GLUTAMINE: controversial but effective

Glutamine use in order to support the effectiveness of weight training is recently being questioned. Its well-established position has been undermined by the results of one study. These findings that "have gone out into the world" have been picked up by many malcontents and hailed as a huge issue, unjustly depreciating this valuable sports supplement. Glutamine opponents often incorrectly or unfairly interpret the findings of the studies which came out very well and clearly prove the use of glutamine as a supplement supporting muscle mass development. Therefore, today I will try to reveal the truth about glutamine.

Anabolic supplement

Glutamine career started almost the same time as creatine, which is somewhere in the late eighties and early nineties. Although glutamine is an amino acid, a building block of protein, it is rather particular: the molecule has a unique ability to store nitrogen in the form of an amino group. It therefore acts as a transporter of this element in our body. We know that nitrogen is a specific protein component, hence nitrogen balance measures protein metabolism. If the balance is positive, i.e. we store more nitrogen than we lose, we know that our body favours anabolism and that our muscles - built predominantly with proteins - grow. Conversely, negative nitrogen balance informs us of predominance of catabolic processes that degrade protein and destroy our muscles.

Firstly, intake of glutamine, which is a nitrogen carrier, improves our nitrogen balance.

Secondly, mobile glutamine amino groups take part in transamination and anabolic processes, helping in amino acid formation and protein restoration. A research done by MacLennan et al. in 1987 was probably the first study that let glutamine in to the arsenal of sports supplements. The scientist saturated isolated rat muscles with glutamine, observing that the amino acid increased protein anabolism by 66% without insulin and by 80% in the presence of insulin.

In 1988 the same scientist done a similar experiment and reported that saturating rat muscles with glutamine more than 10-fold reduced loss of protein and nearly 3-fold inhibited its breakdown , compared with the results obtained in the absence of this amino acid.
Same year, Jepson presented his findings and his research team made it clear that glutamine levels in living rats were closely correlated with the rate of protein synthesis.
In 1989, Millward came to the same conclusion, adding that high levels of glutamine not only stimulated protein anabolism, but also inhibited protein catabolism.
Also in 1989, in the study done by Hammarqvist, two groups of patients who underwent abdominal surgery were fed parenterally. One group received infusion of a standard amino acid mixture, and the second - the same blend, however enriched in glutamine. On the third day of this after surgical treatment nitrogen balance in the glutamine group was over three times higher, and the overall amino acid concentration in skeletal muscles increased by more than 5 percent compared to the control group. Again, the same year (1989) and a similar methodology, but this time Stehle and patients after colorectal cancer surgery came to the arena: it occurred that administering a standard nutrient mix enriched with glutamine peptide (alanyl-glutamine), compared with the control (standard mix plus free alanine and glycine) resulted in 160 percent improvement in nitrogen balance.
However, in 1990 Guoyao and Thompson demonstrated in vitro that the addition of glutamine stimulated protein synthesis in isolated muscle fibres in an amino acid concentration dependent manner. At the highest concentration of glutamine, anabolism increased by 58% compared to no glutamine at all and over 42%, compared with physiological concentrations.

In this situation, we should not be surprised that in the early nineties glutamine has appeared in the arsenal of performance enhancers in strength and physique disciplines.

A backstab

Glutamine career has been interfered by the results of this particular research... It was a study done by Louise Deldicque in 2008, in which the scientist showed that glutamine was a leucine antagonist, interfering with mTOR kinase in muscle cells.

At that time, it was already well known that mTOR kinase is a major stimulator of protein synthesis in muscle fibres: the enzyme becomes active in presence of anabolic hormones, mainly insulin and insulin-like growth factor IGF-1, as well as some amino acids, especially leucine.

