GLUTAMINE – A Supplement Waiting for Science to Catch Up?

Every month we look at a new supplement, and up until now it’s always been on a topic that I have researched in the past and had a real personal interest in. Although I have used glutamine in the past, like many of you I just accepted that there was a host of literature that proved its credentials for use in sports nutrition. For me its use has been in the area of immune system functioning and optimising my post exercise recovery. The conclusions based on the current peer reviewed data may surprise you, as the window for the potential application of this amino acid to significantly aid muscle growth and recuperation are shorter than you may realise!

Here is a supplement that’s been hitting the headlines for at least a decade, offering a host of physiological advantages including increased cell volume, improved protein balance, immune function, pH regulation, and acting as an excitatory neurotransmitter that can aid mental function. Well let’s take a look at the evidence guys and see “what’s the TRUTH”.

There is no doubt that the physiological importance of the amino acid L-glutamine for promoting and maintaining cell function is accepted across the scientific community. It is now well known that a large number of tissues and cells in the body utilize glutamine at high rates, and that glutamine utilization is essential for their function. Because of the vast quantity of literature on glutamine in this issue of Ironmagazine the focus of the review must be selective, with the most influential topics reflecting you guys the readers of Ironmagazine. I believe these areas to be protein synthesis, cell swelling, and immune function (can’t train if you are ill right!).

Glutamine Origin & Function

The immediate product of glutamine metabolism in most cells is glutamate, (see fig.1) which is produced by the action of glutaminase. Glutamine is the most abundant extra-cellular amino acid and its breakdown product glutamate is the most abundant in the intra-cellular environment [1]. Glutamine is utilized by many tissues including, kidneys, gut, and some cells of the immune system. To maintain these extreme demands glutamine must be synthesised by several organs, including skeletal muscle, kidneys, liver, lungs, and heart. The most important site of glutamine metabolism is skeletal muscle. In skeletal muscle glutamine can be synthesised by a variety of biochemical reactions including protein degradation or from the combination of 2-oxoglutarate and branched chain amino acids (leucine, isolucine, valine); it can just as well be taken from the plasma in its whole form or via the deamination of proteins [2].

Figure 1. An overview of the biosynthetic pathways of glutamine and glutamate metabolism. (Adapted from Newsholme et al 2003)

Glutamine

Don’t stress it: Immune function

It is now widely accepted that glutamine is utilized at high rates by isolated cells of the immune system such as lymphocytes, macrophages and neutraphils [3,4]. These cells can be placed under considerable pressure during situations resulting in elevated stress with the consequence being immune-suppression. Exercise is one form of physiological stress that could lead to immune system suppression, but is there a link between glutamine stores and its optimum functioning?

The effect of acute exercise on plasma glutamine concentration appears to be dependent to a large extent to both the intensity and duration of the exercise bout. After prolonged (2>hrs duration) exhaustitive exercise there is generally a small but significant decrease in circulating plasma glutamine concentrations [5,6,7]. Evidence suggests that the suppression of glutamine may remain for up to 4 hours upon the cessation of exercise [8]. Although in some situations this has been shown to be the case in many others it has not. Following ultra-triathlon, plasma glutamine was shown not to change [9], single bouts of high intensity exercise have been shown to both increase and shown no change [10,11]. So why all the confusion between studies? In essence this reflects the fact that measurements are mainly based on plasma analysis rather than assessment of changes within the intracellular environment i.e. “muscle glutamine stores”. In situations where muscle glutamine has been measured, a decrease is seen in many of the above exercise situations. What is still not well understood is why plasma glutamine levels can decrease while muscle glutamine is being released into the plasma (this maybe due to uptake of glutamine by the kidneys to maintain pH). The latest data suggests that in people with a long history of exercising and atypical over-trainers there is a change in the transport system leading to a decrease in the rate of glutamine release from skeletal muscle.

The chronicity of the physiological stress seems to be directly related to the severity of the immune suppression we can experience. This has been shown to be never truer than in clinical environment, and the severe trauma of sepsis and burns [12]. The largest decline reported in plasma glutamine is in severe burns victims where plasma concentration can fall massively from 490 – 200mM [11]. We know of many studies that have shown a direct relationship between glutamine loss and this form of excessive trauma and the need for supplemental glutamine. However to place this in context acute exercise only leads an average decline of only 100mM; much less of a fall and a decline that can be quickly replenished in a health subject. As we already know glutamine feeds a variety immune functioning cells, its is therefore important to understand if the exercise related decrease in plasma glutamine can have an immuno- suppressive effect, and if supplementation could ameliorate these negative consequences.

