Leucine is the essential amino acid that is the primary activator of the mTOR (mechanistic target of rapamycin) pathway — it is the most potent of all the amino acids at stimulating the muscle protein synthesis, and it is the amino acid that is most responsible for the anabolic effect of the protein consumption on the muscle. The mTOR pathway is the master regulator of the cell growth and of the protein synthesis — it integrates the signals from the nutrients (particularly the amino acids), the growth factors (insulin, IGF-1), and the energy status (ATP, AMPK) to regulate the protein synthesis, the ribosome biogenesis, and the autophagy. The leucine activates the mTOR pathway by binding to the leucyl-tRNA synthetase (which is the intracellular leucine sensor) and by promoting the formation of the active mTOR complex 1 (mTORC1), which then phosphorylates the downstream targets (4E-BP1, S6K1, ULK1) to promote the protein synthesis and to inhibit the autophagy. Without adequate leucine and mTOR activation, the muscle protein synthesis is reduced, the muscle mass declines, and the frailty and the metabolic dysfunction develop — the hallmark of the leucine deficiency and of the sarcopenia. The typical dietary leucine intake from the protein-rich foods (meat, fish, poultry, eggs, dairy) is 1-5g daily, and the therapeutic dose for the muscle protein synthesis is 2-5g of leucine per meal (equivalent to approximately 25-40g of high-quality protein, which provides the leucine threshold for the maximal stimulation of the mTOR pathway and the muscle protein synthesis).
Leucine and the mTOR Activation
Leucine activates the mTOR pathway through multiple mechanisms — it binds to the leucyl-tRNA synthetase (LeuRS) in the cytoplasm, which then promotes the translocation of the mTOR to the lysosomal surface and the formation of the active mTORC1 complex; it promotes the GTP loading of the Rag GTPases (which are the nutrient sensors that regulate the mTOR localisation), thereby promoting the mTOR activation on the lysosomal surface; and it antagonises the ATP-analogues that would otherwise inhibit the mTOR activity. The activation of the mTORC1 by the leucine leads to the phosphorylation of the 4E-BP1 (which releases the eIF4E and promotes the translation initiation) and of the S6K1 (which promotes the ribosome biogenesis and the translation elongation) — and these downstream events are the primary mechanisms by which the leucine stimulates the muscle protein synthesis and promotes the muscle growth. The leucine also has other anabolic effects — it promotes the insulin secretion (by acting as a secretagogue for the pancreatic beta cells), it reduces the muscle protein breakdown (by inhibiting the ubiquitin-proteasome system and the autophagy-lysosome system), and it supports the satellite cell proliferation (which is essential for the muscle repair and the muscle growth).
The clinical importance of the leucine for the muscle health is underscored by the observation that the leucine supplementation preserves the muscle mass and improves the physical function in older adults with the sarcopenia. A study in 30 older adults (aged 65-80) with the sarcopenia found that the leucine supplementation at 2.5g per meal (taken at breakfast, lunch, and dinner) for 3 months significantly increased the muscle mass (by 0.5-1.0kg), improved the muscle strength (by 10-15%, as measured by the handgrip strength and the leg press), and improved the physical performance (by 10-15%, as measured by the 6-minute walk test) — demonstrating the potent muscle-protective effect of the leucine in the elderly.
Practical Application
For general leucine supplementation for the muscle protein synthesis support, the evidence-based approach is to supplement with 2-5g of leucine per meal (taken with the breakfast, the lunch, and the dinner, for a total of 6-15g of leucine daily). The leucine should be taken with the other essential amino acids (particularly the valine and the isoleucine, which are the other branched-chain amino acids that work synergistically with the leucine for the muscle protein synthesis) and with the carbohydrates (which enhance the insulin secretion and which promote the amino acid uptake by the muscle). The leucine is generally well-tolerated with no significant adverse effects at doses up to 20g daily, and it does not have any known drug interactions — though people with the maple syrup urine disease (a genetic disorder that impairs the branched-chain amino acid metabolism) should not use the leucine supplementation. For comprehensive muscle and anabolic support, leucine pairs well with the other branched-chain amino acids (valine and isoleucine, which work synergistically with the leucine for the muscle protein synthesis and for the reduction of the muscle protein breakdown), with the vitamin D (which regulates the muscle protein synthesis and which works synergistically with the leucine for the muscle function), with the creatine (which provides the energy for the muscle contraction and which works synergistically with the leucine for the muscle performance), and with the exercise (particularly the resistance exercise, which activates the mTOR pathway and which works synergistically with the leucine for the muscle growth and for the muscle adaptation).
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