Branched Chain Amino Acids

Branched Chain Amino Acids (BCAAs) are three amino acids with similar structures that beneficially influence the muscles. They can be found in any food containing protein, such as eggs or meat. Supplementation is not necessary, but BCAAs may benefit the body if taken at specific times.

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Branched Chain Amino Acids (BCAAs) refers to three amino acids: Leucine, Isoleucine, and Valine.

BCAA supplementation, for people with low dietary protein intake, can promote muscle protein synthesis and increase muscle growth over time. It can also be used to prevent fatigue in novice athletes.

Leucine plays an important role in muscle protein synthesis, while isoleucine induces glucose uptake into cells. Further research is needed to determine valine’s role in a BCAA supplement. Supplementing BCAAs prevents a serum decline in BCAAs, which occurs during exercise. A serum decline would normally cause a tryptophan influx into the brain, followed by serotonin production, which causes fatigue.

BCAAs are important to ingest on a daily basis, but many protein sources, such as meat and eggs, already provide BCAAS. Supplementation is unnecessary for people with a sufficiently high protein intake (1-1.5g/kg a day or more).

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Also Known As

BCAAs, BCAA


Do Not Confuse With

Leucine, Isoleucine, or Valine (all individual BCAAs)


Things to Note

  • There has been a reported stimulatory effect with BCAA supplementation, but due to no research into this topic, the placebo effect cannot be ruled out

BCAA dosages are based on goals. The standard dosage for isoleucine is 48-72mg/kg (assuming a non-obese person). The standard leucine dosage is between 2-10g. A combination dose is 20g of combined BCAAs, with a balanced ratio of leucine and isoleucine.

Isoleucine is used for increasing glucose uptake into cells, while leucine is used to improve muscle protein synthesis.

BCAA supplementation is not necessary if enough BCAAs are provided through the diet. Further research is needed to determine valine’s optimal dosage and reason for supplementation.


I only use them during a fast, usually before a workout.


Sol Orwell

In regards to the anti-fatigue effects, it is highly plausible that this will only apply to untrained or lightly trained persons doing prolonged exercise. There does appear to be a difference between trained and untrained persons, and perhaps this is due to less tolerance to exercise-induced sedation (fatigue tends to set in earlier in newbies, so an anti-fatigue effect is going to affect them more)


Kurtis Frank

The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Branched Chain Amino Acids has in your body, and how strong these effects are.
GradeLevel of Evidence
ARobust research conducted with repeated double blind clinical trials
BMultiple studies where at least two are double-blind and placebo controlled
CSingle double blind study or multiple cohort studies
DUncontrolled or observational studies only
Level of Evidence
EffectChange
Magnitude of Effect Size
Scientific ConsensusComments
BFatigue

Minor

A decrease in fatigue (mental fatigue when measured after the workout) results when BCAA supplementation is taken during exercise at a dose above 10g or so

BFat Oxidation

Minor

In prolonged exercise and somewhat related to the antifatigue effects, an increase in fat oxidation is noted with BCAA supplementation; this is thought to be related to... show

BAerobic Exercise

Minor

An increase in time to exhaustion appears to exist in prolonged endurance exercise, but this benefit may only exist in untrained or lightly trained individuals. Several... show

BLactate Production

There does not appear to be any reliable or significant changes in blood lactate concentrations following exercise with BCAA supplementation

CMuscle Soreness

No significant influence on muscle soreness when assessed 2-3 days after exercise that is preloaded with BCAA supplementation

CProcessing Accuracy

Minor

The increased processing accuracy appears to be secondary to reducing exercise-related fatigue, and occurs when testing is after exercise.

CHeart Rate

No significant alterations in heart rate noted with BCAA supplementation at rest or during exercise

CCortisol

No significant interactions with BCAA supplementation and cortisol

CPower Output

Mixed effects on power output, but when it does occur it is not a per se increase in power output but secondary to reduced muscular soreness after repeated exercise.... show

CRate of Perceived Exertion

Minor

There is some evidence to support a reduction in the rate of perceived exertion during exercise under the influence of BCAA supplementation, but this appears to unreliably... show

CAnaerobic Running Capacity

No significant performance enhancing effect on short-term cardiovascular exercise

COxygen Uptake

Oxygen uptake during anaerobic cardiovascular exercise does not appear to be modified with BCAA supplementation

CWeight Loss

Minor

The weight loss that occurs during prolonged strenuous exercise (in these examples, skiing) are attenuated with BCAA supplementation relative to carbohydrate. This is likely... show

CAmmonia

Minor

Human studies suggest time-dependent influences on ammonia (increase after exercise up until 2 hours, a reduction the next day) while animal studies suggest that overdosing... show

CInsulin

No significant influence of BCAA supplementation on fasting insulin levels

CReaction Time

Minor

A (beneficial) decrease in reaction time has been noted during a stimulated soccer test, which was thought to be secondary to the antifatigue effects. Hypothesized to be... show

CAdrenaline

No significant influence on adrenaline concentrations

CNoradrenaline

BCAA supplementation does not appear to significantly influence noradrenaline concentrations in serum

CDopamine

Similar to the other catecholamines (adrenaline and noradrenaline), serum dopamine does not appear to be altered with supplemental BCAAs.

CBlood Glucose

There does not appear to be a likely alteration in blood glucose concentrations per se with BCAA supplementation, but the increased fat oxidation may attenuate... show

CKetone Bodies

No significant alterations in formation of ketone bodies, which may be due to the ketogenic BCAA (leucine) being offset by the other two glucogenic ones


Studies Excluded from Consideration

  • Multinutrient supplement (included non-BCAA supplements)[1]
  • Confounded with non-BCAA amino acids (such as Citrulline or Glutamine)[2]
  • Paired with ACE inhibitors[3]

Disagree? Join the Branched Chain Amino Acids Discussion

Table of Contents:


Edit1. Sources and Composition

1.1. Sources

The three amino acids Leucine, Isoleucine, and Valine ar referred to as Branched Chain Amino Acids (BCAAs) as they are the only three amino acids to possess a branched side chain; they are all essential amino acids,[4] and collectively form the largest pool of essential amino acids in the bodily pool (35–40%) and are present in high levels (14–18%) in muscle tissue.[5][6][7] The content of BCAAs in the free amino acid pool is relatively small compared to bodily stores (at around 0.1g/kg or 0.6–1.2mmol/kg muscle tissue[7]) and the fasted serum concentration of BCAAs tends to be 0.3–0.4mM (relatively high compared to all other amino acids aside from Glutamine).[8][9]