Lymphocyte Activated Killer cell activity (LAK) an immune cell type that destroy invading organisms, have been shown to be directly linked to glutamine concentrations. Juretic et al [13] discovered that depression of glutamine concentrations negatively affected the LAK activity. In an applied situation measurements of declining serum glutamine taken following a triathlon resulted in a parallel decline in LAK [14]. Many other immune responses have been proposed to be effected including cytokines and macrophages, however although there is a selection of literature linking glutamine with the immune system it is still unknown weather there is a causal relationship between decreased glutamine stores and immuno-suppression or vice versa. One possible way to elucidate this is through monitoring the effects of L-glutamine supplementation of which we will examine later (If you cannot wait skip forward a few paragraphs).

Cell Swelling: Turning up the Anabolic signal

Cellular swelling is often a symptom of a change in the osmotic gradient within the cell. What this means is that if you increase the concentration of a compound outside of the cell membrane above that found inside of the cell, there will be a movement of this compound until extracellular and intracellular contents are equal [15]. The movement of these compounds / solutes result in the uptake of water as they are transported inside the cell and hence a transient expansion of cellular volume (See figure.2).

Figure 2. Effects of glutamine on cellular solutes including K+, Cl-, and NA+ and the associated influence on cell volumization (Adapted from Haussinger et al 1990).

Glutamine

Recent evidence suggests that the state of cellular hydration (cell volume) is an import factor in the control of many important cellular functions. These include modulation of hormones, oxidative stress, and gene expression to name but a few. Several compounds have been shown to have a significant effect on cellular volume. The effect these amino acids have on glycogen synthesis and inhibition of proteolysis can be mimicked by bringing about similar changes in cell volume [16,17,18]. This indicates that many of the effects these amino acids exert can be accounted primarily due to their cell volumizing properties.

Cell swelling also inhibits protein breakdown but conversely cell shrinkage stimulates breakdown [19]. Glutamine has been shown to be a potent player for enhancing cellular swelling [20] (see figure.3). The mechanisms proposed for improved protein turnover as mediated via glutamine induced cell swelling are two-fold. Firstly it may influence the function of cyclic AMP, a chemical messenger associated with many cellular functions including the inhibition of protein synthesis as such, cell swelling may prevent or enhance protein synthesis. Secondly it may have a direct effect on cellular stability [21] however I doubt this hypothesis as recent studies have shown glutamine to have little effect on myofibrillar damage over the short term [22], longer term studies are still needed. Other factors such as nitrogen balance will be affected through glutamine supplementation and this in its own right will have a significant impact on protein synthetic rates.

Figure 3. The associated modulators of cell volumisation and their influence on cellular hydration and metabolism.

Glutamine

The influence of L-Glutamine supplementation

Immune Function

Several research studies have investigated the suggestion that exogenous provision of glutamine supplementation may be beneficial by preventing the impairment of immune function following endurance exercise. Castell [23] was one of if not the primary study demonstrating the influence of glutamine supplementation following exercise. A 5g dose was given immediately post race and 2hrs proceeding the event. Plasma glutamine was still depressed by 20% in both groups although based on questionnaires 80% of athletes reported no incidence of infection up to 7 days post event, were only 48% of the placebo group remained free of infection. However in a follow up study no significant difference in plasma glutamine was demonstrated between swimmers who did or did not develop upper respiratory tract infection (URTI) following and increase in the intensity of their training schedule [5].

It has been hypothesised that the dose of glutamine was not enough to ameliorate the decline in plasma glutamine concentrations, so a new dose protocol was needed. A dose routine using 100mg/kg BW was used 30min pre, immediately post, and 30mins post exercise [24]. The exercise consisted cycling for 60,45, and 30 mins with 2 hr recovery periods. The glutamine supplemented group maintained plasma concentrations above pre supplement levels, whilst the placebo group decrease by about 20% (as in the previous study above). Although the supplemented group maintained plasma glutamine concentration no differences were shown between the groups lymphocytes, leucocytes, or LAK activities, which are all known indicators of immune system function. This data demonstrates that although plasma glutamine concentrations were attenuated the influence of supplementation did not diminish post exercise immuno-suppresion characterised by decreased lymphocyte concentration and LAK activity.

