typically in the form of a whey protein shake consumed im-
mediately after exercise. Resistance exercise is a powerful anabolic signal, which synergizes with
protein or BCAA intake; combining exercise and protein intake thus leads to maximum protein
synthesis (91). The literature on this topic is vast, and we refer the reader to detailed discussions
(92, 93).

BCAA Oxidation
BCAAs that are not reincorporated in the protein pool are instead oxidized to maintain homeosta-
sis. Oxidation must occur at appreciable amounts, because at a steady state of protein maintenance
where there is no net gain or loss of BCAAs, disposal must match intake.
Because BCKAs can activate their own oxidation, oxidation increases after feeding (74, 75).
Conversely, briefly restricting food reduces BCAA oxidation causing plasma BCAA levels to rise

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(interestingly, more so than other amino acids). If fasting continues into starvation, however,
BCAA oxidation once again increases, likely in large part to provide gluconeogenic precursors
to the liver (94). In severe starvation, BCAA oxidation rates fall again, presumably to conserve
essential amino acids. Various factors in addition to BCAA availability modulate BCAA oxidation
rates. For example, insulin increases whole-body BCAA oxidation when amino acid concentration
is maintained (95). Inflammatory cytokines can double whole-body BCAA oxidation in rats (96).
Moreover, thyroid hormone increases BCAA oxidation before it changes energy expenditure, glu-
cose metabolism, or fat metabolism (97, 98), although interestingly, it appears to inhibit oxidation
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in the liver (99).

Exercise also strongly affects BCAA oxidation. The flux of BCAA oxidation increases during
a bout of acute endurance exercise in proportion to (submaximal) intensity (81, 100–103). It is
unclear if the relative preference for BCAA oxidation versus other substrates is also increased.
This increase in BCAA oxidation is not accompanied by increases in oxidation of other essential
amino acids. Females oxidize less leucine than males during exercise (101, 104), and this is at least
in part mediated by estrogen (105). In animals, endurance training clearly drives an adaptation for
increased BCAA oxidation in skeletal muscle (106), probably through induction of the transcrip-
tional activator PGC-1α (106–110). However, results from human studies testing the hypothesis
that endurance training actually increases BCAA oxidation during exercise are controversial (104).
In all of these cases, the molecular mechanisms driving changes in BCAA oxidation—and in
which tissues oxidation is being modulated—are unclear. In fact, there is no good consensus on
the relative distribution of BCAA oxidation between different tissues. The oxidation of BCAAs
occurs after transamination to BCKAs, and these two processes can occur in different tissues. In
fact, some have argued that liver lacks BCAT activity and that BCAAs are largely transaminated
in the muscle and then shuttled to the liver for oxidation (111), although it should be noted that
nonhepatocyte cells in the liver do express BCAT enzymes (112). Regardless, the relative distri-
bution of BCKA oxidation between different tissues has been challenging to address. Enzymes of
BCAA catabolism are expressed throughout the body, in contrast to those of all other essential
amino acids, which are largely confined to the liver (111). To estimate BCAA oxidation flux in
various tissues, many groups have used ex vivo assays of BCAT and BCKDH activities in extracts
or slices from different tissues (7). In general, such studies indicate that BCAT enzyme activity is
highest in heart, kidney, stomach, and pancreas, and is lowest in liver; BCKDH enzyme activity
is highest in liver, less in heart and kidney, and lowest in muscle, adipose tissue, and brain. For
BCKDH, these measured activities typically reflect the phosphorylation status of BCKDH and,
interestingly, correlate poorly with mRNA or protein expression of BCKDH enzymes.
However, these studies with cell extracts or purified enzymes fail to account for the numerous
in vivo regulatory factors (e.g., availability of BCAAs, product inhibition, redox state, subcellular
compartmentalization). Direct measurements of BCAA oxidation can be made in vivo using iso-
topic tracer contributions to each tissue, but such studies are not practical in humans. In mouse
studies, such steady-state heavy isotope infusion studies in vivo have recently demonstrated that
specific rates of BCAA oxidation in fact actively occur in all tissues examined (110). Interestingly,
in the pancreas, BCAAs appear to be a dominant source of oxidative fuel, accounting for >20% of
carbons incorporated into the TCA cycle. Overall, skeletal muscle oxidizes more BCAAs than any
other tissue. Strikingly, oxidative flux correlates poorly with extent of phosphorylation of BCKDH,
again reflecting the likely numerous other factors that dictate BCAA catabolic flux in vivo.
Finally, it should be noted that an implicit assumption in most whole-body studies to date has
been that BCAAs and BCKAs are transported easily and quickly in and out of cells. This area
of BCAA physiology, however, remains poorly understood. There are many amino acid trans-
porters that are often capable of transporting a suite of amino acids, with significant redundancy