Branched chain amino acids are a group of three essential amino acids that are highly involved in the regulation of muscle mass. They are found in the diet, through protein ingestion

1.2. Catabolism and Regulation

Under normal resting unfed states, the enzymes that mediate BCAA catabolism (to be discussed) are at about 4-6% activity in the skeletal muscle of rats[10][11] despite being near full capacity in the liver which is not a main site of catabolism.[10]

Increased dietary protein (from 8% to 30% of the diet) is known to increase the enzyme that catabolizes BCAAs[12] and this is seen with an increase in dietary BCAAs alone (4.8% or 6.2% of the diet of rats)[13] and with exercise;[14] this suggests that BCAA serum concentrations are highly regulated and further suggests an increased dietary need with exercise.[7]

BCAAs have their bodily stores regulated by the BCAA dehydrogenase complex, which is increased in activity with both exercise and a dietary surplus of BCAAs

BCAA catabolism occurs in the cell's mitochondria.[15] The BCAAs undergo reversible conversion to α-keto derivatives (known as branched-chain α-keto acids) via the enzyme branched-chain aminotransferase (BCAT) and then is irreversibly metabolized (oxidative decarboxylation) via the branched-chain α-keto acid dehydrogenase (BCKDH) enzyme[7] which is thought to be the rate-limiting step of BCAA catabolism.[15][10]

The rate limiting step (BCKDH enzyme) is regulated by covalent modification and is activated by BCKDH phosphatase[16] inactivated by BCKDH kinase[17][18] (dephosphorylation and phosphorylation of E1α, respectively). It is thought that the activity of BCKDH kinase is a determinant of BCKDH activity overall as they are inversely correlated,[19] but a lack of information on BCKDH phosphatase exists in general.[7]

Due to the high concentration of BCAT and BCKDH in skeletal muscle and low concentrations in the liver, BCAA catabolism tends to occur in skeletal muscle[20][11] hence its suspectability to physical exercise;[14] most other essential amino acids are catabolized in the liver. There is also a higher concentration of the inhibitory enzyme (BCKDH kinase) in skeletal muscle[21] which is thought to underlie the low rates of catabolism at rest in skeletal muscle (which is not observed in liver tissue).[10][11]

BCAA catabolism is controlled by the rate of the rate limiting enzyme (BCKDH complex) and this enzyme itself is positively (BCKDH phosphatase) and negatively (BCKDH kinase) regulated by other enzymes. They are located in high concentrations in skeletal muscle (hence localized catabolism of BCAAs) and their activity determines BCAA concentrations in a cell

When Leucine is reversibly metabolized into α-ketoisocaproic acid (KIC) by BCAT using α-ketoglutarate as a cofactor (and producing glutamine in this process) and then irreversibly metabolized into isovaleryl-CoA. Isoleucine is reversibly metabolized into 3-methyl-2-oxopentanoate (KMV) by BCAT using the same cofactor, and KMV is irreversibly metabolized into 2-Methylbutyryl-CoA while Valine is metabolized reversibly into 2-ketoisovalerate and then irreversibly into isobutyryl-CoA.[7]

The BCKDH complex is important in muscle protein synthesis (via leucine preservation, more preservation of this amino acid promotes more signalling from it), which is evidenced by the BCKDH kinase inhibitor clofibric acid[22][23] causing myopathy after prolonged usage.[24][25]

Other activators of the BCKDH complex (increasing BCAA catabolism) include TNF-α (following injections which raised activity from 22% to 69-86% at 25-50mcg/kg) secondary to decreasing levels of the negative regulator[26] and starvation (by decreasing the negative regulator).[12] Additionally, all BCAA metabolites (the alpha keto acids) are inhibitors of BCKDH kinase and may increase the activity of the complex[22] with α-ketoisocaproate (from leucine) being more potent than the others;[27] HMB at 2mM does not inhibit this kinase.[22]

Exercise (localized muscle contraction specifically[27]) is well known to activate this complex[12][21] and has been confirmed in human tissue[28] associated with decreasing BCKDH kinase (negative regulator) activity thought to be secondary to altering the levels of bound kinase relative to free kinase.[21]

Activation of the BCKDH complex (resulting in BCAA catabolism) is associated with myopathy, and cytokines or drugs that increase activity of this complex can increase BCAA catabolism and induce myopathy. The immediate metabolites of BCAAs are known to positively influence enzyme activity and encourage their own catabolism, forming a loop of self-regulation. Exercise is known to increase BCAA oxidation by activating this enzyme complex

1.3. Types of BCAAs

Livact is a brand name for BCAA granules that are used in some instances of cirrhosis or clinical settings.[29]


Edit2. Pharmacology

2.1. Absorption

After ingestion, Leucine from food is catalyzed by digestive enzymes into either peptides or free amino acids. Both of these are then taken up from the gut into the liver via their respective transporters. Leucine is taken up into cells via its respective Heterodimeric Amino Acid Transporter[30], most notably the glycoprotein CD98 which also mediates uptake of isoleucine, valine, tryptophan and tyrosine (branched and aromatic amino acids).[31][32] This inhibitions applies to both the blood brain barrier and the intestines.[33]


Edit3. Neurology

3.1. Serotonin

The central hypothesis of fatigue (which assumes that elevated serotonin concentrations in the brain are associated with induction of fatigue[34][35]) is thought to be related to the antifatigue effects of BCAA supplementation.[36] During exercise, the plasma ratio of aromatic amino acids (applies to both tryptophan and L-Tyrosine although the central hypothesis only regards the former) to long chain neutral amino acids (the BCAAs and a few others) is altered in favor of the former[35][37][38] due to BCAAs undergoing oxidation and being destroyed,[14] and due to tryptophan and BCAAs sharing the same transport into the brain[39][40][41] and this act of transportation is the rate limiting step[36] any alteration in the ratio will alter what amino acids transport into the brain, and exercise has been confirmed to increase tryptophan uptake in as little as 30 minutes[42][43] and increasing tryptophan availability via supplementation (without supplemnetal BCAAs) appears to promote fatigue in rats.[44]