There are two other major factors I would like to draw you attention two as regards the hypothesis of L-glutamine supplementation and immuno-suppression. Firstly it has been shown that in-vitro when we decrease the glutamine availability to lymphocytes to the lowest possible levels measured post exercise (300mM) their function was just as efficient as at concentrations similar to that demonstrated at rest (600mM). Secondly data from researchers at the Copenhagen Muscle Research Centre (CMRC) have shown that following an acute bout of cycling plasma glutamine levels decrease as expected, however the concentration in many of the immune cells was maintained and possibly increased. Therefore using the current dosing regimes, oral glutamine ingestion does not positively influence immune functioning in exercising populations.

Cell Swelling & protein sparing

To date there is very little direct data on L-glutamine feeding and protein rates in humans, what you will see quoted is a myriad of papers on malnutrition, AIDS, and people with gastrointestinal disorders. These hardly represent the exercising population and I won’t insult your intelligence by quoting what they have found. I could only really find one real study that has looked at the implication of glutamine supplementation and exercise performance for the resistance trained athlete. Antonio et al [25] investigated the possibility of high dose glutamine supplementation on weightlifting performance (one hour after ingestion) as defined by 2 sets of leg press (200% Bwt) and 2 sets of bench press (100% Bwt). No significant differences were found in the average number of reps performed between all groups. There is no reason why glutamine use would affect this form of performance, other than the far-reaching possibility of controlling/enhancing intracellular pH (ye glutamine may do this also). In this regard there are much more efficient extracellular and intracellular buffers. L-glutamine may also affect proteolysis by inhibiting the catabolic effects of cortisol. Whilst in clinical situations this may have a significant place in the total impact of a sound nutritional program in the experienced athlete I am not as convinced. Many studies have shown cortisol control has no direct impact on exercise performance [26] and possibly zero impact even if we could depress our cortisol levels, as experienced lifters produce less cortisol then their associated sedentary counterparts [27] buts that’s another story…

Glutamine a household name…but where do we go from here?

So what can we take away form the current research on glutamine that may help us improve performance, recovery, and the associated benefits of muscle growth and fat loss? Well there is no doubt that under very stressful conditions the bodies needs for glutamine can outstrip the capacity for production, leading to decreased intramuscular glutamine contents. In disease states associated with excessive muscle catabolism (AIDS for example); glutamine supplementation may maintain a positive nitrogen balance and sustain bodyweight. However the oral infusion of glutamine in healthy subjects has been shown to have no effect on retaining nitrogen balance [28]. Although this data seems to paint to a pretty bleak picture of glutamine, the truth is that much of the research has shown poor physiological benefits for generally athletic population because of a series of factors:

No methodical approach to dosing to find an optimal level to bring about favourable effects.

Many of the studies are short duration and a possible accumulative benefit of glutamine over time is unknown.

The influence of high-dose glutamine ingestion on trained subjects and cellular swelling are still awaiting investigation.

Studies still need to be performed on those athletes that are overtrained and are consistently effected by repeat viral infection. Can glutamine aid in the recovery of repeat infection and cumulative immuno-suppression?

5. Finally the most important factor is that many of the studies on glutamine are significantly influenced by the nutritional state of the study participants. An example of this is the anti-proteolytic effects exerted through the supplementation of glycine. In the fed state its anti-proteolytic effects is only about one third of that found after 24hrs of starvation.

My recommendations would to be make sure you take in at least 5g of glutamine each day as an assurance policy in conjunction with you usual nutritional regime. To try to have a real impact on recovery and maintaining intracellular glutamine stores the relatively high dose of 100mg/kg (equivalent to 7-10g a day) taken pre, post and 30mins will guarantee this result, although at a financial cost. So in essence science has a ways to go to prove the efficacy of glutamine as a vital sports supplement, but evidence is on the way especially in the field of antioxidant capacities and free radical mediated muscle damage prevention [29]. Until the next series of well-designed studies are released I am sure many companies will still promote this important amino acid as one of the best ergogenics out there, but now you know the facts how you use them regarding your core supplement choice is up to you!

