Glutamine Supplementation: Facts and Fiction

I use L-glutamine, glutamine peptides, alpha-ketogluterate, and protein bound glutamine in many of my products, particularly in Amino, Power Drink, Creatine Advantage, Myosin Protein, and MRP LoCarb, but also in other products including MVM, GHboost, Resolve, and TestoBoost. I use glutamine because I believe it has ergogenic effects and has a central role in metabolism intertwinning with other amino acids, acting as an alternate energy source, and having significant beneficial effects on the immune, skeletal muscle, and central nervous system.


As I discuss the effects of glutamine I'll be using the new version of Power Drink as an example of a nutritional supplement that makes full use of all that glutamine has to offer during exercise, training, and competition. For the nutrition panels of the dozen products that have been updated to new versions in the past year have a look at the article on the new supplement panels as of Feb, 2017.


Power Drink contains significant amounts of glutamine and glutamate, as L-glutamine, glutamine peptides, and as part of the amino acid makeup of whey protein.


L-Glutamine (glutamine), the most abundant free amino acid in the body, is involved in multiple aspects of metabolism and signal transduction pathways. While some glutamine comes from dietary sources, most of the systemic glutamine is produced by skeletal muscle from alpha-ketoglutarate/glutamate and ammonia, and has several important effects in the body including its use as an energy substrate since the alpha-ketoglutarate (AKG) is a substrate of the Krebs/TCA/Citric Acid Cycle (the three are used interchangeably) and its formation increases TCA cycle flux and ATP formation.


As well AKG, either directly through the TCA cycle intermediates or indirectly through the formation of alanine formed in muscle via the alanine transaminase reaction. The alanine is then transported out of the muscle and to the liver to undergo gluconeogenesis and thus increase glucose availability.


The ammonia for these processes eventually comes from deamination of the branched chain amino acids (BCAAs – leucine, valine, and isoleucine) and under conditions of stress when more of the BCAAs are used to produce needed alanine and glutamine, the result is a decrease in protein synthesis and the anabolic effects of exercise.


Glutamine has significant effects on body composition and performance as it favorably affects growth hormone and cortisol levels, protein synthesis, cell volume, muscle catabolism (inhibits it) and gastrointestinal and immune function.[i][ii][iii][iv][v] It’s used for energy by most cells in the body but especially by the GI tract, liver, kidney and the immune system. The process for energy production is by successive deamination of glutamine to glutamate, then to alpha-ketoglutarate that enters the TCA/Krebs cycle and through the oxidative phosphorylation forms ATP, the main energy source on which the body functions.


Glutamine is also used as a basis for the synthesis of the ATP molecule itself, nucleic acids (DNA and RNA synthesis and repair), other amino acids and proteins, glucose through gluconeogenetic pathways, carbamoylphosphate, and other metabolites. As well glutamine increases glutathione, a powerful endogenous antioxidant that mitigates the counter-productive effects of exercise on excessive muscle damage without affecting the positive effects of exercise.


The interconversions, reactions, pathways and signaling that glutamine is involved in are complex and impacts many metabolic processes that are beyond the means of this information piece. As an example, glutamate can be used (besides conversion to glutamine) in an alanine aminotransferase reaction to produce alpha-ketoglutarate (AKG) and alanine or by the reverse reaction alpha-ketoglutarate can be aminated by ammonia or via a transamination reaction from other amino acids to form glutamate and pyruvate. The resulting alanine and pyruvate are involved in complex interactions and so the complexity of how glutamine affects metabolism soon increases exponentially.


For now, we’ll simply cover some of the basics on glutamine dynamics, benefits, and what many people consider potential adverse effects from glutamine supplementation.


While normal levels of endogenous glutamine are sufficient under most conditions, at times, such as when the body is under stress, it’s not enough. Depending on endogenous glutamine to supply the glutamine that the body needs under special circumstances including exercise, is like robbing Peter to pay Paul – using up needed carbon skeletons and amino acid precursors from muscle to make glutamine, thus impoverishing muscle tissue, because glutamine is more importantly needed elsewhere in the body for energy, to bolster immunity, and other purposes.