It stimulates translation - a strategic step in the process of protein production, involving binding individual amino acids in the peptide chain complex. Thus, if glutamine acts on mTOR kinase opposedly to leucine, it's clear that it must suppress anabolism. Homegrown gurus in performance enhancement drew such a conclusion from the study and spread it all over the world, although the conclusions of the authors themselves were much wider and what's more important - quite the opposite.

mTOR kinase, like all enzymes in the kinase family, is activated by phosphorylation. Phosphorylation is a process of binding an organic molecule to a phosphate group - the same as the one used by ATP in facilitating working muscle fibres contraction. In the case of mTOR, phosphate groups are bounded by two molecules of serine - the amino acid forming part of the enzyme protein. In the recent study scientists used isolated, aging muscle cells of mice exposed to either leucine or glutamine, or a mixture of these two amino acids. The addition of leucine increased the phosphorylation of the first serine molecule by more than 50%, and the second one - 8-fold. In contrast, the addition of glutamine, in fact, counteracted leucine effect and decreased the phosphorylation of the first serine molecule of approx. 25%, but 2-fold increased of the other serine molecule. The combination of both amino acids increased first serine molecule phosphorylation by more than 40%, while the other - as much as 12-fold.

Active mTOR cascades its signals further, leading to the phosphorylation of the other proteins on the signaling pathway of this enzyme. Phosphorylation (activation) of the ribosomal proteins, marked S6, is a very important point because ultimately it's S6 that starts anabolic processes. The activity of this protein increased in presence of leucine by approx. 75, glutamine by about 30, and the mixture of both aminoacids by about 80 percent.
However, the most important is the end result - the concentration of contractile proteins produced in muscle cells. And here's a surprise: while leucine increased the production of myosin heavy chain in muscle cells by 10%, then glutamine - by 40% and the mixture of both amino acids - drum roll (!) - by as much as 270%.

Surprisingly, the study, which allegedly sinks glutamine, appears to support the theory of the highly anabolic properties of this amino acid.

It is clear that glutamine is a 4 times stronger anabolic than leucine; glutamine works synergistically with leucine, increasing its anabolic activity ... almost 30-fold.

Where should we be looking for the causes of this total misunderstanding ...? Firstly, it's worth to mention the title of this survey, which confuses inexperienced journalists a bit: "Antagonistic effects of leucine and glutamine on mTOR pathway in C2C12 myogenic cells." After reading a widely available, enigmatic abstract of this study, you get the impression that leucine and glutamine act completely opposite on the anabolic mTOR pathway and the process of protein synthesis. Everything becomes clear only after reading the full text, for which Springer publishing house asks for forty dollars minus five cents.

Besides, in 2003 Xia studied the effects of glutamine on isolated striated heart muscle cells (cardiomyocytes). He observed that the addition of this amino acid to the culture activated mTOR and led to cell hypertrophy, increasing the overall concentration of protein in the cells by more than 51% and increasing 4-fold and 6-fold the level of contractile protein synthesis, actin and myosin heavy chain respectively.

In 2007, Evans blocked glutamine transporter SNAT2 in isolated muscle cells in different ways. He observed each time that the inhibition of transport of this amino acid led to the depletion of intracellular glutamine stores and, consequently, to suppression of the entire mTOR signaling pathway and protein synthesis impairment which was comparable to the effects of a well-known, strongest mTOR inhibitor - rapamycin. It was also observed that decline in glutamine levels was accompanied by reduction of the intracellular concentration of leucine because the first amino acid mediates the transport of the other one into muscle cells.

In 2010 Tania Cristina Pithon-Curi examined the effect of glutamine on anabolic and catabolic signaling pathways and protein synthesis, using both isolated muscle cells and live rats. The addition of glutamine to cell culture led to the phosphorylation (activation) of mTOR and increased protein anabolism, measured with leucine incorporation rate into muscle cells. Similar effects were observed in the muscle tissue of rats fed for 15 days with a diet supplemented with glutamine at a dose of 1 g per kilogram of body weight.

Activating effect of glutamine on the kinase mTOR was also observed in 2013 by Adriana Lambertucci, in a study conducted in rats. Here, in the skeletal muscle of healthy rats receiving glutamine by gastric gavage at a dose of 1 g per kilogram of body weight, there was an approx. 5 percent increase in mTOR protein concentration, while in the muscles of diabetic rats - to approx. 80 percent.

In the following years, it has been already demonstrated in subsequent studies that beyond doubt glutamine and leucine cooperate in the activation of mTOR what seems to explain why the combined effect of both amino acids on protein anabolism is much better than each of them individually (Chiu, 2012; Duran, 2012; Jewell, 2015).

Studies discussed above are, of course, not all the studies that demonstrated the anabolic activity of glutamine. In fact, there is a vast amount of similar studies. High time to have a closer look at them...