It is thought the increased tryptophan transport into the brain (which produces serotonin via 5-HTP) is a possible causative factor of fatigue, and replenishing oxidized BCAAs to preserve the ratio can attenuate fatigue production.[36]

Theoretically, tryptophan uptake into the brain increases during exercise. The increased synthesis of serotonin promotes fatigue and sedation. As BCAAs share the same transport into the brain as serotonin, it is thought loading them prior to exercise is able to hinder tryptophan uptake and serotonin production, thus hindering the onset of fatigue

Rats fed 3.57-4.76% of the diet as BCAAs for 6 weeks (control at 1.78%) failed to alter post-exercise serotonin in the hypothalamus as assessed by biopsy[45] but elsewhere valine supplemented (20mg/kg bodyweight) injected immediately prior to running was able to prevent an exercise-induced increase in serotonin production (measured in hippocampus) at 30 minutes, with mixed efficacy at 90 minutes (serotonin was lower, tryptophan and 5-HIAA were not)[46]

Adding BCAAs to the rat diet may not prevent serotonin synthesis in the brain, while timed ingestion prior to physical activity (to ensure high levels in serum) has been noted to be effective with isolated valine

3.2. Excitation

Due to the link between athletes and Amyotrophic lateral sclerosis (ALS, albeit somewhat unreliable of an association that is still up for debate[47] with both positive[48][49] and null[50] evidence) investigation into agents possibly used by these athletes were conducted and BCAAs suspected.

The epidemiological link between ALS and athletes is somewhat weak and inconsistent, and even the link between ALS and BCAA supplementation (hypothesized to be more commonly occurring in athletes) is currently unsupported

BCAAs have been noted to cause hyperexcitation of neurons (without affecting resting membrane potential) in vitro via mTOR dependent means (blocked by rapamycin) and requiring a sodium channel (blocked by Riluzole), and dose-dependence between 10-300μM was shown with Valine;[51] this did not occur with amino acids without a branched chain.

As hyperexcitability of neurons is a pathological feature of ALS in humans[52][53] and of the mouse model which mimicks ALS (the G93A model[54][55]), it was thought that this induced hyperexcitability could be a mechanism of action. BCAA-induced hypersensitivity also appeared to be sodium channel dependent, and occurred in mice (B6SJL strain) raised from birth with 2.5% of the diet as BCAAs (1:1:1 ratio).[51]

It is plausible that BCAAs may increase neuronal excitation via mTOR dependent means, but the in vitro evidence resulted from quite high concentrations, while the mouse model was conducted from birth, which is usually more sensitive to neurological effects but may not accurately represent a non-infant consuming the agent. More research on this topic is needed


Edit4. Interactions with Glucose Metabolism

4.1. Mechanisms

Leucine has potential to promote insulin-induced activation of Akt, but it requires PI3K to be inhibited or suppressed first (and then leucine preserves insulin-induced Akt activation).[56]

In conditions where insulin is not present, 2mM leucine and (to a lesser degree) its metabolite α-ketoisocaproate appear to promote glucose uptake via PI3K/aPKC (atypical PKC[57]) and indepedent of mTOR (blocking mTOR does not alter the effects).[58] This study noted stimulation only at 2-2.5mM for 15-45 minutes (resistance developed at 60 minutes) and was comparable in potency to physiological concentrations of basal insulin but underperformed (50% as potent) as 100nM insulin.[58]

It is possible that leucine can promote glucose uptake in some instances, such as when PI3K is inhibited or when insulin is not present in a cell culture but leucine is (acutely). It appears to have similar mechanisms to isoleucine

Leucine is also able to hinder cellular glucose uptake[59][60][61] which is thought to either be related to activation of mTOR signalling which naturally suppresses AMPK signalling[62] (AMPK signalling being one that mediates glucose uptake during periods of low cellular energy and exercise[63][64]) or due to leucine suppressing glucose oxidation seen during fasting in muscle cells[59] (a relative preservation of glucose would result in higher cellular concentrations and thus less recompensatory uptake) which is also possibly related to mTOR signalling; signalling via this pathway is a negative-feedback mechanism of glucose uptake as it is normally activated by insulin[65] and activation or mTOR eventually hinders IRS-1 signalling[66] (the first substrate after the insulin receptor in the signalling pathway) as mTOR's activation of S6K1 (which induces protein synthesis) also creates serine-threonine kinases which degrade IRS-1.[67]

This does not appear to be immediate, and cellular culture studies that note glucose uptake also note that prolonged (60m) exposure to leucine eliminates any glucose uptake induced by it,[58] which suggests some form of negative feedback. Additionally, this may explain why the leucine-stimulated increase in glucose uptake is suppressed after 60 minutes.[58]

The state of hyperaminoacidemia has been noted to induce a transient and reversible state of insulin resistance, thought to be related to the leucine content[60] and elevated plasma BCAAs are noted in obesity and are correlated with insulin resistance.[68][69] Fasting is accompanied by reduced amino acids in serum and increased insulin sensitivity (thought to be due to the amino acid reduction)[61] and on a cellular level this is alleviated with leucine[59] and seen with mixed amino acids in vivo.[61]

Valine has also shown an inhibitory effect on glucose uptake into muscle cells, but it appears to be more fast acting than leucine (0.3g/kg of either amino acid causing a spike in glucose relative to contrl at 30 minutes (valine) or 90 minutes with leucine).[70]

Leucine, secondary to signalling for muscle protein synthesis, can also suppress glucose uptake into a cell after incubation for about an hour or so, since it may be stimulatory until it suppresses its own actions. Valine has been noted to increase serum glucose more rapidly in the body, suggesting either a faster negative regulation or just no promotion of glucose uptake

Isoleucine is known to promote muscular uptake of glucose.[70][71][72] The effects of isoleucine (which can be read in depth on its respective page) appear to mostly be mostly independent of the mTOR/AMPK axis, fully dependent on PI3K/PKC, and possibly related to reducing gluconeogenesis of fatty acids (producing less glucose would cause more to need to be taken up from the blood to meet cellular demands).