At times when endogenous glutamine resources are stretched beyond what’s needed, a time when glutamine becomes an essential amino acid since not enough can be formed endogenously, glutamine supplementation becomes a necessity.


Supplementation with glutamine, optimally as a free amino acid, or as glutamine peptides for quick access when needed, and from whole proteins that contain high levels of glutamine to keep glutamine levels optimized for normal times, has many beneficial effects by allowing other tissues access to the glutamine they need to function optimally, and by increasing health, body composition (fat loss and muscle hypertrophy), and physical and mental performance.


Glutamine has both direct and indirect anabolic effects. Glutamine directly increases energy metabolism and protein synthesis. Indirect effects include decreasing the deamination of the BCAAs and other amino acids and thus keeping their levels higher in skeletal muscle. Increased levels of leucine, for example, has stimulatory effects on protein synthesis and inhibitory effects on protein degradation/muscle catabolism. Also, transitory increases in ammonia, by providing amine groups for the formation of various amino acids, has an inhibiting effect on skeletal muscle proteolysis/breakdown.


Oral supplementation with L-glutamine, in free or dipeptide form, can restore the glutamine-glutathione axis, and provide cytoprotection mediated by HSP-27, thus attenuating biomarkers of cell disruption and damage, as shown in rats submitted to high-intensity resistance and endurance exercise training.[vi][vii]


A recent paper found that glutamine supplementation improves some parameters of sport and exercise performance, and chronic supplementation appears to be of special importance for increasing tolerance to intermittent exercise, lowering feelings of fatigue, and optimizing recovery from muscle damage.[viii] Glutamine may also act as a relevant resource for rehydration during strenuous and prolonged physical activity.


Glutamine and Ammonia


Ammonia is produced in the body from several processes including amino acid (mostly from glutamine and BCAAs) and purine deamination.


As far as adverse effects, there are none from the use of several grams of glutamine before and after exercise. However, there is a long-standing misconception that glutamine supplementation increases ammonia to the point that it has a negative effect physically and mentally on exercise performance.


The basis of this often-repeated belief is that glutamine acts as an important energy source for various tissues, including the gastrointestinal tract, the liver and skeletal muscle. The successive deaminations from glutamine to alpha-ketoglutarate results in the formation of 2 molecules of ammonia (NH3) and it’s the potential ammonia accumulation that many feel may make glutamine supplementation counter-productive by increasing physical and mental fatigue.


The ammonia-fatigue theory is almost a century old (a paper published in 1922 first suggested the correlation between ammonia accumulation and fatigue[ix]) and based on the link between exercise and muscle derived ammonia production with the results of studies where ammonia production was correlated with fatigue under pathological conditions in which increases in ammonia resulted in neuromuscular dysfunction.


This association was then falsely extrapolated to suggest that further increases in ammonia during exercise from glutamine supplementation results in fatigue and compromised exercise performance.


This ammonia-fatigue theory, especially involving glutamine supplementation, while hopelessly outdated, persists. But the fact is that a normal person without significant liver or kidney disease or genetic mutations that results in a deficiency of one of the six enzymes in the urea cycle, can keep in check, and even get beneficial effects from any ammonia formed during even the most extreme exercise or sporting event with or without the use of glutamine supplements.


It’s been shown that the regular use of glutamine in sports that do not require continuous exertion for long periods of time, because of compensating mechanisms as ammonia levels rise, decreases systemic and skeletal muscle levels of ammonia rather than increasing it. [x]


The decrease in ammonia is the result of adaptation responses to the increased glutamine breakdown including the suppression of synthesis of endogenous glutamine (thus sparing skeletal muscle BCAAS, and especially leucine and thus preserving the anabolic effects of intense exercise), elevating the expression of enzymes of the urea cycle, and priming both hepatic and renal systems to increase the disposition of ammonium.


In continuous, prolonged and strenuous exercise ammonium levels rise as exercise progresses but is easily kept in even with the use of glutamine supplements. On the contrary physiological increases in levels of ammonia in healthy people during exercise can have significant ergogenic effects.