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(reviewed in 113). The most prominent transporter of BCAAs into cells is the large neutral amino
acid (LNAA) transporter, a heterodimer composed of LAT1 and its molecular chaperone CD98
(SLC7A5 and SLC3A2, respectively) (114–116). Genetic and pharmacologic inhibition studies
indicate that, at least for some cell types in cell culture, LNAA mediates most BCAA uptake (117).
To what extent these transporters are rate limiting under physiological conditions is not clear.
The LNAA also transports aromatic amino acids (AAAs), and the frequent correlation between
plasma levels of BCAAs and AAAs (e.g., in prediabetes) has been ascribed to competition for these
transporters (118). The transporter is highly expressed in the blood-brain barrier, where it has
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been estimated to be 96% saturated with LNAAs, mostly leucine and phenylalanine (119). Based
on this observation, treatment with BCAAs has been proposed to competitively prevent uptake
of AAAs into the brain in, for example, hepatic encephalopathy, with variable results (120). If so,
then LNAA transport does likely contribute a rate-limiting step in systemic BCAA homeostasis,
although the LNAA transporter may have lower affinity for BCAAs in tissues other than the brain.
BCKAs may be transported by nonspecific monocarboxylate transporters (121).
BCAAs are also important for interorgan nitrogen exchange, most often studied between mus-
cle and liver (122). BCAT enzymes operate near equilibrium in most tissues, and rates of transam-
ination generally far outstrip rates of BCKA oxidation, thus allowing BCAA amino groups to con-
tribute significantly to the transamination pool. Alanine is a major circulating metabolite (with
higher turnover than glutamine, glycerol, or pyruvate) (79), which is in large part secreted by
skeletal muscle; it is also an important source for gluconeogenesis in the liver (123). Muscle secre-
tion of alanine requires amination of pyruvate, and strikingly, leucine alone accounts for 20% of
this nitrogen (124). Valine and isoleucine likely contribute proportionally. BCAAs thus participate
as nitrogen donors both to move nitrogen to the liver for urea synthesis and to facilitate moving
carbons to the liver for gluconeogenesis. Of note, net transfer of nitrogen from BCAAs requires
the concomitant removal of BCKAs to prevent the reverse reaction, which is achieved via either
BCKA secretion or oxidation (125). BCAA nitrogen can also be transferred to glutamine, a sub-
strate for gluconeogenesis in the kidney (126) and in the brain; to the synthesis of both excitatory
glutamate and inhibitory GABA neurotransmitters; and to the neuroprotective astrocyte/neuron
glutamine/glutamate shuttle (127).
In summary, whole-body BCAA metabolism reflects a balance between protein ingestion, cy-
cling of protein synthesis and breakdown, and BCAA oxidation. Large gaps still exist in our un-
derstanding of how these processes are regulated and how they differ between tissues.

