In order to understand how leucine benefits muscle protein synthesis it is important to understand some of the biology which underlies muscle protein development. Protein synthesis is not growth of current muscle, instead it is the construction of new proteins.
It starts by process of transcription, which is where a DNA blueprint is transferred to a molecule of mRNA, and taken to muscle cells. At the cells it attaches to the ribosome (cellular protein builders) and the proteins connected to the ribosome. This facilitates a secondary process called translation, which is where the protein is constructed.
This process is ongoing and balanced with protein degradation. Greater protein synthesis means development of more skeletal muscle; greater degradation means more muscle atrophy. Synthesis rates are altered by various things, including exercise, feeding, fasting and sleeping.
The main role of leucine can be summarised by three biological functions (1):
1) A regulator of protein synthesis
2) A modulator of signalling cascades
3) A donor of nitrogen to assist the muscle to produce alanine and glutamine
Where leucine does its work initially is at the stage of “translation”. The translation process is triggered by specific proteins (eukaryotic initiation factors) which are more abundant when leucine is in greater supply. However, there is a stage in the middle which needs to be discussed.
Leucine doesn’t directly trigger these translational processes to increase. Instead a specific protein kinase called Mechanistic Target of Rapamycin (mTOR) is responsible for these changes, and has a key role in regulation of cell growth and proliferation.
MPS and mTOR
mTOR is a two component complex, one of which is activated by leucine. This complex involves mTOR working alongside other proteins, such as Raptor (regulatory associated protein of TOR), GβL (G-protein β-subunit like protein) and PRAS40 (proline-rich PKB/ Akt substrate of 40kDa) (2-3).
This combination of proteins works in away to facilitate a myriad of cellular signals which subsequently promotes protein synthesis.
In simplest terms, increased leucine stimulates mTOR (4-5), which in turn stimulates a specific enzyme (namely p70S6 kinase) via a genetically encoded protein pathway. P70S6 kinase then positively enhances muscle protein synthesis (6).
Leucine additionally enhances further protein translation to further promote muscle protein synthesis (7,8-9).
These changes in mTOR activation (10-11), and p70S6 kinase activation (12) have importantly been confirmed in human tissues following supplementation of leucine to show transfer from the science to real life practice for those considering supplementation.
Also, importantly this anabolic effect of leucine is further boosted by muscular contraction during physical activity (13), leading some researchers to suggest there is added benefit of pre-loading prior to exercise (14-15). Following exercise our muscles are in a state of negative protein balance, where degredation rates supersede synthesis. The combination of muscle contraction, with sufficient leucine, allows both muscle recovery and post exercise synthesis to be enhanced.
Needless to say, all agree that leucine seems to be the most potent of all amino acids for muscle protein synthesis (16).
Not All Proteins Are Created Equal
Leucine Concentration for Muscle Growth
Animal studies examining the percentage concentration of leucine in different dietary proteins show that the amount of leucine is critical for evaluating the quality of protein needed to stimulate muscle protein synthesis (17).
Wheat (6.8%), soy (8%), egg (8.8%) and whey proteins (10.9%) all have differing leucine concentrations. This experiment showed that if the dose of protein is the same, only egg and whey protein have sufficient leucine content to stimulate protein synthesis. However, if wheat protein is provided with extra leucine (to the level of whey) then the rate of muscle protein synthesis similarly increases!
Research on young athletes given 1.5g per kg of body weight per day of a “leucine rich” protein showed 7.5% greater increases in lean mass, alongside a 10% greater reduction in fat mass, compared to casein (18).
Another study comparing whey hydrolysate (which quickly increases plasma leucine concentration) with soy and casein protein, showed that the whey protein was more efficient at triggering MPS (19). This further highlights the importance of the leucine concentration of protein when considering which type to opt for!
Take Home Message
To reiterate – protein synthesis is not growth of current muscle, instead it is the construction of new proteins.
I hope your understanding of Leucine is now a little more in depth!
1. Norton, L.E. and Layman, D.K., 2006. Leucine regulates translation initiation of protein synthesis in skeletal muscle after exercise. The Journal of nutrition, 136(2), pp.533S-537S.