Isoleucine is not known to increase glycogen synthesis[70] like leucine is[73] possibly due to glycogen synthesis from amino acids being dependent on mTOR activation[74][73] which is the result of leucine[62] and not isoleucine.[58]

Isoleucine counters leucine and can promote glucose uptake into a muscle cell, and although the mechanisms are not fully established, it may be secondary to reducing gluconeogenesis of amino acids. Glycogen synthesis is not upregulated with isoleucine, only uptake and consumption

Both Valine and isoleucine are glucogenic amino acids, and may be converted into glucose in the human body,[75] leucine is unable to do this and is known as ketogenic (produces ketone bodies).

Two of the three BCAAs (not leucine) can be converted into glucose

4.2. Glycogen

It has been noted that activation of BCAA transaminase occurs during glycogen depletion[76][77] and that the two BCAAs known as isoleucine and valine are capable of being converted to succinyl-CoA (and possibly increase fat oxidation secondary to oxaloacetate;[78] any increase in fat oxidation being able to suppress the rate of glycogen loss during exercise due to comparatively using more lipids).

Branched chain amino acid supplementation has been noted to preserve hepatic and skeletal muscle glycogen stores after a bout of acute exercise relative to placebo[13][45] which has been noted in humans subject to submaximal cycling with 90mg/kg BCAAs[79] with no inherent effect on glycogen at rest.[13]

300g/kg BCAA supplementation (distribution not disclosed) has noted an increase in blood glucose without altering plasma free fatty acids and lactate in otherwise healthy men subject to glycogen depletion, although a reduction in RER (indicative of more fat oxidation) was noted.[78]

4.3. Blood Glucose

Possibly related to the general benefits in liver pathology (usually chronic hepatitis),[80][81] increased muscular glucose uptake has been noted in a rat model of liver cirrhosis[82] which has spurred human research. In persons with chronic hepatitis C and insulin resistance given BCAA supplementation (12.45g after breakfast and dinner and one before sleep) was able to improve insulin sensitivity (Matsuda; no change in HOMA-IR) in a subset of the sample who also benefitted with reduced HbA1c; this did not occur in all persons.[83]

There appear to be possible benefits to insulin sensitivity and muscular glucose uptake in people with hepatitis, but this affect appears to be unreliable

4.4. Insulin Sensitivity

Serum BCAAs appear to be elevated in the fasted state in both obesity[84][85] and when investigating dietary intake of insulin sensitive and resistant persons (resistance also associated with higher fasting BCAA intake[68] and improvement upon weight loss is correlated with normalization of BCAA metabolism[86]) there do not appear to be large dietary differences.[87][69]

At least in rats, the increase in serum BCAAs appears to correlate with less activity of the BCKDH enzyme complex in adipose tissue[88] and this enzyme complex appears to be downregulated in the adipose of obese, insulin resistance individuals relative to their monozygotic twins.[89] Although less researched, it is possible this extends to skeletal muscle tissue as well as a downregulation of some enzymes in the BCAA catabolic chain (methyl-malonate-semialdehyde dehydrogenase and propionyl-CoA carboxylase β) have been noted in humans.[90]

It is theoretically plausible that excess serum leucine can exacerbate insulin resistance, but the overall relationship is not completely clear[91] since both leucine deprivation[92] and high leucine feeding[93] improve insulin resistant states in rats.

In insulin resistant states, there appears to be a higher circulating level of BCAAs, which is due to the catabolism of BCAAs being impaired. The serum BCAAs are more a biomarker of insulin resistance than anything (signifying a disturbance of adipose-related insulin sensitivity) and their potentially causative role is not well understood


Edit5. Skeletal Muscle and Physical Performance

5.1. Mechanisms (Skeletal Muscle)

Leucine is able to activate a protein known as 'Target of Rapamycin' (TOR or mTOR in mammals) which stimulates protein synthesis, and inhibiting this protein can prevent the anabolic effects of leucine in rats[94] and humans.[95] mTOR is commonly referred to as the main metabolic target of leucine, and mTOR itself activates the p70 subunit of S6 Kinase (p70S6K in short, ultimately via Ser483[96]) which upregulates ribosomal protein S6 and protein synthesis via signalling through the genome.[97] The eukaryotic binding factor (eIF) is activated and its binding factor (the eukaryotic initiation factor 4E-binding protein; 4E-BP1) suppressed by mTOR[98][99][100] and beyond leucine mTOR can be activated by exercise (muscle contraction, requires a 1-2 hour delay[101][102] related to increasing phosphatidic acid signalling[103] and reducing negative regulators[104]) insulin,[105] and a caloric excess (without altering nutrition) can increase mTOR activity.[106]

This has all been found in human muscle (assessed via biopsy) following exercise and ingestion of BCAAs at [97] and mTOR activation has been noted in human muscle at rest following ingestion of BCAAs[107] and isolated leucine[108][109] and both 4E-BP1 and p70S6K have also been confirmed with BCAA[110] and leucine.[111]

Although Akt (also known as Protein Kinase B or PKB; downstream of the insulin receptor and upstream of mTOR) can activate mTOR directly[112] or indirectly via TSC2[113][114] which enhances protein translation (via deactivating GSK-3 and enhancing eIF2B signalling[115]) induced by S6K1[116] this pathway is mostly irrelevant to leucine supplementation as leucine does not influence Akt nor GSK-3.[111][97]

The anabolic effects of leucine are mediated via the mTOR pathway, which responds to dietary leucine to induce muscle protein synthesis. Although mTOR is activated by Akt/PKB signalling (usually from insulin signalling), leucine does not activate this protein and seems to selectively activate mTOR

MAFbx (muscle atrophy F-box) and MuRF-1 (muscle RING-finger 1) are two muscle specific proteins associated with catabolism and atrophy[117][118] which are positively regulated by FOXO signalling[119] (FOXO signalling is negatively regulated by PI3K/Akt[120]).

mRNA for MAFbx appears to be reduced by BCAA supplementation (85mg/kg with 45% leucine and 30% valine) following rest (30%) and exercise (50%) and MuRF-1 levels which are induced by exercise are augmented (50% greater than placebo) with BCAA supplementation despite the protein content of MuRF-1 being suppressed (20% increase in placebo).[121]

Proteins involved in muscle protein atrophy (breakdown) appear to be suppressed following ingestion of BCAA supplementation and exercise, which could be an indirect mechanism of muscle protein synthesis