BRANCHED CHAIN AMINO ACIDS IN DISEASE

Inborn Errors of BCAA Metabolism
Inborn errors of BCAA metabolism have demonstrated the importance of evolutionarily honed
BCAA homeostatic mechanisms to prevent excess of BCAAs or their derivatives. Maple syrup
urine disease (MSUD), first described in the 1950s (128–130), is an autosomal recessive disease
caused by mutations in the first two subunits of BCKDH (the BCKDHA/BCKDHB heterote-
tramer or DBT) and occurs in approximately 1:200,000 births. Mutations in the third subunit
of BCKDH, DLT, lead to more severe and distinct disease because DLT is shared with PDH
and αGDH. Plasma BCAAs, α-ketoacids, and hydroxy-BCAAs are high, and elevations in l-
alloisoleucine are pathognomonic (131). Accumulation of a rare catabolic product, sotolone, gives
the urine its characteristic odor (132, 133). The disease presentations are variable, in part de-
pending on which subunit of BCKDH is affected (134). Untreated, MSUD leads to encephalopa-
thy, cerebral edema, and death. The mechanism of encephalopathy remains unclear, but it likely

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involves disturbed neurotransmission. BCAAs, especially leucine, donate via BCAT transamina-
tion one-third or more of the amino groups in brain glutamate, the major excitatory neuro-
transmitter, and are critical to maintain nitrogen homeostasis in the astrocyte/neuron glutamate/
glutamine cycle (127, 135, 136); elevations in α-KIC may thus contribute to glutamate depletion.
In addition, as noted above, BCAAs (especially leucine) compete with AAAs for transport across the
blood-brain barrier, thus potentially limiting important neurotransmitter precursors. Numerous
other mechanisms have been proposed (137). Upon diagnosis, patients are treated by aggressive
protein withdrawal, and then amino acid–defined diets are slowly reintroduced to maintain BCAA
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levels as close to normal as possible (138). Liver transplantation is curative, which demonstrates
that providing ∼10% of total body BCKDH activity is sufficient to restore BCAA homeostasis
(139). Conversely, MSUD patients can serve as liver donors (140), indicating that BCKDH ac-
tivity outside the liver is also sufficient to maintain BCAA homeostasis. Gene therapy to deliver
functional BCKDH or edit the endogenous mutations may provide viable alternatives to liver
transplant.
More recent work shows that mutations in BCKDK, leading to excess, rather than restricted
BCAA oxidation may lead to autism spectrum disorder with epilepsy (141, 142). In addition,
homozygous mutations in SLC7A5, a component of the LNAA transporter (see above), have
been found in patients with autistic traits. Deletion of Slc7A5 in endothelial cells of mice
leads to low brain BCAAs and severe neurological symptoms, and intracerebroventricular ad-
ministration of BCAAs partially reverses these abnormalities (143). Thus, excess or insufficient
BCAAs/BCKAs in the brain contributes to neurologic diseases, underscoring the importance of
BCAA homeostasis for normal brain function, although in both cases the mechanisms remain
unclear.

Diabetes
Unlike the clear neurotoxic effects of large excesses in BCAAs that are seen in MSUD patients,
the possible pathogenic consequences of milder elevations in BCAAs are only slowly coming to
light. Elevations of BCAA levels in blood of patients with obesity and insulin resistance were first
noted in the 1960s (144, 145). Recent work has revitalized these observations and supports the no-
tion that elevations in BCAAs in fact contribute causally to insulin resistance, as supported by the
following observations: (a) Unbiased metabolomic studies with plasma from normal subjects with
normal insulin sensitivity identified elevations in plasma BCAAs as the strongest predictor for de-
veloping diabetes in the subsequent decade or more, indicating that changes in BCAA metabolism
precede detectable insulin resistance (146–149); (b) Mendelian genetics studies revealed that poly-
morphisms near the PPM2 gene (encoding for the BCKDH phosphatase) that affect BCAA levels
also increase the risk of insulin resistance (150); and (c) BCAAs infused into the circulation of
healthy adults are sufficient to impair glucose disposal (151). Moreover, adding BCAAs to a high-
fat diet worsens the development of glucose intolerance in rodents (147), whereas limiting BCAAs
improves glucose tolerance and insulin sensitivity (152). Together, these data support the notion
that BCAAs contribute to insulin resistance, likely via a mechanism dependent on excess lipid
availability. Conversely, insulin resistance itself likely can cause elevations in BCAAs, establishing
a feed-forward loop (153, 154).
Identifying the mechanisms that lead to BCAA elevations may present novel targets for in-
terventions early in the progression to insulin resistance. Multiple mechanisms are likely at play,
involving multiple organs (Figure 5). To date, nearly all mechanistic studies are largely based
on rodent studies. In adipose tissue of insulin resistant people and animals, gene expression of
nearly every enzyme required for BCAA oxidation is suppressed (155–160). Cell culture studies

