Leucine: Functions

Leucine occupies a special function in protein metabolism. The essential amino acid is predominantly involved in building new tissues and is very effective for enhanced protein biosynthesis in muscle and liver. In muscle tissue, leucine inhibits protein breakdown and promotes the maintenance and build-up of muscle protein. In addition, the branched-chain amino acid supports healing processes.Leucine plays an essential role in:

  • Strength and endurance sports
  • STH secretion
  • Stress
  • Diseases and diet

Leucine as an energy supplier in strength and endurance sportsLeucine enters the hepatocytes (liver cells) after absorption via the portal vein. This is where amino acid breakdown takes place. Ammonia (NH3) is cleaved from leucine, producing an alpha-keto acid. Alpha-keto acids can be used directly for energy production. In addition, they serve as a precursor for the synthesis of acetyl-coenzyme A.Acetyl-CoA is an essential starting product of lipogenesis – formation of fatty acids. Since leucine is a ketogenic amino acid, acetyl-CoA as a product of fatty acid breakdown can also be used for the synthesis of ketone bodies (ketogenesis). Both fatty acids and the ketone bodies acetacetate and betahydroxybutyrate represent important energy suppliers to the body – especially during physical exertion.Ketone bodies are formed in the mitochondria of the liver, particularly during periods of reduced carbohydrate intake, for example during fasting cures or in preparation for competitions, and serve as an energy source for the central nervous system. In starvation metabolism, the brain can obtain up to 80% of its energy from ketone bodies. Meeting energy needs from ketone bodies during a dietary restriction serves to conserve glucose. Thus, leucine reduces both the breakdown of glucose in muscle and brain and the catabolism of muscle protein for gluconeogenesis (new glucose formation).In contrast, isoleucine and valine are used mainly for gluconeogenesis in liver and muscle during periods of carbohydrate deficiency. In contrast, erythrocytes (red blood cells) and the renal medulla cannot use ketone bodies for energy production and are completely dependent on glucose.When glucose and fatty acids are broken down in the muscles, adenosine triphosphate (ATP) is formed, the cell’s most important energy carrier. When its phosphate bonds are hydrolytically cleaved by enzymes, ADP or AMP is formed. The energy released in this process enables chemical, osmotic or mechanical work, such as muscle contractions. After processing in the liver, almost 70% of all amino acids entering the blood are BCAAs. They are rapidly absorbed by the muscles. In the first three hours after a high-protein meal, leucine, isoleucine, and valine account for about 50-90% of the muscles’ total amino acid intake. Muscle tissue is made up of 20% protein. The BCAAs are a component of these muscle proteins, which in detail include the contractile proteins actin, myosin, troponin and tropomyosin, the enzymes of energy metabolism, the scaffold protein alpha-actinin and myoglobin. The latter, like the hemoglobin of the blood, can absorb, transport and release oxygen. Thus, myoglobin enables the slowly contracting skeletal muscle to produce energy aerobically.Physical exertion leads to the oxidation of amino acids. In this process, proteins are burned for energy. The resulting metabolic products have a significant influence on growth processes, among other things. When leucine is oxidized in muscle tissue, ketoisocaproate (KIC) is formed, which presumably stimulates protein formation and thus muscle growth. Oxidation of KIC produces beta-hydroxy methyl butyrate (HMB), which prevents the breakdown of muscle protein and may thus contribute to the maintenance of muscle mass.The BCAAs promote the release of insulin from the beta cells of the pancreas (pancreas), with leucine having the strongest insulin-stimulating effect. In addition, the amino acids arginine and phenylalanine also increase insulin release. High insulin concentrations in the blood accelerate amino acid uptake into myocytes (muscle cells).Increased transport of amino acids into myocytes leads to the following processes.

  • Increased protein buildup in the muscles
  • Rapid decrease in the concentration of the stress hormone cortisol, which promotes muscle breakdown and inhibits amino acid uptake into muscle cells
  • Better storage of glycogen in myocytes, maintenance of muscle glycogen.