Leucine may also increase insulin secretion,[122][123] and insulin can induce phosphorylation of mTOR via its receptor.[105] So although branched chain amino acids and leucine regulate protein synthesis via an Akt/mTOR axis, so does insulin.[100] The usage of norleucine, which shares the properties of leucine in regards to mTOR but not in the secretion of insulin demonstrate that insulin per se is not required to achieve relatively similar levels of protein synthesis.[124][125][126]

Leucine can act on mTOR directly, but may additively work via this pathway, secondary to insulin release from the pancreatic beta-cells

5.2. Mechanisms (Fatigue)

Ammonia (a possible promotor of fatigue associated with muscle breakdown[127][34]) appears to have bilateral influences with BCAA supplementation. Increasing the dietary intake of BCAAs to 3.57% in rats (a 50% dietary intake for 6 weeks) is able to improve exercise by 37% associated with a reduction in ammonia production while a 100% increase (4.76% overall) reverses this trend and impairs exercise by 43% associated with an increase in ammonia production.[45] In humans, 100mg/kg of a 2:1:1 BCAA solution (favoring leucine) prior to a squat exercise in untrained females appears to increase ammonia concentrations relative to placebo 0-2 hours after exercise yet decrease it at 2 days after (no difference at 3 days).[128]

Lactate has been noted to be decreased in untrained females given 100mg/kg BCAAs[128] but does not appear to be a requirement in rats (fatigue has been noted to be reduced despite no changes in lactate).[45]

BCAA supplementation prior to exercise (beyond the serotonergic mechanisms) may also reduce glycogen depletion rates and is known to interact with ammonia in serum

5.3. Interventions (Aesthetics)

4g of isolated leucine supplementation in untrained men (dietary protein intake of 0.90g/kg) given a new workout program for 12 weeks is able to promote power output (from 31.0% in placebo to 40.8%) without significantly affecting lean mass or fat mass.[129]

In trained men given 14g BCAAs daily for 8 weeks alongside a routine weightlifting plan, consumption of BCAAs promoted fat loss (2.2% body fat) and promoted lean mass accrual (4.2kg) to a greater extent than 28g whey protein (2.1kg lean mass and 1.2% body fat) and 28g carbohydrate (1.4kg lean mass and 0.6% body fat).[2] Although this study is promising, it has a few complications (diet was not recorded nor controlled, BCAAs were confounded with the inclusion of Glutamine (5g) and Citrulline malate (2g), funded by a supplement company known as Scivation).[2]

Currently, the evidence examines muscle protein synthesis is promising, but there are a few problems with interpreting this research: aside from being externally funded by the producers of the supplement, it was further confounded with Glutamine and Citrulline and possibly also B6, as this study likely used the Scivation product known as Xtend, despite not saying that outright

5.4. Interventions (Fatigue)

In twelve elite male offshore racers divided into two groups prior to a prolonged test (33 hours and 155 miles) ingesting a supplement containing high levels of BCAAs (36.25g valine, 25.4g leucine, 10.9g isoleucine) ever six hours noted that the supplementation group noted that only on the second day of sailing did the BCAA group report themselves as less tired while the increase in memory errors noted in control did not occur in BCAAs.[130] Elsewhere, 6-8 hours of ski mountaineering have failed to get benefit (assessed by power output on a erg) with BCAA supplementation[131] while one study comparing a 91g glucose beverage as placebo against a 40g glucose/51g amino acid (BCAA and Arginine) in fatigue on a mountain trial walking test (14km, 2857m mountain) in older individuals noted that the substitution of amino acids preserved jump squat performance by 10% (but only a trend to reduce perceived soreness).[132]

For trials that are prolonged and involve outdoor activities (skiing, hiking, sailing), supplementation of BCAAs in high doses (usually above 50g taken over multiple hours) appears to reduce physical and mental fatigue by a small amount

In trained cyclists given supplemental BCAAs (90mg/kg of 40% valine and 35% leucine) during cycling and rating their perceived fatigue every 10 minutes, BCAA supplementation was associated with a 7% reduction in percieved exertion and 15% reduction in mental fatigue, and an antifatigue effect was noted after the workout as assessed by stroop test.[79] There was no significant performance enhancement associated with BCAA supplementation, as although 3 subjects had improvements the other 4 did not[79] and this lack of performance enhancement has been noted elsewhere in trained cyclists given 6-18g BCAA.[133] Elsewhere, BCAA supplementation during a marathon has noted benefits to performance only in the slower runners and not in the faster runners (although antifatigue effects were noted in both groups given BCAAs as assessed via Stroop test)[134] while a test in 'active healthy males' (no indiciation of having a training status) noted a 17.2% increased time to exhaustion in cycling with 300mg/kg BCAA supplementation.[78]

In 6 females given a drink containing 7.5g BCAAs per liter (40% valine and 35% leucine) with 6% carbohydrates (relative to carbohydrate only placebo) during a soccer game noted that the stroop colour and word test after the game (biomarker of fatigue) was improved with BCAAs; physical performance not measured and overall liquid consumption not recorded.[135] Another study has used a simulated soccer test (via treadmill) with 7g BCAA one hour prior to exercise noted that BCAA supplementation was able to preserve reaction time after exercise.[136]

In aerobic exercise, such as cycling or team sports (soccer), supplementation of BCAAs appears to preserve cognition in the later stages of exercise and appears to reduce neural fatigue. There does not appear to be a reliable enhancement of physical performance, although it may occur in untrained people

In 12 untrained females given BCAA supplementation (approximately a 2:1:1 ratio favoring leucine) at 100mg/kg prior to high volume squat exercises noted that the BCAA group (relative to carbohydrate placebo) experienced less soreness when measured 2 days later (peak soreness from this protocol[7]) and the reduction of power output seen in placebo at this time (80% of baseline) was abolished[128] (study replicated in Medline[137]).