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a b
Health: Insulin resistance:
balanced BCAA oxidation shunted BCAA oxidation
?
Plasma BCAA Plasma BCAA

Reduced Shunted
oxidation oxidation
Oxidation Oxidation
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Basal lipid uptake Controlled lipid Aberrant lipid Excess lipid uptake
and accumulation homeostasis release and accumulation

Minimal muscle lipotoxicity Muscle lipotoxicity

Figure 5
Proposed model of casual relationship between altered tissue branched chain amino acid (BCAA) oxidation
and elevated circulating BCAA levels in insulin resistance. In healthy conditions (a), BCAA oxidation is
balanced among different organs. Genetic and environmental factors suppress BCAA oxidation in the liver
and adipose tissues (b), causing increased circulating BCAA levels and overflow of BCAAs into skeletal
muscle, which results in lipotoxicity and insulin resistance. Adapted with permission from Reference 110.

suggest that hypoxia, endoplasmic reticulum stress, and inflammation contribute to this suppres-
sion (161, 162), and thiazolidinediones rescue expression in vivo (158, 163). In the liver, BCKDH
phosphorylation is increased, which is likely driven by high BCKDK expression (159, 164–166).
Suppression of BCAA oxidation in liver and adipose tissue promotes elevations in plasma BCAAs,
likely shunting BCAA oxidation to permissive organs (118). Consistent with these observations,
recent studies in whole animals with steady-state heavy isotope infusions revealed in db/db mice
blunted BCAA oxidation in fat and liver, with consequent significant shunting of oxidation to
skeletal muscle (110). Recent work also showed that fructose ingestion induces the hepatic tran-
scription factor ChREBP-β, which in turn activates BCKDK transcription, thus linking fructose
and BCAA metabolism. This suggests a mechanism by which the modern dietary choices of high
fructose and protein consumption synergistically conspire to elevate plasma BCAAs (166). Revers-
ing the effects of BCKDK by liver-targeted overexpression of the PPCM phosphatase PPM1K, or
by systemic pharmacological inhibition of BCKDK, improved glucose tolerance in Zucker fatty
rats (166), strongly supporting the causal role of reduced liver BCAA oxidation in the development
of insulin resistance.
How elevations in BCAAs cause insulin resistance remains unclear. In fact, it remains uncertain
if elevations in BCAAs per se promote insulin resistance; alternative explanations include the con-
sequences of decreased oxidation in some tissues (e.g., adipose) or shunted increased oxidation in
others (e.g., muscle). Few mechanisms have been proposed to connect impaired BCAA oxidation
in the liver with direct effects within the liver. Interestingly, BCKDK in the liver appears to also
phosphorylate and inhibit ATP citrate lyase, a rate-limiting step for de novo lipogenesis, possi-
bly providing an alternative explanation for insulin resistance in the face of elevated BCKDK
(166). The near complete loss of BCAA oxidation in adipose tissue may also have important

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cell-autonomous consequences. In cultured adipocytes, leucine and isoleucine contribute 30% of