2. Wullschleger, S., Loewith, R. and Hall, M.N., 2006. TOR signaling in growth and metabolism. Cell, 124(3), pp.471-484.
3. Kim, D.H., Sarbassov, D.D., Ali, S.M., King, J.E., Latek, R.R., Erdjument-Bromage, H., Tempst, P. and Sabatini, D.M., 2002. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 110(2), pp.163-175.
4. Drummond, M.J. and Rasmussen, B.B., 2008. Leucine-enriched nutrients and the regulation of mammalian target of rapamycin signalling and human skeletal muscle protein synthesis. Current Opinion in Clinical Nutrition & Metabolic Care, 11(3), pp.222-226.
5. Anthony, J.C., Anthony, T.G., Kimball, S.R., Vary, T.C. and Jefferson, L.S., 2000. Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation. The Journal of nutrition, 130(2), pp.139-145.
6. Blomstrand, E., Eliasson, J., Karlsson, H.K. and Köhnke, R., 2006. Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. The Journal of nutrition, 136(1), pp.269S-273S.
7. Anthony, J.C., Anthony, T.G., Kimball, S.R., Vary, T.C. and Jefferson, L.S., 2000. Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation. The Journal of nutrition, 130(2), pp.139-145.
8. Fischer, P.M., 2009. Cap in hand: targeting eIF4E. Cell Cycle, 8(16), pp.2535-2541.
9. Kimball, S.R. and Jefferson, L.S., 2001. Regulation of protein synthesis by branched-chain amino acids. Current Opinion in Clinical Nutrition & Metabolic Care, 4(1), pp.39-43.
10. Nair, K.S., Schwartz, R.G. and Welle, S.T.E.P.H.E.N., 1992. Leucine as a regulator of whole body and skeletal muscle protein metabolism in humans. American Journal of Physiology-Endocrinology And Metabolism, 263(5), pp.E928-E934.
11. Alvestrand, A., Hagenfeldt, L., Merli, M., Oureshi, A. and Eriksson, L.S., 1990. Influence of leucine infusion on intracellular amino acids in humans. European journal of clinical investigation, 20(3), pp.293-298.
12. Greiwe, J.S., Kwon, G., McDaniel, M.L. and Semenkovich, C.F., 2001. Leucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscle. American Journal of Physiology-Endocrinology And Metabolism, 281(3), pp.E466-E471.
13. Tipton, K.D., Elliott, T.A., Ferrando, A.A., Aarsland, A.A. and Wolfe, R.R., 2009. Stimulation of muscle anabolism by resistance exercise and ingestion of leucine plus protein. Applied Physiology, Nutrition, and Metabolism, 34(2), pp.151-161.
14. Tipton, K.D., Elliott, T.A., Cree, M.G., Aarsland, A.A., Sanford, A.P. and Wolfe, R.R., 2007. Stimulation of net muscle protein synthesis by whey protein ingestion before and after exercise. American Journal of Physiology-Endocrinology and Metabolism, 292(1), pp.E71-E76.
15. Tipton, K.D., Rasmussen, B.B., Miller, S.L., Wolf, S.E., Owens-Stovall, S.K., Petrini, B.E. and Wolfe, R.R., 2001. Timing of amino acid-carbohydrate ingestion alters anabolic response of muscle to resistance exercise. American Journal of Physiology-Endocrinology And Metabolism, 281(2), pp.E197-E206.
16. Anthony, J.C., Anthony, T.G. and Layman, D.K., 1999. Leucine supplementation enhances skeletal muscle recovery in rats following exercise. The Journal of nutrition, 129(6), pp.1102-1106.
17. Norton, L.E., Wilson, G.J., Layman, D.K., Moulton, C.J. and Garlick, P.J., 2012. Leucine content of dietary proteins is a determinant of postprandial skeletal muscle protein synthesis in adult rats.Nutrition & metabolism, 9(1), p.1.
18. Cribb PJ, Williams AD, Carey MF, Hayes A. The effect of whey isolate and resistance training on strength, body composition, and plasma glutamine. Int J Sport Nutr Exerc Metab 2006; 16:494–509
19. Tang JE, Moore DR, Kujbida GW, et al. 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; 107:987–992.