Leucine: The Anabolic Trigger

Protein synthesis is a term you may see often when you read articles dealing with building muscle. But what is it? Quite simply, it is the synthesis of new skeletal muscle proteins.

When this occurs on a large scale it is known as skeletal muscle hypertrophy (growth) and it is the process by which our muscles get bigger. The focus of this article is how dietary Amino Acids, in particular Leucine, regulate skeletal muscle protein synthesis after exercise.

Background

Different forms of exercise affect muscle protein turnover in different ways. Endurance exercise affects skeletal muscle protein turnover by decreasing the rate of skeletal muscle protein synthesis and increasing the rate of protein degradation (muscle breakdown).¹

Resistance exercise is unique in comparison to other forms of exercise as an acute bout of resistance exercise actually elevates skeletal muscle protein synthesis in addition to increasing the rate of skeletal muscle protein degradation. The overall effect in both cases is a negative net protein balance (overall breakdown).²

In the short term therefore, exercise results in a catabolic condition. Long term exercise however, is associated with maintenance or increases in muscle mass.

Leucine

It has been shown that in order for protein balance to become positive post workout, dietary protein, specifically the amino acid leucine, must be consumed and protein balance will remain negative until it is consumed.^3,4

Leucine is one of the three branched chain amino acids (BCAAs) and is unique in its ability to stimulate skeletal muscle protein synthesis. In fact, leucine has about a 10 fold greater impact on protein synthesis than any other amino acid!

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So how does leucine stimulate skeletal muscle protein synthesis? Well first we need to understand more about the pathway that leucine activates. It has been shown that leucine activates a major complex in the anabolic pathway called the mammalian target of rapamycin (mTOR).⁵ Think of mTOR as the amino acid sensor of the cell. mTOR is sensitive to leucine concentrations.

Decreasing leucine concentrations signal to mTOR that there is not enough dietary protein present to synthesize new skeletal muscle protein and it is deactivated. As leucine concentrations increase, it signals to mTOR that there is sufficient dietary protein to synthesize new skeletal muscle protein and mTOR is activated.

mTOR Activation

Though researchers are not sure exactly how leucine activates mTOR, it has been shown that mTOR is sensitive to leucine concentrations and ATP levels (decreasing ATP levels can also reduce the activation of mTOR).^6,7

Activation of mTOR is strongly associated with increased protein synthesis. mTOR increases protein synthesis through two different mechanisms:⁸

Mechanism 1

It phosphorylates a binding protein called 4E-BP1, inactivating it. When active, 4E-BP1 binds a protein called eIF4E (an initiation factor), preventing it from associating with another protein called eIF4G to form the eIF4E*eIF4G complex.

The formation of this complex is critical in order for protein synthesis to proceed.

So in short, mTOR allows protein synthesis to proceed by inactivating 4E-BP1, thus allowing the eIF4E*eIF4G complex to form, which is crucial for protein synthesis to proceed.

I could go into more detail, but I would most likely lose most of my audience and the current level of discussion is fine for understanding the pathway.

Mechanism 2

mTOR activates a protein called ribosomal protein S6 (aka rpS6 or p70 S6). rpS6 increases the synthesis of components of the protein synthesis pathway. So not only does mTOR increase protein synthesis, it increases the capacity for synthesis.

An analogy to help you understand this would be a contractor building a new skyscraper.

The contracting company is mTOR, the skyscraper is the protein you are trying to synthesize, the machines (bulldozers, cranes, etc) you use to make the building are the protein synthesis pathway components, and leucine is the cash needed to make the project work.

When enough cash is available (increasing leucine concentrations), the contracting company can not only start building the skyscraper (synthesizing muscle protein), they can also purchase more machines (increased synthetic components) to increase the capacity and speed at which they construct the skyscraper (the muscle protein being synthesized).

Leucine also increases protein synthesis is by increasing the availability of eIF4G for the eIF4E*eIF4G complex by increasing the phosphorylation of eIF4G.⁹

Layman's Terms

Now that the thick science is out of the way, what does this tell us? Is it beneficial to supplement with extra leucine? Or do we get enough in a high protein diet? There is some evidence that supplemental leucine may be beneficial even if one supplies ample protein.