lipogenic acetyl-CoA, and BCAA oxidation is required for differentiation (35). These observations
predict that loss of BCAA oxidation could impair lipid storage in adipocytes, thus contributing to
ectopic lipid deposition and insulin resistance. Adipocytes also use BCAAs to synthesize odd-chain
fatty acids (35, 41), but the role for these unique lipids is unknown.
Skeletal muscle is the predominant site of glucose disposal after a carbohydrate load (167), and
thus it represents a critical site of insulin resistance. Several mechanisms have been proposed to
connect elevated BCAAs or increased BCAA oxidation to insulin resistance in skeletal muscle.
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mTOR activation by leucine has been investigated, but mTOR does not appear to be responsi-
ble for the effects of BCAAs on insulin resistance, because treating rats with rapamycin does not
abrogate the effects of BCAAs (147). In fact, in general, diets supplemented with leucine only,
rather than all three BCAAs, tend to improve insulin resistance rather than worsen it (168). Com-
petition of elevated BCAA oxidation with oxidation of other substrates, notably glucose, has also
been proposed, but this mechanism is unlikely because the relative contribution of BCAAs to total
muscle fuel oxidation is small (110). In one proposed mechanism that connects BCAAs and ec-
topic lipid accumulation, high BCAA oxidation in skeletal muscle depletes the intracellular pool
of glycine, thereby impairing lipid export of acyl-glycine adducts, resulting in accumulation of
acyl-CoA species (165). Glycine levels frequently correlate inversely with BCAAs (145–147), and
a low-BCAA diet raised glycine back to normal levels (165). Finally, elevated oxidation of va-
line likely increases production of 3-HIB, increasing fatty acid uptake via paracrine promotion
of transendothelial fatty acid transport (65). Plasma concentrations of 3-HIB are associated with
the future development of diabetes, even after adjusting for body mass index and plasma BCAAs
(169). Despite this multitude of potential mechanisms, no studies have definitively demonstrated
that any of these changes in BCAA oxidation in specific tissues are sufficient to cause insulin
resistance.

Cancer
Because BCAAs are essential amino acids, a growing tumor must obtain them from either the cir-
culation or surrounding tissue. Alterations in circulating BCAA levels in patients diagnosed with
cancer have long been noted (170–173). Recent retrospective metabolomic studies demonstrated
that elevated plasma BCAA levels are associated with a greater than twofold increased risk in pan-
creatic cancer and precede clinical presentation by many years. The observation was recapitulated
in mice genetically engineered to develop pancreatic ductal adenocarcinoma and is likely caused
by subclinical systemic protein breakdown during early tumorigenesis, which is presumed to ser-
vice the BCAA needs of the growing tumor (171). Interestingly, the same appears not to be true
of other tumors, even when driven by the same mutations in KRAS and p53 (174). Whether these
alterations in systemic BCAA metabolism contribute to tumor growth or metastasis remains un-
clear. Regardless, opportunities for biomarker development are an area of intense investigation
(175, 176).
A recent surge of studies on tumor BCAA metabolism has focused largely on BCAT1, the ex-
pression of which is altered in numerous cancers, and in many cases correlates with poor out-
come (177–179). Notably, in glioblastomas containing wild-type isocitrate dehydrogenase (IDH),
half express high levels of BCAT1, whereas IDHmut tumors suppress BCAT1 expression (180).
The latter suppression may be mediated by the oncometabolite 2-hydroxyglutarate (2-HG) that
is generated by mutant IDH. 2-HG potently inhibits dioxygenases, including histone demethy-
lases (181), leading to widespread suppressive hypermethylation of promoters, including that of
BCAT1 (180). Conversely, several mechanisms to explain elevated BCAT1 expression in various

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cancers have been proposed, including increased binding of BCAT1 mRNA transcript to RNA-
binding protein MSI2 (182) chromatin hyperacetylation of the BCAT1 gene by the MLL1 fusion
protein (183), and transcriptional activation by the myc oncogene (184, 185). It remains unclear
precisely how BCAT1 expression promotes tumor growth, but it likely differs between tumors. In
IDHwt acute myeloid leukemia, BCAT1 expression correlates with shorter survival and has been
proposed to mimic IDHmut acute myeloid leukemia by virtue of depleting αKG, leading to in-
activation of αKG-dependent dioxygenases, which is analogous to inhibition of the same dioxy-
genases by 2-HG in IDHmut cells. Suppression of dioxygenases ultimately promotes growth via
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HIF-1α stabilization and by altering the epigenomic landscape (186). Conversely, 2-HG produced
in IDHmut glioma cells inhibits BCAT1, thus limiting the supply of glutamate and opening a vul-
nerability to treatment with inhibitors of glutaminase, the other main source of glutamate (187).
In chronic myeloid leukemia, BCAT1 is proposed to promote blast crisis by aminating BCKAs
to produce BCAAs, leading to progrowth mTOR activation; however, it is unclear how BCAT1
enzymatic activity should be limited to only one direction (182). BCAT1 overexpression also pro-
motes mTORC1 activity in breast cancer through unclear mechanisms (188). In summary, data
strongly point to an important role for BCAT1 in multiple cancer types, likely via multiple different
mechanisms unique to each cancer.