Finally, an intake of foods rich in leucine, isoleucine and valine results in optimal muscle growth and maximum accelerated regeneration.For the breakdown and conversion of BCAAs, biotin, vitamin B5 (pantothenic acid) and vitamin B6 (pyridoxine) are essential. Only as a result of a sufficient supply of these vitamins can the branched-chain amino acids be optimally metabolized and used. A deficit of vitamin B6 can lead to a leucine deficiency.Several studies show that both endurance sports and strength training require an increased protein intake. In order to maintain a positive nitrogen balance – corresponding to tissue regeneration – the daily protein requirement for endurance athletes is between 1.2 and 1.4 g per kg body weight and for strength athletes 1.7-1.8 g per kg body weight.During endurance sports, leucine, isoleucine and valine in particular are used for energy production. The supply of energy from these amino acids increases when the glycogen stores in the liver and muscles become increasingly depleted as physical activity progresses. The reason for this is that the organism initially relies on glucose for energy production during physical exertion. If there is no longer sufficient glucose available, proteins are broken down from the liver and muscles. Finally, endurance athletes should consume sufficient carbohydrates as well as proteins in their diet in order to prevent protein breakdown. In this way, the organism does not fall back on its own BCAAs from the muscles during physical exertion and protein catabolism is prevented. The supply of BCAAs is also recommended after training. Leucine quickly raises insulin levels after the end of training, stops protein breakdown caused by the previous exertion and initiates renewed muscle growth. In order to be able to use leucine optimally in terms of muscle building, attention should be paid to the supply of high-quality protein with a high leucine content. A protein is of high quality if, on the one hand, it contains essential and non-essential amino acids in a balanced ratio. On the other hand, the proportion of absorbed dietary protein that is retained in the body to meet individual requirements for defined physiological functions plays a role.The joint intake of branched-chain amino acids in the ratio leucine:isoleucine:valine = 1-2:1:1 in combination with other protein is also recommended. Isolated intake of isoleucine or leucine or valine may temporarily interfere with protein biosynthesis for muscle building.A sole intake of BCAAs should be considered critically, especially before endurance training, due to oxidation under stress and urea attack. The breakdown of 1 gram of BCAAs produces about 0.5 grams of urea. Excessive urea concentrations put a strain on the organism. Therefore, in connection with BCAAs intake, increased fluid intake is crucial. With the help of plenty of fluid, the urea can be quickly eliminated via the kidneys. Finally, an increased intake of isoleucine, leucine or valine must be weighed up during endurance exercise.Performance improvements for the endurance athlete only occur when the BCAAs are used during altitude training or training in high heat.As a result of a high protein intake or physical stress, high amounts of nitrogen in the form of ammonia (NH3) are produced as a result of protein breakdown. This has a neurotoxic effect in higher concentrations and can result, for example, in hepatic encephalopathy. This condition is a potentially reversible brain dysfunction that results from inadequate detoxification function of the liver. Most importantly, by increasing protein biosynthesis (new protein formation) and decreasing protein breakdown, leucine and isoleucine can reduce the level of free toxic ammonia in the muscles-a significant benefit to the athlete. In the liver, arginine and ornithine keep the ammonia concentration at a low level.Scientific studies have shown that the administration of 10-20 grams of BCAAs under stress can delay mental fatigue [5, 6 12].However, there is still no evidence that branched-chain amino acids lead to an increase in performance. Similarly, improved adaptation to exercise has not been demonstrated.