The formation of ammonium from ammonia plus H+ an acid moiety rather than being counter-productive, has an ergogenic effect as it plays an important role in the regulation of the acid-base balance in the body. The activation of renal production of ammonium from glutamine breakdown and subsequent excretion of ammonium decreases the adverse effects of increasing acidity as exercise progresses, thus further decreasing fatigue and improving exercise performance.


The degree to which ammonia forms the ammonium ion depends on the pH of the solution. If the pH is low, the equilibrium shifts to the right: more ammonia molecules are converted into ammonium ions. If the pH is high (the concentration of hydrogen ions is low), the equilibrium shifts to the left: the hydroxide ion abstracts a proton from the ammonium ion, generating ammonia, which in turn can be used for the synthesis of amino acids, nucleotides, ATP, etc. or can be converted to urea for excretion, or the ammonium can be directly excreted.


The use of glutamine supplements besides increasing the production of ammonium through the deamination processes leading to glutamate and then alpha-ketoglutarate also has beneficial effects on systemic acid accumulation secondary to prolonged strenuous exercise. After formation of ammonium from glutamine, the alpha-ketoglutarate may be degraded to produce two molecules of bicarbonate, which are then available as buffers for dietary acids, thus adding to the net acid disposition that occurs with ammonium excretion and resulting in a decrease in fatigue and improved exercise/sport performance.


It’s also been shown that ammonium regulates mTORC1 and mTORC2 signaling. A recent study concluded that “ammonium triggers the AKT-dependent phosphoinhibition of the TSC complex and of PRAS40, two negative regulators of mTORC1. Consistent with mTORC1 stimulation, ammonium induces the inhibitory phosphorylation of 4EBP1, a negative regulator of protein biogenesis. mTORC1 responds to nutrients, energy levels and growth factors and stimulates translation and anabolic metabolism while inhibiting autophagy. ammonium derived from upregulated glutaminolysis, could turn advantageous for proliferation by triggering key signaling pathways promoting growth.”[xi]


Enhancing the Beneficial Effects of Glutamine


But there’s more to the story since Power Drink contains several other ingredients that have additive and synergistic effects on body composition and performance but also facilitate the benefits of glutamine supplementation.


Glutamine plus Alanine


As an example, L-alanine, which is also in Power Drink, is a non-essential amino acid that has benefits on its own but also works to improve the beneficial effects of other ingredients that are also in Power Drink.


Studies have shown that the combination of glutamine and alanine is an effective non-invasive alternative to increase body L-glutamine pools.  And that chronic oral supplementation with L-glutamine, whether in its dipeptide form or in the free form, to a limited extent by itself but better if taken along with L-alanine, represents an effective nutritional method to maintain L-glutamine stores, which attenuate the release of substances indicative of muscle damage and oxidative stress by enhanced glutathione antioxidant system and HSP70 response, thus improving the beneficial effects of high-intensity endurance and resistance exercise training.[xii][xiii][xiv][xv][xvi][xvii][xviii]


The basis as to why glutamine plus alanine is more effective to bring out the benefits of glutamine supplementation on body composition and performance enhancement has not been fully worked out. However, alanine and glutamine metabolic routes often work in parallel, particularly in active muscle as both are transported from muscle to other tissues for various reasons.


The formation of both for transport to other parts of the body, especially the liver, and immune and gastrointestinal systems involves the catabolism of other skeletal muscle amino acids, specifically, leucine, isoleucine, valine, aspartate, glutamate, asparagine, arginine, and proline. Supplementation with both alanine and glutamine spares these amino acids so they can be used to maintain or increase skeletal muscle mass.


During exercise, as systemic glucose levels decrease, both glutamine, mostly in the kidney, and alanine, mostly in the liver, are used for glucose formation by gluconeogenesis. Alanine supplementation decreases the breakdown of muscle tissue to procure both alanine and glutamine so they can be used to replenish systemic glucose. It also decreases the use of muscle pyruvate for the formation of alanine, which is then exported out of skeletal muscle to be used mainly by the liver to make glucose via gluconeogenesis.