Glutamine and hormones

We should not miss a review of the results of the glutamine influence on catabolic and anabolic hormones, because relationships in our hormonal system can tell us a lot about the potential pro-muscular action of this amino acid.

First of all, glutamine is a signal molecule involved in the mechanisms associated with the release of probably the most powerful anabolic hormone - insulin.

This is apparent in the work of Li, 2004, where the author proved in experiments on rats that glutamine mediates amino acids and glucose-stimulated insulin secretion by pancreatic cells that produce this hormone.
In this situation it is not surprising that in 2009 Greenfield, who administered his volunteers 30 g of glutamine per day on three separate days, observed a significant increase in bloodstream insulin level in both lean, healthy obese and obese suffering from type 2 diabetes subjects. However, administering 0.5 g of glutamine per 1 kg of body weight to boys with muscular dystrophy resulted in an increase in insulin levels by nearly 43 percent after 5 hours.
However, glutamine not only increases the release of insulin, but also enhances its activity in the target tissues, which improves the so-called insulin sensitivity. It was proved, amongst others, in 2006 by Bakalar in a study on a group of 40 hospitalised patients.
This is largely a consequence of the fact presented above: glutamine has a positive effect on the insulin signaling pathway that for example runs in the muscle cells.

It should be noted that the effect of glutamine on insulin sensitivity is quite specific...

You may remember that this powerful anabolic hormone has a major drawback: it is just as effective with regards to anabolic muscle tissue as is to fat. Not only does it facilitate muscle mass development, but also fat accumulation. However, in 2007 Prada proved in his study on rats that glutamine supplementation lowers insulin sensitivity of adipose tissue and increases sensitivity in muscles, which leads to a reduction in fat mass.

In 1995 in a study done by Welbourne, the volunteers were given 2 grams of glutamine dissolved in Coca-Cola within twenty minutes after they had a light breakfast. After 90 minutes Welbourne observed that even this small dose of the amino acid leads to a considerable (over 4-fold) increase in anabolic growth hormone (GH)..

In 2003, Arwert also gave glutamine to the volunteers, however it was enriched in glycine and nicotinic acid (vitamin PP); total daily dose of both amino acids was 5 grams. After three weeks of supplementation he noted that in the glutamine group, compared with the placebo group, the level of growth hormone in the bloodstream was increased by 70 percent.

In 2013 Amy Ellis conducted a study that involved twenty nine elderly, healthy volunteers, aged between 65 and 87 years. The subjects were administered daily either 28 grams of glutamine, arginine and HMB or an isocaloric placebo. After six months of supplementation a significant increase in muscle mass and anabolic IGF-1 in the blood of the glutamine group was observed; in the placebo group, there were no changes within these two parameters.

But glutamine, as demonstrated by Coeffier in 2003, has also a positive effect on IGF-1 levels in young men.

Coeffier gave twenty young (average age 22 years) and healthy volunteers enterally via a gastric feeding tube either saline or a mixture of amino acids, or glutamine. Compared to saline, glutamine increased IGF-1 levels in the blood by 4.75%, and compared to the amino acids - by about 5.55%. There was also an increase in insulin - by 90% and 20% respectively.

Also, in 2005 Moeser proved a positive effect of glutamine administration on maintaining a high level of IGF-1 in the blood plasma in the experiment on pigs as an animal model research.

In 2009, in a study done by Dabidi Roshan, twenty-four 18yr old, physically active males performed two exercise bouts to exhaustion, separated by a four day break. These young men were divided into two groups, with one drinking sugar-free lemonade (placebo) and the other group drinking the same drink, but enriched with 6 grams of glutamine, for four days between exercise bouts. Compared to the placebo group and baseline levels, cortisol levels in saliva were reduced by nearly 15 percent in the glutamine group.

In 2010, Sharp conducted a study on eight athletes performing heavy weight training. He divided the volunteers into two groups - the first was given 2 g glutamine and 4 g BCAA per day during 4 week training protocol and the second group was given placebo. Blood samples were taken before, after and during the supplement-training programme in order to determine changes in the levels of testosterone and cortisol. Compared to the placebo group and baseline levels, in the glutamine group anabolic testosterone levels increased almost 2.5-fold, while the level of catabolic cortisol decreased 2-fold. Finally, in the glutamine group there was more than 7-fold increase in testosterone-cortisol ratio what defines the anabolic potential of a strength athlete.