Recently researchers conducted an experiment where subject resistance trained for forty five minutes and then supplemented with carbohydrate alone, carbohydrate plus protein (approximately 30g) or carbohydrate plus protein and leucine.

They found that the carbohydrate/protein/leucine supplement reduced protein breakdown and increased skeletal muscle protein synthesis to a greater degree than the carbohydrate/protein supplement and to a much greater degree than the carbohydrate only supplement.¹⁰

A possible explanation for these results could be due to the rapid spike in plasma leucine that a free form leucine supplement could achieve. Whole proteins take long periods of time to empty from the stomach into the small intestine and finally into circulation. Thus, plasma levels increase slowly and plateau.

Even with a fast digesting protein such as whey, it can take hours for the leucine in whey to be liberated from the protein & enter circulation; therefore leucine concentrations in the plasma never spike to high levels.

An isolated leucine supplement however, would be quickly absorbed into circulation, thus spiking plasma leucine levels & drastically increasing intracellular leucine concentrations and activating the aforementioned anabolic pathways.

Conclusion

In conclusion, it is clear that leucine increases protein synthesis by increasing the activity of mTOR & the phosphorylation of eIF4G.

Leucine has a far greater stimulatory effect on protein synthesis than any other amino acid and it has been shown that protein synthesis increases similarly in response to a relatively small dose of leucine compared to a whole food meal.

It has also been demonstrated that adding leucine to a protein rich meal further increases the rate of skeletal muscle protein synthesis.

Whether or not it is of benefit for athletes and bodybuilders to supplement with additional leucine on top of a high protein diet to further increase muscle mass in the long term has yet to be determined however.

References

1. Dohm, G. L., Kasperek, G.J., Tapscott, E. B., & Beecher G., R. (1980) Effect of exercise on synthesis and degradation of muscle protein. Biochem. J. 188: 255-262.
2. Phillips, S., M, Tipton, K. D., Aarsland, A., Wolf, S. E., & Wolfe, R. R. Mixed muscle protein synthesis and breakdown after resistance exercise in humans. (1997) Am. J. Physiol. 273(1 Pt 1): E99-107.
3. Gautsch, T. A., Anthony, J. C., Kimball, S. R., Paul, G. L., Layman, D. K., & Jefferson, L. S. (1998) Availability of eIF4E regulates skeletal muscle protein synthesis during recovery from exercise. (2 Pt 1):C406-414.
4. Levenhagen, D. K., Carr, C., Carlson, M. G., Maron, D.J., Borel, M. J., Flakoll, P. J. (2002) Postexercise protein intake enhances whole-body and leg protein accretion in humans. Med Sci Sports Exerc. 34(5):828-37.
5. Anthony, J. C., Yoshizawa, F., Anthony, T. G., Vary, T. C., Jefferson, L. S., & Kimball, S. R. (2000) Leucine stimulates translation inititation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J. Nutr. 130: 2413-2419.
6. Crozier, S. J., Kimball, S.R., Emmert, S. W., Anthony, J. C., & Jefferson, L.S. (2005) Oral leucine administration stimulates protein synthesis in rat skeletal muscle. J. Nutr. 135: 376-382.
7. Bolster, D. R., Crozier, S. J., Kimball, S. R., & Jefferson, L. S. (2002) AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J. Biol. Chem. 277: 23977-23980.
8. Merrick, W. C., & Hershey, J. W. B. (2000) The pathway and mechanism of initiation of protein synthesis. In: Sonnenberg N, Hershey JWB, Mathews MB, editors. Translational control of gene expression. Cold Spring Harbor Laboratory Press.*
9. Bolster, D. R., Vary, T. C., Kimball, S. R., & Jefferson, L. S. (2004) Leucine Regulates Translation Initiation in Rat Skeletal Muscle Via Enhanced eIF4G Phosphorylation. J. Nutr. 134: 1704-1710.
10. Koopman R, Wagenmakers AJ, Manders RJ, Zorenc AH, Senden JM, Gorselink M, Keizer HA, van Loon LJ. (2005) Combined ingestion of protein and free leucine with carbohydrate increases postexercise muscle protein synthesis in vivo in male subjects. Am. J. Physiol. Endocrinol. Metab. 288(4): E645-653.