Effectiveness of oral leucine supplementation for increased STH secretion

Somatotropic hormone (STH) stands for somatotropin, a growth hormone produced in the adenohypophysis – anterior pituitary gland. It is secreted in batches and broken down in the liver within a short time. Subsequently, somatomedins (growth factors) are synthesized. STH and somatomedins are essential for normal growth in length. Especially during puberty, its production is very pronounced. STH affects almost all tissues of the body, especially bones, muscles and liver. Once the genetically determined body size is reached, somatotropin mainly regulates the ratio of muscle mass to fat.The growth hormone is secreted especially in the first hours of deep sleep and in the morning hours shortly before awakening – diurnal rhythm. In addition, increased STH production occurs as a result of energy-consuming processes, such as injuries, emotional stress, fasting and physical training. The reasons for this include low blood glucose levels during fasting or high lactate levels during intense exercise, which stimulate STH secretion.An increased concentration of somatotropin in the blood now causes a reduced uptake of glucose into the cells, causing the blood glucose level to rise. As a result, more insulin is secreted from the pancreas (pancreas). Somatotropin and insulin work together. Both hormones increase the transport rate of amino acids into the cells of the muscles and liver during increased physical energy requirements and thus promote protein biosynthesis and the formation of new tissue. Furthermore, somatotropin and insulin lead to the mobilization of free fatty acids from the body’s own fat depots, which are used for energy production. In order to maintain or even increase normal STH production, an adequate supply of B-complex vitamins, especially vitamin B6 (pyridoxine), is important. A deficit of vitamin B6 reduces STH release by up to 50%. In addition, a pyridoxine deficiency negatively affects insulin synthesis. The minerals calcium, magnesium and potassium as well as the trace element zinc also play a significant role in the STH regulatory circuit. Studies have shown that individuals suffering from zinc deficiency have a significantly low secretion of growth hormones and an impaired formation of gonadal hormones.Several scientific studies show that supplementation with leucine, isoleucine and valine slightly increased the increase in STH secretion induced by physical exertion. Thus, BCAAs promote anabolic or anticatabolic protein metabolism via increased secretion of somatotropin. The process of building muscle protein is accelerated and fat burning is stimulated – a welcome effect for both athletic and diet-conscious individuals.Such an effect could also be supported by a study in which a daily intake of 14 g of branched-chain amino acids over a 30-day period led to an increase in lean body mass.

Leucine in situations of stress-induced exercise

During increased physical and exercise stress, such as injury, illness, and surgery, the body breaks down more protein. Increased intake of leucine-rich foods can counteract this. Protein catabolism is halted as leucine rapidly raises insulin levels, promotes amino acid uptake into cells, and stimulates protein buildup. Protein anabolism is important for the formation of new body tissue or for healing wounds and increasing resistance to infection. Finally, leucine helps to regulate metabolism and the body’s defenses. In this way, important muscle functions can be supported during increased physical stress.

Leucine in diseases and diets

Acutely ill or convalescent patients have an increased need for essential amino acids. Due to a frequently insufficient intake of high-quality protein and a restricted food intake, an increased intake of leucine, isoleucine and valine in particular is recommended.BCAAs can accelerate convalescence – recovery.Specific benefits of leucine occur in the following conditions:

  • Fibromyalgia
  • Cirrhosis of the liver
  • Hepatic encephalopathy
  • Coma hepaticum
  • Schizophrenia
  • Phenylketonuria (PKU)
  • Dystones syndrome

FibromyalgiaFibromyalgia is a chronic pain disorder with symptoms of the joint or musculoskeletal system. Patients, especially women between 25 and 45 complain of diffuse pain of the musculoskeletal system especially with exertion, stiffness, easy fatigue, difficulty concentrating, non-restorative sleep, and significantly reduced mental and physical performance. A typical feature of fibromyalgia is specific pressure-dolent areas on the body. Several lines of evidence suggest that, among other factors, a deficiency of BCAAs plays a role in the development of fibromyalgia. Since BCAAs are essential for protein and energy metabolism in the muscle, too low BCAA concentrations lead to a muscular energy deficit, which could be the trigger of fibromyalgia. In addition, significantly decreased serum levels of leucine, isoleucine, and valine can be seen in affected individuals.Accordingly, branched-chain amino acids may counteract the pathogenesis of fibromyalgia as well as favorably influence the treatment of this disease.Liver cirrhosis, hepatic encephalopathy, and coma hepaticumLiver cirrhosis is the end stage of chronic liver disease and develops over a period of years to decades. Patients exhibit a disturbed structure of liver tissue with nodular changes and excessive formation of connective tissue – fibrosis – as a result of progressive tissue loss. Eventually, circulatory disturbances occur, resulting in the inability to properly deliver portal vein blood – vena portae – from the unpaired abdominal organs to the liver. The blood thus accumulates at the hepatic portal (portal hypertension).Patients with liver cirrhosis break down endogenous proteins, especially muscle mass, faster than healthy individuals. Despite the higher requirement, they must not consume too much protein with food, since their cirrhotic liver can only detoxify the toxic ammonia (NH3) produced by protein breakdown to a limited extent via the urea cycle. If NH3 concentrations are too high, there is a risk of hepatic encephalopathy, a subclinical brain dysfunction resulting from inadequate detoxification function of the liver. Hepatic encephalopathy is characterized by the following features:

  • Mental and neurologic changes
  • Decrease in practical intelligence and ability to concentrate
  • Increased fatigue
  • Reduced fitness to drive
  • Impairment in manual occupations

It is believed that 70% of patients with liver cirrhosis suffer from latent hepatic encephalopathy, the precursor of manifest hepatic encephalopathy.Coma hepaticum is the most severe form of hepatic encephalopathy (stage 4). Nerve damage in the central nervous system results in, among other things, unconsciousness without response to pain stimuli (coma), extinction of muscle reflexes, and muscle rigidity with flexion and extension.Patients with and without hepatic encephalopathy usually show reduced plasma concentrations of branched-chain amino acids and increased plasma levels of the aromatic amino acids phenylalanine and tyrosine. In addition, the concentration of free tryptophan shows a slight increase. In addition to accelerated protein breakdown, the cause of this amino acid imbalance could also be the hormonal imbalance between insulin and glucagon that frequently occurs in patients with liver cirrhosis.Insulin is produced in excess quantities due to the underactive liver. This leads to a significantly increased insulin concentration in the serum, which provides for increased transport of amino acids, including leucine, to the muscles. In the blood, the leucine concentration is consequently lowered.Since the BCAAs and the essential amino acid tryptophan use the same transport system in the blood, i.e. the same carrier proteins, tryptophan can occupy many free carriers due to the low serum leucine level and be transported towards the blood-brain barrier.L-tryptophan competes with 5 other amino acids at the blood-brain barrier for entry into the nutrient fluid of the brain – namely with the BCAAs and aromatic amino acids phenylalanine and tyrosine. Due to the excess of tryptophan in the brain, phenylalanine, the precursor of catecholamines, such as the stress hormones epinephrine and norepinephrine, is also displaced in addition to tyrosine and the BCAAs. Finally, tryptophan can cross the blood-brain barrier unhindered. Because of phenylalanine displacement, sympathetic activation in the brain is absent, limiting catecholamine synthesis in the adrenal medulla.In the central nervous system, tryptophan is converted to serotonin, which functions as a tissue hormone or inhibitory (inhibitory) neurotransmitter in the central nervous system, intestinal nervous system, cardiovascular system, and blood. The increased levels of tryptophan eventually entail increased serotonin production. In the case of liver dysfunction, excessive amounts of serotonin cannot be broken down, which in turn leads to severe fatigue and even unconsciousness – coma hepaticum.Other authors, however, see another reason for the development of hepatic encephalopathy or coma hepaticum in addition to increased serotonin secretion [Bernadini, Gerok, Egberts, Kuntz, Reglin]. Due to the low serum concentration of BCAAs in liver cirrhosis patients, the aromatic amino acids phenylalanine, tyrosine, and tryptophan can cross the blood-brain barrier and enter the central nervous system without much competition. There, instead of being converted into catecholamines, phenylalanine and tyrosine are converted into “false” neurotransmitters, such as phenylethanolamine and octopamine. Unlike catecholamines, these are not sympathomimetics, i.e., they can exert no or only a very slight excitatory effect at the sympathetic alpha and beta receptors of the cardiovascular system. Tryptophan is increasingly used in the central nervous system for serotonin synthesis.Finally, both factors, the formation of false neurotransmitters as well as increased serotonin production are held responsible for the occurrence of hepatic encephalopathy and coma hepaticum, respectively. Increased intake of leucine prevents increased production of serotonin as well as false neurotransmitters via the mechanism of displacement of tryptophan, phenylalanine, and tyrosine at the blood-brain barrier and inhibition of uptake of these amino acids into the central nervous system. In this way, leucine counteracts the occurrence of coma hepaticum.Furthermore, leucine helps to keep ammonia levels in the body at a low level. This is a significant advantage for patients with cirrhosis of the liver, who are unable to sufficiently detoxify NH3. Ammonia accumulates and in high concentrations promotes the development of hepatic encephalopathy. By stimulating protein biosynthesis in muscular tissues and inhibiting protein breakdown, leucine incorporates more ammonia and releases less ammonia. In addition, in both muscle and brain, leucine can be converted to glutamate, an important amino acid in nitrogen (N) metabolism, which binds excess ammonia to form glutamine and thus detoxifies it temporarily. For final detoxification, NH3 is converted to urea in the hepatocytes (liver cells), which is eliminated as a non-toxic substance by the kidneys. BCAAs stimulate the urea cycle and thus promote NH3 excretion.The efficacy of leucine, isoleucine, and valine with respect to hepatic encephalopathy was confirmed in a randomized, placebo-controlled, double-blind study. Over a period of 3 months, 64 patients were to ingest 0.24 g/kg body weight of branched-chain amino acids daily. The result was a significant improvement in chronic hepatic encephalopathy compared with placebo.In a placebo-controlled double-blind cross-over study, patients in the latent hepatic encephalopathy stage received 1 g protein/kg body weight and 0.25 g branched-chain amino acids/kg body weight daily.Already after a 7-day treatment period, a clear improvement of psychomotor functions, attention and practical intelligence was observed in addition to a reduced ammonia concentration.Furthermore, in a randomized double-blind study over a period of one year, the effectiveness of BCAAs was tested in patients with advanced liver cirrhosis. The result was a lower risk of mortality and morbidity. In addition, the patients’ anorexia nervosa and quality of life were positively affected. The average number of hospitalizations was decreased and liver function was stable or even improved.However, there are also studies that have not demonstrated a significant relationship between BCAAs and liver disease. Nevertheless, in patients with liver dysfunction, supplementation with leucine, isoleucine, and valine is recommended because of their beneficial effects on protein metabolism, especially in patients with impaired protein tolerance.Overview of important effects of branched-chain amino acids on protein metabolism:

  • Improvement of the nitrogen balance
  • Increase protein tolerance
  • Normalization of the amino acid pattern
  • Improvement of cerebral blood flow
  • Promote ammonia detoxification
  • Improve transaminase levels and caffeine clearance.
  • Positive influence on the mental status

SchizophreniaBecause BCAAs reduce the level of tyrosine in the blood and thus in the central nervous system, leucine can be used in orthomolecular psychiatry, for example in schizophrenia. Tyrosine is the precursor of dopamine, a neurotransmitter in the central nervous system from the catecholamine group. Excessive dopamine concentration in certain brain areas leads to central nervous hyperexcitability and is associated with the symptoms of schizophrenia, such as ego disorders, thought disorders, delusion, motor restlessness, social withdrawal, emotional impoverishment and weakness of will.PhenylketonuriaWith leucine, isoleucine and valine, specific benefits can also be achieved in the treatment of phenylketonuria (PKU). PKU is an inborn error of metabolism in which the phenylalanine hydroxylase system is defective. Due to the impaired activity of the enzyme phenylalanine hydroxylase, which has tetrahydrobiopterin (BH4) as a coenzyme, the amino acid phenylalanine cannot be degraded. Mutations of the phenylalanine hydroxylase gene as well as genetic defects of the biopterin metabolism have been identified as the cause of the disease. In affected individuals, the disease can be recognized in the form of elevated serum phenylalanine levels. As a result of the accumulation of phenylalanine in the organism, the concentrations of this amino acid increase in the cerebrospinal fluid and various tissues. At the blood-brain barrier, phenylalanine displaces other amino acids, causing the uptake of leucine, isoleucine, valine, tryptophan, and tyrosine into the central nervous system to decrease, while that of phenylalanine increases. As a result of the amino acid imbalance in the brain, the formation of the catecholamines – epinephrine, norepinephrine and dopamine -, the neurotransmitters serotonin and DOPA, and the pigment melanin, which in humans causes the coloration of the skin, hair or eyes, is reduced to a minimum. Due to the melanin deficiency, patients exhibit conspicuously light skin and hair.If infants with phenylketonuria are not treated in time, the above-average phenylalanine concentration in the central nervous system entails neurological-psychiatric disorders. These lead to nerve damage and subsequently to severe mental developmental disorders. Affected individuals have been observed to have intelligence defects, language development disorders, and behavioral abnormalities with hyperactivity and destructiveness. About 33% of patients also suffer from epilepsy – spontaneously occurring seizures.Such severe cerebral disorders can be significantly alleviated or even prevented in patients already on a low-phenylalanine diet by increasing BCAAs intake. High serum leucine levels decrease the binding of phenylalanine to transport proteins in the blood and its concentration at the blood-brain barrier, thereby reducing phenylalanine uptake into the brain.Thus, with the help of BCAAs, an abnormally high phenylalanine concentration can be normalized both in the blood and in the brain.Dystones SyndromeFurthermore, with the help of branched-chain amino acids, there are advantages for people with so-called dystonic syndrome (dyskinesia tarda). This condition is characterized, among other things, by involuntary movements of the facial muscles, for example spasmodic sticking out of the tongue, by spasms of the pharynx, spasmodic reclination of the head and hyperextension of the trunk and extremities, torticollis and torsion-like movements in the neck and shoulder girdle area with preserved consciousness.DietsDiet-conscious individuals who often have an insufficient supply of protein or predominantly consume foods with a low leucine content have an increased need for BCAAs. The intake of leucine, isoleucine and valine should eventually be increased so that the body does not draw on its own protein reserves, such as those from the liver and muscles, in the long term. If protein intake is too low, the body’s own protein is converted into glucose and used as an energy source by the brain and other metabolically active organs. Protein loss in the muscles leads to a decrease in energy-consuming muscle tissue. The more a dieting person loses muscle mass, the more the basal metabolic rate or energy expenditure decreases and the body burns fewer and fewer calories. Finally, a diet should aim to preserve muscle tissue or increase it through exercise. At the same time, the proportion of body fat should be reduced. During a diet, BCAAs help to prevent protein breakdown and thus a drop in the basal metabolic rate, as well as to increase fat breakdown. A new study at Arizona State University suggests that a diet high in branched-chain amino acids can increase basal metabolic rate by 90 kilocalories per day. Extrapolated over a year, that would mean a weight loss of about 5 kilograms without calorie reduction or exercise.Furthermore, branched-chain amino acids are needed in amounts appropriate for maintaining normal plasma albumin levels. Albumin is one of the most important blood proteins and consists of about 584 amino acids, including the BCAAs. Low concentrations of leucine, isoleucine, and valine are associated with a decrease in plasma albumin levels, which lowers the colloid osmotic pressure of the blood. As a result, edema (water retention in the tissues) and impaired diuresis (urine excretion via the kidneys) may occur. Accordingly, diet-conscious individuals can help prevent edema formation (water retention in the tissues) themselves with an adequate intake of BCAAs in their diet and thus maintain their water balance.