BCAAs ingested prior to resistance training protocols may be able to reduce soreness relative to carbohydrates. It is unsure (but plausible) that this can be mimicked through dietary protein intake


Edit6. Safety and Toxicity

6.1. General

Testing the Tolerable Upper Intake (TUL) in young healthy men given graded intakes of Leucine (50-1250mg/kg bodyweight; correlating to Estimated Average Requirement[6] and up to 25-fold the EAR) the estimated TUL was set at 500mg/kg bodyweight (about 35g daily for average weight males) due to levels higher than that causing an increase in serum ammonia.[138]

References

  1. A multi-nutrient supplement reduced markers of inflammation and improved physical performance in active individuals of middle to older age: a randomized, double-blind, placebo-controlled study
  2. Consuming a supplement containing branched-chain amino acids during a resistance-training program increases lean mass, muscle strength and fat loss
  3. Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: a randomized control trial
  4. Yoshizawa F. New therapeutic strategy for amino acid medicine: notable functions of branched chain amino acids as biological regulators. J Pharmacol Sci. (2012)
  5. Dietary Protein Impact on Glycemic Control during Weight Loss
  6. Riazi R, et al. The total branched-chain amino acid requirement in young healthy adult men determined by indicator amino acid oxidation by use of L-{1-13C}phenylalanine. J Nutr. (2003)
  7. Nutraceutical Effects of Branched-Chain Amino Acids on Skeletal Muscle
  8. Ahlborg G, et al. Substrate turnover during prolonged exercise in man. Splanchnic and leg metabolism of glucose, free fatty acids, and amino acids. J Clin Invest. (1974)
  9. Wahren J, Felig P, Hagenfeldt L. Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus. J Clin Invest. (1976)
  10. Harris RA, et al. Regulation of the branched-chain alpha-ketoacid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease. Adv Enzyme Regul. (1990)
  11. Shimomura Y, et al. Branched-chain alpha-keto acid dehydrogenase complex in rat skeletal muscle: regulation of the activity and gene expression by nutrition and physical exercise. J Nutr. (1995)
  12. Kobayashi R, et al. Hepatic branched-chain alpha-keto acid dehydrogenase complex in female rats: activation by exercise and starvation. J Nutr Sci Vitaminol (Tokyo). (1999)
  13. Shimomura Y, et al. Suppression of glycogen consumption during acute exercise by dietary branched-chain amino acids in rats. J Nutr Sci Vitaminol (Tokyo). (2000)
  14. Howarth KR, et al. Exercise training increases branched-chain oxoacid dehydrogenase kinase content in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol. (2007)
  15. Harper AE, Miller RH, Block KP. Branched-chain amino acid metabolism. Annu Rev Nutr. (1984)
  16. Damuni Z, Reed LJ. Purification and properties of the catalytic subunit of the branched-chain alpha-keto acid dehydrogenase phosphatase from bovine kidney mitochondria. J Biol Chem. (1987)
  17. Popov KM, et al. Branched-chain alpha-ketoacid dehydrogenase kinase. Molecular cloning, expression, and sequence similarity with histidine protein kinases. J Biol Chem. (1992)
  18. Shimomura Y, et al. Purification and partial characterization of branched-chain alpha-ketoacid dehydrogenase kinase from rat liver and rat heart. Arch Biochem Biophys. (1990)
  19. Shimomura Y, et al. Regulation of branched-chain amino acid catabolism: nutritional and hormonal regulation of activity and expression of the branched-chain alpha-keto acid dehydrogenase kinase. Curr Opin Clin Nutr Metab Care. (2001)
  20. Suryawan A, et al. A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr. (1998)
  21. Xu M, et al. Mechanism of activation of branched-chain alpha-keto acid dehydrogenase complex by exercise. Biochem Biophys Res Commun. (2001)
  22. Paxton R, Harris RA. Regulation of branched-chain alpha-ketoacid dehydrogenase kinase. Arch Biochem Biophys. (1984)
  23. Kobayashi R, et al. Clofibric acid stimulates branched-chain amino acid catabolism by three mechanisms. Arch Biochem Biophys. (2002)
  24. Teräväinen H, Larsen A, Hillbom M. Clofibrate-induced myopathy in the rat. Acta Neuropathol. (1977)
  25. Paul HS, Adibi SA. Paradoxical effects of clofibrate on liver and muscle metabolism in rats. Induction of myotonia and alteration of fatty acid and glucose oxidation. J Clin Invest. (1979)
  26. Shiraki M, et al. Activation of hepatic branched-chain alpha-keto acid dehydrogenase complex by tumor necrosis factor-alpha in rats. Biochem Biophys Res Commun. (2005)
  27. Shimomura Y, et al. Branched-chain 2-oxo acid dehydrogenase complex activation by tetanic contractions in rat skeletal muscle. Biochim Biophys Acta. (1993)
  28. Wagenmakers AJ, et al. Exercise-induced activation of the branched-chain 2-oxo acid dehydrogenase in human muscle. Eur J Appl Physiol Occup Physiol. (1989)
  29. Yoshiji H, et al. Combination of branched-chain amino acid and angiotensin-converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis. Mol Med Report. (2012)
  30. Reynolds B, et al. Amino acid transporters and nutrient-sensing mechanisms: new targets for treating insulin-linked disorders. Biochem Soc Trans. (2007)
  31. Boado RJ, et al. Selective expression of the large neutral amino acid transporter at the blood-brain barrier. Proc Natl Acad Sci U S A. (1999)
  32. Pardridge WM, Choi TB. Neutral amino acid transport at the human blood-brain barrier. Fed Proc. (1986)
  33. Effects of leucine on intestinal absorption of tryptophan in rats
  34. Ament W, Verkerke GJ. Exercise and fatigue. Sports Med. (2009)
  35. Davis JM, Alderson NL, Welsh RS. Serotonin and central nervous system fatigue: nutritional considerations. Am J Clin Nutr. (2000)
  36. Blomstrand E. A role for branched-chain amino acids in reducing central fatigue. J Nutr. (2006)
  37. Blomstrand E. Amino acids and central fatigue. Amino Acids. (2001)
  38. Blomstrand E, Celsing F, Newsholme EA. Changes in plasma concentrations of aromatic and branched-chain amino acids during sustained exercise in man and their possible role in fatigue. Acta Physiol Scand. (1988)
  39. Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological regulation by plasma neutral amino acids. Science. (1972)
  40. Fernstrom JD, Faller DV. Neutral amino acids in the brain: changes in response to food ingestion. J Neurochem. (1978)
  41. Pardridge WM. Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res. (1998)
