Leucine: what it is and how it works

Leucine is called "the main anabolic amino acid," and there are reasons for this. The editorial team explains what leucine is, where it is found, exactly how it switches on muscle protein synthesis and why isolated leucine supplements do not work the way advertising promises.

What leucine is

Leucine is one of the nine essential amino acids that the human body cannot synthesize and must obtain from food. Together with isoleucine and valine, it belongs to the group of branched-chain amino acids (BCAA), so named because of the special structure of the side chain.

Leucine is a proteinogenic amino acid: it is part of practically all of the body's proteins, from muscle contractile proteins to enzymes. However, its importance is not limited to the role of a building block. Leucine is also a signaling molecule that "informs" the cell about the arrival of protein.

The recommended daily allowance of leucine for adults, established by the US Institute of Medicine (2005), is about 42 mg per kilogram of body weight. A person who consumes enough protein usually gets significantly more, so an isolated leucine deficiency in developed countries is rare.

In sports nutrition, leucine became known thanks to studies of the 2000s that showed its key role in triggering muscle protein synthesis. Since then it has appeared in BCAA, EAA and proteins with an "increased leucine content."

Sources of leucine in the diet

Leucine is found in all complete protein products. It is most abundant in animal products, especially in dairy proteins. Whey protein is known as one of the richest sources of leucine, which is exactly why it so effectively stimulates muscle protein synthesis (Tang et al., 2009).

Plant proteins, as a rule, contain less leucine per gram of protein and have lower digestibility. This does not mean they are worse for health, but to get the same amount of leucine you need to eat more of them or combine different sources.

Below is an approximate share of leucine in common protein sources. The values are approximate and depend on the specific product and analysis method.

For practical understanding: a serving of 20–25 g of whey protein contains about 2–3 g of leucine. This is exactly the range that usually appears in discussions of the "leucine threshold."

How leucine triggers protein synthesis

The central target of leucine is the protein complex mTORC1, the main regulator of cell growth. When mTORC1 is activated, it phosphorylates the proteins p70S6K1 and 4E-BP1, which removes the inhibition and triggers the initiation of translation — the process of reading messenger RNA for protein synthesis (Kimball, Jefferson, 2006).

Exactly how the cell "senses" leucine long remained a mystery. In 2016, Wolfson and colleagues published a study in the journal Science that showed that the protein Sestrin2 binds leucine and thereby transmits a signal to mTORC1. This discovery explained why it is leucine, and not other amino acids, that has a special signaling role.

Leucine also moderately stimulates insulin secretion, and insulin, in turn, suppresses the breakdown of muscle protein. This effect complements the direct action on mTORC1.

Important: leucine only gives the signal to "build." For actual protein synthesis, all essential amino acids are needed as building material. Without them, the leucine signal quickly "fades" — this is the basis of the criticism of isolated leucine and BCAA supplements (Wolfe, 2017).

The metabolism of leucine and its metabolites

Unlike most amino acids, which are broken down mainly in the liver, BCAA, including leucine, are largely metabolized in skeletal muscle. The first reaction is transamination with the formation of alpha-ketoisocaproate (KIC).

Next, KIC is oxidized by the branched-chain ketoacid dehydrogenase complex. A small share — estimated at about 5% — is converted into beta-hydroxy-beta-methylbutyrate (HMB), a well-known sports supplement considered as a means of reducing muscle protein breakdown.

The end products of leucine oxidation are acetyl-CoA and acetoacetate, so leucine belongs to the purely ketogenic amino acids. During prolonged exercise, the oxidation of BCAA increases, but their contribution to energy supply remains small compared with carbohydrates and fats.

A rare hereditary disease — maple syrup urine disease — is associated with a deficiency of the branched-chain ketoacid dehydrogenase complex. In such patients, leucine and its metabolites accumulate to toxic levels, and for them leucine supplements are strictly contraindicated.

Leucine in sports practice

For athletes, the main practical conclusion is: what matters is not only the total amount of protein per day, but also a sufficient amount of leucine at each meal. The ISSN position on protein (Jäger et al., 2017) mentions a guideline of about 700–3000 mg of leucine per intake together with complete protein.

• Young adults:20–25 g of quality protein per intake usually provide a sufficient amount of leucine.
• Older people:because of "anabolic resistance," more leucine per intake may be needed (Katsanos et al., 2006).
• Plant-based diet:larger portions of protein or combining sources to reach the threshold.

Isolated leucine as a supplement makes sense mainly when protein intake is small: for example, in older people with a low appetite. For a young person with a sufficient protein diet, additional leucine most likely will not give a noticeable effect.

Leucine is not on the WADA Prohibited List. It is present in ordinary foods and is a common dietary component.

Editorial conclusions

Leucine is an essential amino acid with a dual role: a building block of proteins and a signaling molecule that triggers muscle protein synthesis through Sestrin2 and mTORC1.

The best source of leucine is complete protein products, especially dairy ones. A serving of 20–25 g of quality protein provides an amount of leucine sufficient to stimulate protein synthesis in most young people.

Isolated leucine supplements have a narrow niche: they supplement insufficient protein intake but do not replace it.

We recommend reading "The benefits of Leucine for athletes: the evidence base," as well as our materials on L-ornithine — "L-ornithine: what it is and how it works" and "What to combine L-ornithine with."

References

1. Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: National Academies Press; 2005.
2. Kimball SR, Jefferson LS. Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. J Nutr. 2006;136(1 Suppl):227S–231S.
3. Wolfson RL, Chantranupong L, Saxton RA, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016;351(6268):43–48.
4. Norton LE, Layman DK. Leucine regulates translation initiation of protein synthesis in skeletal muscle after exercise. J Nutr. 2006;136(2):533S–537S.
5. Tang JE, Moore DR, Kujbida GW, Tarnopolsky MA, Phillips SM. Ingestion of whey hydrolysate, casein, or soy protein isolate: effects on mixed muscle protein synthesis at rest and following resistance exercise in young men. J Appl Physiol. 2009;107(3):987–992.
6. Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR. A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab. 2006;291(2):E381–E387.
7. Jäger R, Kerksick CM, Campbell BI, et al. International Society of Sports Nutrition Position Stand: protein and exercise. J Int Soc Sports Nutr. 2017;14:20.
8. Wolfe RR. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality? J Int Soc Sports Nutr. 2017;14:30.