Leucine as a starting building block for the synthesis of nonessential amino acids

Reactions by which amino acids are newly formed are called transaminations. In this process, the amino group (NH2) of an amino acid, such as leucine, alanine, or aspartic acid, is transferred to an alpha-keto acid, usually alpha-ketoglutarate. Alpha-ketoglutarate is thus the acceptor molecule. The products of a transamination reaction are an alpha-keto acid, such as pyruvate or oxaloacetate, and the nonessential amino acid glutamic acid or glutamate, respectively.For transaminations to occur, special enzymes are required – called transaminases. The two most important transaminases include alanine aminotransferase (ALAT), also known as glutamate pyruvate transaminase (GPT), and aspartate aminotransferase (ASAT), also known as glutamate oxaloacetate transaminase (GOT). The former catalyzes the conversion of alanine and alpha-ketoglutarate to pyruvate and glutamate. ASAT converts aspartate and alpha-ketoglutarate to oxaloacetate and glutamate.Coenzyme of all transaminases is the vitamin B6 derivative pyridoxal phosphate (PLP). PLP is loosely bound to the enzymes and is essential for optimal activity of the transaminases.Transamination reactions are localized in liver and other organs. The transfer of alpha-amino nitrogen from leucine to an alpha-keto acid by transaminases with the formation of glutamate takes place in the muscles.Glutamate is considered the “hub” of amino nitrogen metabolism. It plays a key role in the formation, conversion and degradation of amino acids.Glutamate is the starting substrate for the synthesis of proline, ornithine and glutamine. The latter is an essential amino acid for nitrogen transport in the blood, protein biosynthesis, and for the excretion of protons in the kidney in the form of NH4. Glutamate the major excitatory neurotransmitter in the central nervous system. It binds to specific glutamate receptors and can thus control ion channels. In particular, glutamate increases the permeability of calcium ions, an important prerequisite for muscle contractions. Glutamate is converted to gamma-aminobutyric acid (GABA) by splitting off the carboxyl group – decarboxylation. GABA belongs to the biogenic amines and is the most important inhibitory neurotransmitter in the gray matter of the central nervous system. It inhibits neurons in the cerebellum.