  42. Blomstrand E, et al. Effect of carbohydrate ingestion on brain exchange of amino acids during sustained exercise in human subjects. Acta Physiol Scand. (2005)
  43. Nybo L, et al. Neurohumoral responses during prolonged exercise in humans. J Appl Physiol. (2003)
  44. Meeusen R, et al. Effects of tryptophan and/or acute running on extracellular 5-HT and 5-HIAA levels in the hippocampus of food-deprived rats. Brain Res. (1996)
  45. Falavigna G, et al. Effects of diets supplemented with branched-chain amino acids on the performance and fatigue mechanisms of rats submitted to prolonged physical exercise. Nutrients. (2012)
  46. Gomez-Merino D, et al. Evidence that the branched-chain amino acid L-valine prevents exercise-induced release of 5-HT in rat hippocampus. Int J Sports Med. (2001)
  47. Armon C. Sports and trauma in amyotrophic lateral sclerosis revisited. J Neurol Sci. (2007)
  48. Chiò A, et al. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain. (2005)
  49. Belli S, Vanacore N. Proportionate mortality of Italian soccer players: is amyotrophic lateral sclerosis an occupational disease. Eur J Epidemiol. (2005)
  50. Valenti M, et al. Amyotrophic lateral sclerosis and sports: a case-control study. Eur J Neurol. (2005)
  51. Carunchio I, et al. Increased levels of p70S6 phosphorylation in the G93A mouse model of Amyotrophic Lateral Sclerosis and in valine-exposed cortical neurons in culture. Exp Neurol. (2010)
  52. Vucic S, Kiernan MC. Cortical excitability testing distinguishes Kennedy's disease from amyotrophic lateral sclerosis. Clin Neurophysiol. (2008)
  53. Zanette G, et al. Changes in motor cortex inhibition over time in patients with amyotrophic lateral sclerosis. J Neurol. (2002)
  54. Pieri M, et al. Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis. Exp Neurol. (2009)
  55. van Zundert B, et al. Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J Neurosci. (2008)
  56. Hinault C, et al. Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from db/db mice. FASEB J. (2004)
  57. Uberall F, et al. Evidence that atypical protein kinase C-lambda and atypical protein kinase C-zeta participate in Ras-mediated reorganization of the F-actin cytoskeleton. J Cell Biol. (1999)
  58. Nishitani S, et al. Leucine promotes glucose uptake in skeletal muscles of rats. Biochem Biophys Res Commun. (2002)
  59. Chang TW, Goldberg AL. Leucine inhibits oxidation of glucose and pyruvate in skeletal muscles during fasting. J Biol Chem. (1978)
  60. Tessari P, et al. Hyperaminoacidaemia reduces insulin-mediated glucose disposal in healthy man. Diabetologia. (1985)
  61. Flakoll PJ, et al. Short-term regulation of insulin-mediated glucose utilization in four-day fasted human volunteers: role of amino acid availability. Diabetologia. (1992)
  62. Du M, et al. Leucine stimulates mammalian target of rapamycin signaling in C2C12 myoblasts in part through inhibition of adenosine monophosphate-activated protein kinase. J Anim Sci. (2007)
  63. Hardie DG. Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism. Proc Nutr Soc. (2011)
  64. O'Neill HM. AMPK and Exercise: Glucose Uptake and Insulin Sensitivity. Diabetes Metab J. (2013)
  65. Tremblay F, Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem. (2001)
  66. Takano A, et al. Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin. Mol Cell Biol. (2001)
  67. Haruta T, et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol. (2000)
  68. Newgard CB, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. (2009)
  69. Wang TJ, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. (2011)
  70. Doi M, et al. Isoleucine, a potent plasma glucose-lowering amino acid, stimulates glucose uptake in C2C12 myotubes. Biochem Biophys Res Commun. (2003)
  71. Doi M, et al. Hypoglycemic effect of isoleucine involves increased muscle glucose uptake and whole body glucose oxidation and decreased hepatic gluconeogenesis. Am J Physiol Endocrinol Metab. (2007)
  72. Doi M, et al. Isoleucine, a blood glucose-lowering amino acid, increases glucose uptake in rat skeletal muscle in the absence of increases in AMP-activated protein kinase activity. J Nutr. (2005)
  73. Peyrollier K, et al. L-leucine availability regulates phosphatidylinositol 3-kinase, p70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin (mTOR) pathway in the L-leucine-induced up-regulation of system A amino acid transport. Biochem J. (2000)
  74. Armstrong JL, et al. Regulation of glycogen synthesis by amino acids in cultured human muscle cells. J Biol Chem. (2001)
  75. Letto J, Brosnan ME, Brosnan JT. Valine metabolism. Gluconeogenesis from 3-hydroxyisobutyrate. Biochem J. (1986)
  76. van Hall G, et al. Mechanisms of activation of muscle branched-chain alpha-keto acid dehydrogenase during exercise in man. J Physiol. (1996)
  77. Gibala MJ, Young ME, Taegtmeyer H. Anaplerosis of the citric acid cycle: role in energy metabolism of heart and skeletal muscle. Acta Physiol Scand. (2000)
  78. Gualano AB, et al. Branched-chain amino acids supplementation enhances exercise capacity and lipid oxidation during endurance exercise after muscle glycogen depletion. J Sports Med Phys Fitness. (2011)
  79. Blomstrand E, et al. Influence of ingesting a solution of branched-chain amino acids on perceived exertion during exercise. Acta Physiol Scand. (1997)
  80. Marchesini G, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology. (2003)
  81. Kawamura-Yasui N, et al. Evaluating response to nutritional therapy using the branched-chain amino acid/tyrosine ratio in patients with chronic liver disease. J Clin Lab Anal. (1999)
  82. Nishitani S, et al. Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol. (2005)
  83. Takeshita Y, et al. Beneficial effect of branched-chain amino acid supplementation on glycemic control in chronic hepatitis C patients with insulin resistance: implications for type 2 diabetes. Metabolism. (2012)
  84. Felig P, Marliss E, Cahill GF Jr. Plasma amino acid levels and insulin secretion in obesity. N Engl J Med. (1969)
  85. Caballero B, Finer N, Wurtman RJ. Plasma amino acids and insulin levels in obesity: response to carbohydrate intake and tryptophan supplements. Metabolism. (1988)
  86. Shah SH, et al. Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss. Diabetologia. (2012)
  87. Tai ES, et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia. (2010)
  88. She P, et al. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab. (2007)
  89. Pietiläinen KH, et al. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med. (2008)