In 2012 Hakimi conducted a study where thirty young students were performing the same weight training program for 8 weeks. Young males were randomly divided into two groups - a glutamine supplementation group taking 25 grams of glutamine per day or the same amount of starch as a placebo. Compared to the control group, the glutamine group showed significantly greater hormonal increases - 303% increase in growth hormone, 128% increase in testosterone and 115% increase in IGF-1 while cortisol levels dropped by 433%.

At this point it is worth noting that glutamine effect on cortisol is not only limited to decreasing the level of this hormone in athletes (which this amino acid is probably the best known for).

Indeed, in 2006 Salehian confirmed that the amino acid inhibits the catabolic activity of cortisol at the same time. The researcher referred here to the old study of Hickson, 1995, in which it was observed that administering glutamine to rats, together with cortisol acetate, inhibits muscle mass loss by 70%, which is the effect of the hormone catabolic activity. To prove this thesis, Salehian gave rats dexamethasone (used in medicine superactive 30-fold more potent analogue of cortisol) or dexamethasone with glutamine. He also treated isolated muscle cells with either dexamethasone or dexamethasone-glutamine blend. It was found in the study that glutamine significantly inhibits dexamethasone-induced muscle breakdown and the mechanism of its anti-catabolic activity is based largely on... inhibiting the cortisol induced production of catabolic and anti-anabolic myostatin.

It should be stressed here that only glutamine supplements have the ability to inhibit the activity of cortisol , not bound amino acid that forms dietary proteins.

A similar conclusion was reached in 2001 by Boza who fed dexamethasone-treated rats a glutamine-rich diet, whereas the other rats were given its equivalent in the form of free amino acid. Only in the free glutamine group there has been more than 50-percent increase in the rate of protein anabolism. The author argued that glutamine, bound to dietary proteins, is mainly used in visceral tissues for their own purposes.

Apart from cortisol, factor TNF-alpha is another catabolic hormone that strongly stimulates the production of myostatin in muscles.

And in fact: when Bonetto added TNF-alpha to a muscle cell culture, myostatin levels increased by approx. 220 percent compared to the control cells cultured with medium alone. However, in cell cultures treated with both TNF-alpha and glutamine, there was only approx. 90 percent increase in myostatin levels. Finally, we can conclude that glutamine decreases myostatin levels in muscles treated with TNF-alpha by about 130%. This observation is very important mainly because most of TNF-alpha is produced during anaerobic exercise where no lactic acid is produced and which lead to muscle fibres damage and are specific to bodybuilding workouts (Zembrom-Łacny, 2008).

Glutamine, muscles, anabolism

Since glutamine, as we have seen, strongly enhances and improves the activity of anabolic hormones, while reducing the level and inhibiting the activity of catabolic hormones, it should improve the status of the whole body and have a positive effect on our muscle mass. Due to these properties of glutamine, the molecule was repeatedly tested in clinical trials that saw it as an anabolic drug that improves nitrogen balance and inhibits muscle loss in severe debilitating illnesses.

For example, Carroll (study published in 2004) administered parenterally either conventional food mixture, or glutamine supplement to nineteen patients in critical condition and observed a 120-percent improvement in the protein balance. in the second group compared to the first one.

Let's go back for a moment to 2000 to a very interesting experiment conducted on rats by Holeček who studied the effects of bacterial toxins on protein metabolism in relation to glutamine. When rodents were exposed to a bacterial toxin, catabolic processes in rodent muscles significantly increased while anabolic processes decreased, resulting in a significant deterioration in protein balance of the whole body. However, administration of glutamine after 30 minutes to the animals reversed these effects by inhibiting catabolism and improving the overall protein balance. Why did I find these findings particularly interesting ...? After all, we are dealing with a situation often encountered in sport: a bacterial infection destroys much of the hard-earned muscles. Athletes often include glutamine in their supplementation due to its ability to improve immunity and this is what this amino acid is particularly known for.

However, the above study shows us that not only does glutamine protect against infection, but it also prevents muscle loss that is its unwelcome consequence.