Heart Failure
BCAA metabolism has also garnered much attention in the context of cardiovascular disease and
heart failure. Elevations in plasma BCAAs and their metabolites are independently associated with
cardiovascular disease risk (189–191), a topic reviewed elsewhere (192). Additionally, circulating
and cardiac BCAAs and BCKAs rise in response to ischemic and hemodynamic murine models
of heart failure (193–195). In these studies, the increase in cardiac and plasma BCAAs coincides
with diminished expression of multiple components of the BCAA catabolic pathway. However,
the heart consumes far fewer BCAAs than other organs (196–198), making it unlikely that di-
minished cardiac BCAA catabolism alone accounts for increased plasma BCAAs. Suppression of
whole-body BCAA catabolism via deletion of PP2Cm elevates circulating and cardiac BCAA lev-
els and worsens cardiac response to aortic constriction and ischemia/reperfusion injury (193, 194).
Additionally, dietary BCAA supplementation worsens contractility and increases infarct size fol-
lowing myocardial infarction (195). Conversely, pharmacological promotion of systemic BCAA
catabolism lowers circulating and cardiac BCAA levels and improves cardiac function in both
hemodynamic and ischemic challenges (193–195). These data strongly support the notion that
alterations of BCAA metabolism contribute to heart failure in numerous contexts.
The mechanisms by which BCAAs affect cardiac function, however, remain poorly under-
stood. As in the case of insulin resistance, multiple mechanisms likely contribute. Diminished
cardiac BCAA catabolism per se is not likely to compromise ATP production in heart failure
because BCAA oxidation contributes to a negligible amount (<5%) of ATP production even in
the healthy heart (110, 199; reviewed in 200, 201). It is thus more likely that altered concen-
trations of BCAAs or BCKAs in the heart affect function. High levels of intracellular cardiac
leucine may activate mTOR, thus promoting cardiac insulin resistance and hypertrophy. Indeed,
mTOR inhibition mitigates cardiac dysfunction in multiple heart failure models (195, 202, 203;
reviewed in 204). Conversely, even transient exposure of isolated rodent hearts to high concen-
trations of BCAAs impairs contractility. This may occur in part via inhibition of mitochondrial
ATP production, as high levels of BCAAs inhibit both pyruvate and αKG dehydrogenases (193,
205). Overall, however, how alterations of systemic BCAA metabolism alter heart failure remains
unclear.

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CONCLUSION
BCAAs have been the subject of often intense study since their discovery in the mid-nineteenth
century. More than 50,000 studies are reported in PubMed. Space constraints invariably precluded
us from covering all that is to be said about these fascinating molecules. We have succinctly re-
viewed here the basic biochemistry and physiology of mammalian BCAA metabolism, much of
which was elucidated in the latter part of the twentieth century. This is followed by examples of
more recent investigations pointing to a potentially important role for BCAAs in the development
of numerous prevalent diseases that increasingly afflict the modern world. Armed with improved
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understanding of BCAA physiology and pathophysiology, we anticipate that interventions appro-

priately targeting BCAA metabolism will help improve treatment of these modern ailments.

DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS
We apologize for omitting a number of additional important topics and studies due to space con-
straints. The authors were supported by grants from the US National Institutes of Health: T32
GM-07229 (M.N.), F30HL142186-01 (D.M.), and R01 DK107667, DK114103 (Z.A.).

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