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Extending Muscle Protein Synthesis

www.ironmanmagazine.comIn a recent edition of this column I discussed new research showing that all it takes to stimulate muscle protein synthesis after a workout is essential amino acids. Prior studies had suggested that a combination of a fast-acting protein, such as whey, along with a simple sugar, would be more effective than the protein alone. The rationale behind that idea was that the simple carbs would provoke a higher insulin response than the protein alone, which would increase the muscle-protein-synthesis effect; however, the new study found that amino acids alone would promote enough insulin release to maximize protein synthesis.

At the end of the article, though, I suggested that bodybuilders interested in maximum recovery and muscle repair should still include simple carbs in their postworkout drink. My reasoning was that the carbs would help replenish depleted muscle glycogen. Without that glycogen, trained muscle doesn’t fully recover before the next workout, leading to reduced pump and rapid fatigue.

Since I wrote about that study, another study has been published that confirms my suggestion to include carbs in a postworkout recovery drink.1 It involved rats, and while you must always exercise caution when extrapolating animal studies to human physiology, the mechanisms involved are fully functional in both rats and humans.

The researchers noted that muscle protein synthesis increases after a protein-containing meal but returns to baseline within three hours. That’s true even if the blood still contains elevated amounts of amino acids. Aminos, particularly leucine, one of the three branched-chain amino acids, stimulate protein synthesis by activating a protein called Mammalian Target of Rapamycin, or mTOR. In fact, leucine alone is the primary activator of mTOR.

When mTOR is activated, it initiates a cascade of reactions known as transcription and translation between genes and amino acids that causes new proteins to be formed. Most studies have shown that, as with amino acid blood levels, elevated mTOR does not extend protein synthesis beyond three hours after a protein meal.

The researchers developed a hypothesis that providing either additional leucine or simple carbs would break the three-hour barrier. They deprived rats of any food for 12 hours and then gave them a meal containing 20 percent whey protein. Then two and a quarter hours after the meal they gave the rats either simple carbs, leucine or both, while another group of rats got just water. The result: The rats that got leucine and/or carbs showed continued muscle protein synthesis after three hours.

The protein-synthesis-initiation factors are stimulated by amino acids and insulin, both of which are elevated after a meal. Some studies have suggested that the muscles become resistant to amino acid stimulation after a certain amount of time, usually within two to three hours after a meal. One study involved infusing a complete amino acid mixture into human adults for six hours. While the infusion nearly doubled the plasma amino acids, it only stimulated increased protein synthesis for two hours; however, animal studies using pigs as subjects found that as long as the animal were given amino acids, muscle protein synthesis continued.

The question is, What is it that causes muscle protein synthesis to downgrade, even with a high level of essential amino acids in the blood? The answer has to do with another protein called AMPK, which is the yin to mTOR’s yang. In other words, while mTOR is the primary promoter of muscle protein synthesis, AMPK blocks mTOR’s activity, effectively shutting down protein production.

AMPK is primarily an energy sensor. Whenever body energy stores drop, AMPK is activated to maintain and boost them. Those in zero-carb diets get a much greater elevation of AMPK because it’s also activated when muscle glycogen is low. One way that AMPK boosts energy is by promoting increased fat burning in muscle, which of course is a good thing. In relation to muscle proteins synthesis, however, AMPK would have to be considered a catabolic substance.

Some emerging studies show that boosting AMPK may also increase longevity. While mTOR is great for boosting muscle mass, it does have a dark side. It’s involved in increased aging of cells as well as the spread of cancer through the body. Boosting AMPK tempers the bad effects of mTOR.

In fact, a drug commonly prescribed to treat diabetes called metformin works by increasing AMPK. That helps control elevated blood glucose, a hallmark of diabetes, and as a bonus, studies show that it also appears to help prevent several types of cancer.

You don’t need to use drugs to boost AMPK. It’s naturally boosted by exercise alone, especially aerobic exercise, and also by training under reduced-energy conditions, such as when you’re dieting. Supplements that boost AMPK include resveratrol and curcumin.

AMPK is released when the immediate energy source of the body, adenosine triphosphate, is degraded. ATP produces energy when one of its three phosphate bonds is broken off. That reduces ATP to ADP—adenosine diphosphate. When that happens, AMPK suddenly appears to help resuscitate the depleted ATP stores.

How does that relate to the new research about muscle protein synthesis? It turns out that the primary reason that protein synthesis ceases after two to three hours following a meal, despite a lot of amino acids circulating in the blood, is the high energy cost of protein synthesis. Within three hours the energy level drops sufficiently to trigger a release of AMPK, which stops protein synthesis dead in its tracks. Not even the mighty mTOR can overcome the dominance of AMPK because the body considers energy production to be exceedingly more important than protein synthesis. After all, without available energy, muscle protein synthesis cannot proceed anyway.

What the new study found was that either leucine, simple carbs or a combination of the two had the ability to extend the limited time span of muscle protein synthesis following a meal. The key to the effect was that leucine and carbs both had the ability to turn off AMPK, and that enabled protein production to continued unabated.

This study illustrates that muscles do not become unresponsive to the anabolic effects of amino acids, as was previously believed. Rather, it’s the dominance of AMPK and the need for energy that determine the time span of protein synthesis. Leucine and carbs work because they are readily used energy sources. Leucine is converted into a metabolite called ketoisocaproate that can be oxidized in the cellular energy cycle to produce needed ATP.

In addition, when ketoisocaproate is boosted in muscle, it promotes the oxidation of all three branched-chain amino acids by stimulating the activity of the primary muscle enzyme responsible for that. In this study providing extra leucine reduced the other two BCAAs, isoleucine and valine, by 50 to 100 percent. Again, that occurred because the BCAAs were oxidized by ketoisocaproate from the extra leucine. The net effect is energy, and it’s that energy that turns off AMPK and enables protein synthesis to continue.

What are the practical implications of the study? It appears that while protein synthesis lasts only two to three hours following a high-protein meal after a workout, you can extend it significantly by either supplementing with extra leucine or adding simple carbs to your postworkout recovery drink. The usual suggested ratio of carbs to protein for such drinks is 4-1.

The favored postworkout protein source is whey—for a good reason. First, whey is a rapidly absorbed protein source, and you would want a ready supply of essential amino acids in muscle for protein synthesis after a workout. In addition, the aminos in whey will promote an insulin release, which also helps ferry them from the whey into muscle. Since whey is composed of 26 percent BCAAs, it may not be necessary to add more leucine to the drink, except under one condition.

Recent studies show that those over 40 are somewhat unresponsive to the anabolic effects of amino acids compared to younger people. As such, adding leucine to the drink may even the playing field for them in terms of protein synthesis. For all others, it’s important to ensure that you always get both rapidly absorbed protein and simple carbs. The simple carbs will not only aid muscle recovery through muscle glycogen replenishment but also extend the time for muscle protein synthesis by blocking the effects of AMPK.  


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1 Wilson, G.J., et al. (2011). Leucine or carbohydrate supplementation reduces AMPK and eEF2 phosphorylation and extends postprandial muscle protein synthesis in rats. Am J Physiol Endocrinol Metab. 301(6):E1236-42.

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