In 2002, May tested the usefulness of glutamine in cachexia - muscle wasting syndrome associated with severe illness. He divided thirty-two patients suffering from cancer into two groups, where one group (control group) was receiving daily a balanced (in terms of the nitrogen content) mixture of amino acids, whereas the second group (experimental) was receiving 14 g of glutamine in combination with arginine and HMB. After four weeks of the experiment, the muscle mass in the control group decreased by 1.34, while in the glutamine group increased by 1.12 kilogram.

In 2010 a very interesting experiment was conducted by Momekav... The scientist isolated human muscle fibres, keeping them in medium at 4 times lower concentration than required for optimal cell growth. He then left a control group of cells on this medium and treated two other groups with physiological concentrations of two forms of glutamine - ordinary and specially stabilised amino acid. After 72 hours, compared with the control group, the protein content in the fibres treated with an ordinary amino acid increased by 30 percent and with stabilised glutamine - by 50 percent.

Glutamine for bodybuilders

In 1995 Varnier administered either 30 mg/kg glutamine, a mixture of alanine with glycine or a saline solution to cyclists who were intensively training for 90 minutes. Two hours after training he recorded over a 3-fold higher concentration of glycogen in the muscles of the glutamine group athletes, compared with the amino acid and saline groups.
I don't need to remind you what this high increase in muscle glycogen means to bodybuilders and physique athletes...

Obviously muscles saturated with glycogen are large and full and are able to perform more reps with heavier weights.

In 2001 for 6 weeks Candow was giving young (18-24 years), strength athletes either 0,9 g/kg of glutamine (approx. 35 g), or the same amount of maltodextrin as placebo. After the experiment, compared with the placebo group, the subjects from the glutamine group increased their strength and muscle mass by 1% and 0.3% respectively; the rate of muscle catabolism measured by a marker of protein breakdown in the urine decreased in this group by 15%.

The results of the above studies are worth a closer look because they tend to be used as arguments by glutamine opponents. The authors of this study, in fact, concluded that glutamine supplementation does not significantly affect muscle performance, body composition and protein breakdown in young healthy athletes. This conclusion, however, remains a matter of interpretation ... Please note that 1% strength increase in six weeks, compared to placebo, means about 1 kilogram more on a barbell for an athlete with 100 kgs 1RM. In contrast, 0.3% greater muscle mass means for an average bodybuilder about 150 grams of lean muscle mass; this translates into about 1.2 kilogram of muscles more after a year. And every bodybuilder knows best how difficult it is to gain one kilogram of muscle mass.

The second snag lies in the methodology of the experiment ... The experiment was done in accordance with the standards laid down for clinical trials, i.e. with placebo control. Let me remind you that clinical trials are designed to test drugs that we use in milligram doses. In this situation tens or even hundreds of milligrams of maltodextrin (carbohydrate) would be a perfect placebo i.e. medically ineffective treatment.

However, perfectly digestible maltodextrin stops to be indifferent at a dose of 35 g and it does not meet the criteria for placebo.

Ultimately, in the above experiment the scientist didn't study glutamine activity compared to placebo, but to carbohydrates. And carbohydrate intake at such high doses before and after training leads to a significant increase of muscle mass and strength (eg Andersen, 2005; Cribb, 2006). Because maltodextrin undoubtedly falsified the results, it is best to rely here on the effects obtained with respect to the baseline. If we approach the issue in this way, we will see that within six weeks glutamine supplementation led to up to 6% strength increase and 2% muscle mass gain, which certainly is a statistically significant result.
At this point you can ask (as indeed one of my opponents once did in a similar discussion): if a several dozens of grams of carbohydrates haven't got much weaker effects as a similar serving of glutamine, is it not better to take just carbohydrates, because it would be cheaper to do so? I will answer a question with a question: when do you usually take glutamine? When we're shredding and cutting carbs! And all in order to burn fat without muscle loss.

Another study, which results also tend to be a subject of manipulation, refers precisely to the relationship between glutamine and carbohydrates. In 2006, Wilkinson decided to see if glutamine supports the beneficial effects of essential amino acids (EAA) and carbohydrates on our muscles. The volunteers did an hour and a half of moderate intensity cycling training. Then, they were divided into two groups - one group received a mix of carbohydrates and EAA (approx. 70 g carbs and 9 g EAA), whereas the other group received the same drink but enriched with about 20 g glutamine (0.3 g/kg). As it turned out, in a three-hour period of restitution, the addition of glutamine did not increase the effect of amino acids and carbohydrates on glycogen and protein synthesis. Glutamine opponents often confine on this information, omitting the final conclusion, saying that glutamine led to a strong inhibition of catabolic processes in subsequent stages of post-exercise recovery.