The more strenuous the exercise, the more alanine is produced and less pyruvate is available in skeletal muscle which compromises protein synthesis and skeletal muscle performance. To some extent the degree in which pyruvate is cannibalized to form alanine for glucose formation outside of skeletal muscle can be seen by elevations of the enzyme alanine transaminase (ALT), often elevated with exercise and just as often mistaken as a sign of liver disease when in fact it’s more a sign of alanine formation due to depletion of glucose secondary to exercise. Alanine supplementation with exercise will decrease ALT levels since the transamination reaction to form alanine isn’t as active.


Other Examples


Glutamine, along with other osmolytes in Power Drink, including betaine, glycerol, creatine, and the amino acids arginine, lysine, taurine, and proline, protect cells from stress and increase protein synthesis secondary to the volumizing effects on muscle cells.


However, excessive amounts of glutamine are not necessary to obtain all the effects of glutamine supplementation since the inclusion of glutamate and alpha-ketogluterate in Power Drink also contribute to the beneficial effects of Power Drink on health, body composition and performance.


One 44 gram serving of Power Drink contains over 8 grams of glutamine, glutamate, and alpha-ketogluterate.


Bottom Line


The bottom line is that glutamine’s beneficial effects on body composition, performance, and recovery is a consequence of multifactorial cell and systemic mechanisms, including inhibition of inflammatory pathways, accumulation of intracellular osmolytes thus affecting hydration, synthesis of antioxidants especially the potent endogenous antioxidant glutathione, energy metabolism intermediates especially alpha-ketoglutarate, control of global ammonia levels throughout exercise, decreasing acidity secondary to exercise, increased protein synthesis through activations of mTORC1, decreasing excessive muscle damage and the suppression of neutrophil function, working additively and synergistically and affecting the metabolism of other amino acids such as the BCAAs and alanine, and activation of heat shock response intermediates especially HSF-1 and HSP70.[xix][xx][xxi][xxii][xxiii]


Simply put glutamine supplementation decreases fatigue, and improves the body composition and performance enhancing effects of exercise.




[i][i] Laviano A, Molfino A, Lacaria MT, Canelli A, De Leo S, Preziosa I, Rossi Fanelli F. Glutamine supplementation favors weight loss in nondieting obese female patients. A pilot study. Eur J Clin Nutr. 2014 Nov;68(11):1264-6.

[ii] Legault Z, Bagnall N, Kimmerly DS. The Influence of Oral L-Glutamine Supplementation on Muscle Strength Recovery and Soreness Following Unilateral Knee Extension Eccentric Exercise. Int J Sport Nutr Exerc Metab. 2015 Oct;25(5):417-26.

[iii] Phillips GC. Glutamine: the nonessential amino acid for performance enhancement. Curr Sports Med Rep 2007; 6: 265-8.

[iv] Koo GH, Woo J, Kang S, Shin KO. Effects of Supplementation with BCAA and L-glutamine on Blood Fatigue Factors and Cytokines in Juvenile Athletes Submitted to Maximal Intensity Rowing Performance. J Phys Ther Sci. 2014 Aug;26(8):1241-6.

[v] Cruzat VF, Bittencourt A, Scomazzon SP, Leite JS, de Bittencourt PI Jr, Tirapegui J. Oral free and dipeptide forms of glutamine supplementation attenuate oxidative stress and inflammation induced by endotoxemia. Nutrition. 2014 May;30(5):602-11.

[vi] Petry ÉR, Cruzat VF, Heck TG, Homem de Bittencourt PI Jr, Tirapegui J. L-glutamine supplementations enhance liver glutamine-glutathione axis and heat shock factor-1 expression in endurance-exercise trained rats. Int J Sport Nutr Exerc Metab. 2015 Apr;25(2):188-97.

[vii] Petry ÉR, Cruzat VF, Heck TG, Homem de Bittencourt PI Jr, Tirapegui J. L-glutamine supplementations enhance liver glutamine-glutathione axis and heat shock factor-1 expression in endurance-exercise trained rats. Int J Sport Nutr Exerc Metab. 2015 Apr;25(2):188-97.

[viii] Freitas HR. Glutamine in Sport and Exercise. International Journal of Medical and Biological Frontiers Hauppauge 2016; 22.4 :277-291.

[ix] Tashiro S, Ammonia production in the nerve fiber during excitation. Am. J. Physiol; 1922:60, 519–543.