REFERENCES

1.P.Newsholme et al, “Glutamine and glutamate as vital metabolites,” Braz J Med Biol Res, 36 (2003): 153 -163
2.M.Stumvoll et al, “Role of glutamine in human carbohydrate metabolism in kidney and other tissues,” Kid Int. 5 (1999): 778 – 779
3.M.Elia et al, “ Amino acid metabolism in muscle and in the whole body of man before and after ingestion of a single mixed meal,” Am J Clin Nutr. 49 (1989): 1203 – 1210
4.S.Yoshida et al, “Effects of total parental nutrition, systemic sepsis, and glutamine on gut mucosa in rats,” Am J Physiol. 163 (1992): E368 – E373
5.L.M.Castell et al, “Some aspects of the acute phase response after a marathon race, and the effects of glutamine supplementation,” Eur J Appl Physiol. 73 (1997): 47 – 53
6.J.Decombaz et al, “Biomechanical changes in a 100km run: free amino acids, urea and creatinine,” Eur J Appl Physiol. 73 (1979): 61 – 72
7.M.Parry-Billings et al, “Plasma amino acid concentration in the over-training syndrome: Possible effects on the immune system,” Med Sci Sports Ex. 24 (1992): 1353 – 1358
8.N.His***** et al, “Exercise-induced immuno-depression – plasma glutamine not the link,” J Appl Physiol. 93 (2002): 813 – 822
9.M.Lehman et al, “Serum amino acid concentration in nine athletes before and after the 1993 Colmar ultra-triathlon,” Int J Sports Med. 16 (1995): 155 – 159
10.D.Keast et al, “Depression of plasma glutamine concentration after exercise stress and its possible influence on the immune system. Med J Aust. 162 (1995): 15 – 18
11.M.Parry-Billings et al, “Does glutamine contribute to majour burns?,” Lancet. 336 (1990): 523 -525
12.R.J.Smith, “Glutamine metabolism and its physiological importance,” JPEN.(1990):14
13.A.Juretic et al, “Glutamine requirements in the generation of the lymphokine – activated killer cells,” Clin Nutr. 13 (1994): 42 – 49
14.T.Rohde et al, “The immune system and serum glutamine during triathlon,” Eur J Appl Physiol. 74 (1996): 428 – 434
15.D.Haussinger, “The role of cellular hydration in the regulation of cell function,” J Biochem. 313 (1996): 697 – 710
16.C.Hallbrucker, “Control of hepatic proteolysis by amino acids. The role of cell volume,” Eur J Biochem. 197, 3 (1991): 717 – 724
17.A.Baquet, “Swelling of rat hepatocytes stimulates glycogen synthesis,” J Biol Chem. 15, 265 (1990): 955-959
18.D.Haussinger et al, “Involvement of microtubles in the swelling-induced stimulation of transcellular taurocholate transport in perfused rat liver,” J Biochem. 15,291 (1993): 355 – 360
19.A.J. Meijer, “Cell swelling and the sensitivity of autophagic proteolysis to inhibition by amino acids in isolated rat hepatocytes,” Eur J Biochem. 215,2 (1993): 449 – 454
20.J.Kruppa, “Differential kinetics of changes in the state of phosphorylation of ribosomal protein S6 and in the rate of protein synthesis in MPC 11 cells during tonicity shifts,”EMBO. 3,1 (1984): 95 – 100
21.D.Haussinger et al, “Effect of hepatocyte swelling on microtubule stability and tubulin mRNA levels,” Biochem Cell Biol. 72, 1-2 (1994): 12 -19
22. glutamine myocellular stability ref….
23.L.M.Castell et al, “Does glutamine have a role in reducing infections in athletes?,” Eur J Appl Physiol. 73 (1996): 488 – 490
24.T.Rhode et al, “Effect of glutamine supplementation on changes in the immune system induced by repeated exercise. Med Sci Sports Ex. 30 (1997): 856 – 862
25.J.Antonio et al, “ The effects of high-dose glutamine ingestion on weightlifting performance,” J Strength Cond Res. 16,1 (2002): 157 -160
26.P.Del Corral et al, “Metabolic effects of low cortisol during exercise in humans,” J Appl Physiol. 84,3 (1998): 939 – 947
27.J.L.McMillan et al, “20-hour physiological responses to a single weight-training session,” J Strength Con Res. 7,1 (1993): 9-21
28.T.R.Zeigler et al, “Safety and metabolic effects of L-Glutamine administration in humans. JPEN. 14,4 (1990): 137S -146S
29.U.B.Flaring et al, “Glutamine attenuates post-traumatic glutathione depletion in human skeletal muscle.Clin Sci. 104,3 (2003): 275 – 282
 

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