In 2003, Lehmkuhl gathered a group of 29 athletes, including sprinters, jumpers and throwers, and put the young athletes on an 8 week progressive strength training program. The aim of this study was to verify the reports on the anabolic activity of the two most popular bodybuilding supplements at that time - creatine and glutamine. The scientist divided the athletes into three groups, with the control group receiving a placebo, the creatine group receiving creatine (0.3 g/kg in the first week, and 0.03 g/kg for the next seven weeks) and the third group receiving the same amount of creatine and 4 g of glutamine.
The results obtained were as follows: muscle mass - placebo - 0.5 kg increase, creatine - 2.2 kg increase, creatine plus glutamine - 3 kg increase; fat tissue – placebo - 0.2 kg decrease, creatine - 0.5 kg decrease, creatine plus glutamine - 0.8 kg decrease.
The positive effect of glutamine on adipose tissue and fat loss, observed by Prada in rats, also applies to strength athletes. However, if the figures relating to the increase in muscle mass measured in kilograms are converted into percentage, we will see that even 4 g glutamine increase the anabolic activity of creatine by more than 36% (2.2 kg + 36.4% = 3.0 kg).

Let's go back for a moment to the study from 2010 done by Sharp on eight athletes performing heavy weight training. He divided the volunteers into two groups - the first group was given 2 g glutamine and 4 g BCAA per day during 4 week training protocol and the second group was given placebo. Compared to the placebo group and the baseline, in the glutamine group testosterone increased nearly 2.5-fold and cortisol levels decreased 2-fold. Finally, in the glutamine group the testosterone to cortisol ratio increased more than 7-fold what defines the anabolic potential of strength athletes.

It is worth adding that in the glutamine group, compared to the placebo group, the breakdown of muscle fibres measured by the creatine kinase levels was reduced by nearly 30 percent.

Concluding the review of studies proving glutamine usefulness in bodybuilding and other strength or physique disciplines, I will go back to already partly discussed Hakimi work done in 2012.

Let me remind you that the author put 30 students on an eight week's weight training program, dividing young men into two groups - one receiving 25 grams of glutamine per day and the other the same amount of starch as placebo (raw starch, in contrast to maltodextrin, is a carbohydrate almost not digestible in the gastrointestinal tract and not absorbed by our body).

Compared with the control group, in the glutamine group the following hormonal changes occurred: growth hormone - 303% increase; testosterone - 128% increase; IGF-1 - 115% increase; cortisol - 433% decrease. Now, we should see to what extent these very favourable changes had impact on the final training effects. These were as follows: bench press - placebo - 3.53 kg increase, glutamine - 6.25 kg increase; squat - placebo - 3.54 kg increase, glutamine - 6.02 kg increase; muscle mass - placebo - 0.9 kg increase, glutamine - 2.9 kg increase; fat - placebo - 0.2 kg decrease, glutamine - 0.6 kg decrease.

Wrapping up...

The results of the last study probably leave no doubt:

glutamine is a powerful anabolic, supporting the development of muscle mass and strength in athletes, and on top of that - quite active fat burner, facilitating adipose tissue reduction.

The aforementioned rich arsenal of research on glutamine makes us think about this amino acid as a great performance enhancer in strength and physique disciplines.

It needs to be highlighted that these experiments demonstrated synergism occurring between glutamine and creatine and BCAA. Please note that in studies using glutamine alone doses ranged from 25 g to 35 g, wherein it is the lower dose that gave better results in muscle mass and strength gains. However, where the excellent results were achieved and glutamine was combined with creatine or BCAA (possibly with HMB - the most active metabolite of BCAA), the doses ranged between 2 to 14 grams. All this shows us that we do not need to use monstrous doses of glutamine to achieve desired results, but its fusion with creatine and BCAA can result in better growth with less money spent on supplementation.

From the above research review another conclusion emerges confirming the old truth: creatine plus glutamine plus BCAA is a base of performance enhancement in strength and physique sports.

BACK ›

GUIDE