[x] Bassini-Cameron, A., Monteiro, A., Gomes, A., Werneck-de-Castro, J., & Cameron, L. (2008). Glutamine protects against increases in blood ammonia in football players in an exercise intensity-dependent way. British Journal of Sports Medicine, 42 (4), 260-266.

[xi] Merhi A, Delrée P, Marini AM. The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling. Sci Rep. 2017 Mar 17;7:44602.

[xii] Jang HJ, Kwak JH, Cho EY, We YM, Lee YH, Kim SC, Han DJ. Glutamine induces heat-shock protein-70 and glutathione expression and attenuates ischemic damage in rat islets. Transplant Proc. 2008 Oct;40(8):2581-4.

[xiii] Petry ER, Cruzat VF, Heck TG, Leite JS, Homem de Bittencourt PI Jr, Tirapegui J. Alanyl-glutamine and glutamine plus alanine supplements improve skeletal redox status in trained rats: involvement of heat shock protein pathways. Life Sci. 2014 Jan 17;94(2):130-6.

[xiv] Cruzat VF, Pantaleão LC, Donato J Jr, de Bittencourt PI Jr, Tirapegui J. Oral supplementations with free and dipeptide forms of L-glutamine in endotoxemic mice: effects on muscle glutamine-glutathione axis and heat shock proteins. J Nutr Biochem. 2014 Mar;25(3):345-52.

[xv] Raizel R, Leite JS, Hypólito TM, Coqueiro AY, Newsholme P, Cruzat VF, Tirapegui J. Determination of the anti-inflammatory and cytoprotective effects of l-glutamine and l-alanine, or dipeptide, supplementation in rats submitted to resistance exercise. Br J Nutr. 2016 Aug;116(3):470-9.

[xvi] Zhang B, Lin M, Yu C, Li J, Zhang L, Zhou P, Yang W, Gao F, Zhou G. Alanyl-glutamine supplementation regulates mTOR and ubiquitin proteasome proteolysis signaling pathways in piglets. Nutrition. 2016 Oct;32(10):1123-31.

[xvii] Petry ÉR, Cruzat VF, Heck TG, Homem de Bittencourt PI Jr, Tirapegui J. L-glutamine supplementations enhance liver glutamine-glutathione axis and heat shock factor-1 expression in endurance-exercise trained rats. Int J Sport Nutr Exerc Metab. 2015 Apr;25(2):188-97.

[xviii] Leite JS, Raizel R, Hypólito TM, Rosa TD, Cruzat VF, Tirapegui J. l-glutamine and l-alanine supplementation increase glutamine-glutathione axis and muscle HSP-27 in rats trained using a progressive high-intensity resistance exercise. Appl Physiol Nutr Metab. 2016 Aug;41(8):842-849.

[xix] Girven M, Dugdale HF, Owens DJ, Hughes DC, Stewart CE, Sharples AP. l-glutamine Improves Skeletal Muscle Cell Differentiation and Prevents Myotube Atrophy After Cytokine (TNF-a) Stress Via Reduced p38 MAPK Signal Transduction. J Cell Physiol. 2016 Dec;231(12):2720-32.

[xx] Favano A, Santos-Silva PR, Nakano EY, Pedrinelli A, Hernandez AJ, Greve JM. Peptide glutamine supplementation for tolerance of intermittent exercise in soccer players. Clinics (Sao Paulo). 2008 Feb;63(1):27-32.

[xxi] Sasaki E, Umeda T, Takahashi I, Arata K, Yamamoto Y, Tanabe M, Oyamada K, Hashizume E, Nakaji S. Effect of glutamine supplementation on neutrophil function in male judoists. Luminescence. 2013 Jul-Aug;28(4):442-9.

[xxii] Freitas HR, da Silva PA, da Silva RT. (2015). The effects of acute/chronic glutamine and glutamine peptide supplementation on the performance and immune function in young active adult athletes. Current Nutrition and Food Science, 11 (4), 315-322.

[xxiii] Freitas HR. Glutamine in Sport and Exercise. International Journal of Medical and Biological Frontiers Hauppauge 2016; 22.4 :277-291.

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