  90. Lefort N, et al. Increased reactive oxygen species production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle. Diabetes. (2010)
  91. Lu J, et al. Insulin resistance and the metabolism of branched-chain amino acids. Front Med. (2013)
  92. Xiao F, et al. Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes. (2011)
  93. Dietary Leucine - An Environmental Modifier of Insulin Resistance Acting on Multiple Levels of Metabolism
  94. Anthony JC, et al. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J Nutr. (2000)
  95. Drummond MJ, et al. Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis. J Physiol. (2009)
  96. Phosphorylation and Activation of p70s6k by PDK1
  97. Blomstrand E, et al. Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. J Nutr. (2006)
  98. Wang X, Proud CG. The mTOR pathway in the control of protein synthesis. Physiology (Bethesda). (2006)
  99. Proud CG. mTOR-mediated regulation of translation factors by amino acids. Biochem Biophys Res Commun. (2004)
  100. Kimball SR, Jefferson LS. Regulation of global and specific mRNA translation by oral administration of branched-chain amino acids. Biochem Biophys Res Commun. (2004)
  101. Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle
  102. Resistance Exercise Increases Muscle Protein Synthesis and Translation of Eukaryotic Initiation Factor 2Bϵ mRNA in a Mammalian Target of Rapamycin-dependent Manner
  103. Hornberger TA, Chien S. Mechanical stimuli and nutrients regulate rapamycin-sensitive signaling through distinct mechanisms in skeletal muscle. J Cell Biochem. (2006)
  104. Corradetti MN, Inoki K, Guan KL. The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J Biol Chem. (2005)
  105. Vander Haar E, et al. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. (2007)
  106. Elmadhun NY, et al. Metformin alters the insulin signaling pathway in ischemic cardiac tissue in a swine model of metabolic syndrome. J Thorac Cardiovasc Surg. (2013)
  107. Louard RJ, Barrett EJ, Gelfand RA. Effect of infused branched-chain amino acids on muscle and whole-body amino acid metabolism in man. Clin Sci (Lond). (1990)
  108. Nair KS, Schwartz RG, Welle S. Leucine as a regulator of whole body and skeletal muscle protein metabolism in humans. Am J Physiol. (1992)
  109. Alvestrand A, et al. Influence of leucine infusion on intracellular amino acids in humans. Eur J Clin Invest. (1990)
  110. Liu Z, et al. Branched chain amino acids activate messenger ribonucleic acid translation regulatory proteins in human skeletal muscle, and glucocorticoids blunt this action. J Clin Endocrinol Metab. (2001)
  111. Greiwe JS, et al. Leucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscle. Am J Physiol Endocrinol Metab. (2001)
  112. Navé BT, et al. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J. (1999)
  113. Inoki K, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. (2002)
  114. Manning BD, et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. (2002)
  115. Glass DJ. Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat Cell Biol. (2003)
  116. Browne GJ, Proud CG. Regulation of peptide-chain elongation in mammalian cells. Eur J Biochem. (2002)
  117. Jones SW, et al. Disuse atrophy and exercise rehabilitation in humans profoundly affects the expression of genes associated with the regulation of skeletal muscle mass. FASEB J. (2004)
  118. Bodine SC, et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science. (2001)
  119. Sandri M, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. (2004)
  120. Stitt TN, et al. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell. (2004)
  121. Borgenvik M, Apró W, Blomstrand E. Intake of branched-chain amino acids influences the levels of MAFbx mRNA and MuRF-1 total protein in resting and exercising human muscle. Am J Physiol Endocrinol Metab. (2012)
  122. Newsholme P, et al. New insights into amino acid metabolism, beta-cell function and diabetes. Clin Sci (Lond). (2005)
  123. Co-Ingestion of a Protein Hydrolysate with or without Additional Leucine Effectively Reduces Postprandial Blood Glucose Excursions in Type 2 Diabetic Men
  124. Lynch CJ, et al. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Am J Physiol Endocrinol Metab. (2002)
  125. Lynch CJ, et al. Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats. Am J Physiol Endocrinol Metab. (2002)
  126. Lynch CJ, et al. Regulation of amino acid-sensitive TOR signaling by leucine analogues in adipocytes. J Cell Biochem. (2000)
  127. Jin G, et al. Changes in plasma and tissue amino acid levels in an animal model of complex fatigue. Nutrition. (2009)
  128. Shimomura Y, et al. Branched-chain amino acid supplementation before squat exercise and delayed-onset muscle soreness. Int J Sport Nutr Exerc Metab. (2010)
  129. Ispoglou T, et al. Daily L-leucine supplementation in novice trainees during a 12-week weight training program. Int J Sports Physiol Perform. (2011)
  130. Portier H, et al. Effects of branched-chain amino acids supplementation on physiological and psychological performance during an offshore sailing race. Eur J Appl Physiol. (2008)
  131. Bigard AX, et al. Branched-chain amino acid supplementation during repeated prolonged skiing exercises at altitude. Int J Sport Nutr. (1996)
  132. Shimizu M, et al. Energy expenditure during 2-day trail walking in the mountains (2,857 m) and the effects of amino acid supplementation in older men and women. Eur J Appl Physiol. (2012)
  133. van Hall G, et al. Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance. J Physiol. (1995)
  134. Blomstrand E, et al. Administration of branched-chain amino acids during sustained exercise--effects on performance and on plasma concentration of some amino acids. Eur J Appl Physiol Occup Physiol. (1991)
  135. Effect of branched-chain amino acid supplementation on mental performance
  136. Wiśnik P, et al. The effect of branched chain amino acids on psychomotor performance during treadmill exercise of changing intensity simulating a soccer game. Appl Physiol Nutr Metab. (2011)
  137. Shimomura Y, et al. Effects of squat exercise and branched-chain amino acid supplementation on plasma free amino acid concentrations in young women. J Nutr Sci Vitaminol (Tokyo). (2009)
  138. Elango R, et al. Determination of the tolerable upper intake level of leucine in acute dietary studies in young men. Am J Clin Nutr. (2012)
  139. Blomstrand E, Hassmén P, Newsholme EA. Effect of branched-chain amino acid supplementation on mental performance. Acta Physiol Scand. (1991)

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