Leucine: The Anabolic Trigger
By: Layne Norton BS Biochemistry
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.
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. 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 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!
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. 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). 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. 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 sky
scraper. 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).
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.
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
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AJ, Manders
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AH, Senden
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