Alanine Glutamate Glutamine Glycine
110 826 1038 62
From Morgan, H.E. et al., J. Biol. Chem, 246, 2152, 1971.
on bone growth also may be related to its ability to enhance calcium absorption and renal conservation, as well as to its participation in the cross-linking process of bone collagen formation.35-37 Additionally, lysine competes with the AA ARG for tissue uptake, which provides some of the basis for its clinical applications in the treatment and prevention of recurrent herpes simplex infections.38
The most common rationale in support of lysine supplementation in sport or fitness applications is in the raising of GH levels. According to the athletic culture theory, that effect should in turn enhance exercise-induced outcomes. The use of AAs for stimulating GH release dates back to the 1960s, when infusion of ARG was introduced as a potential diagnostic test for GH secretion.39 Intravenous infusion of 183 mg of ARG per kilogram of body weight increased plasma GH 20-fold in females.40 Infusion of other AAs in combination or singularly, including lysine, was also demonstrated to promote 8- to 22-fold increases in circulating GH levels.41
Lysine may exert its putative GH-releasing effects on the anterior pituitary by the production of one of its metabolites, pipecolic acid, which acts as an agonist for the gamma-aminobutyric acid (GABA) receptors and enhances the GABA influence on GH release.42-45
It may also have been assumed (perhaps falsely) that lysine's ability to enhance bone growth may be due to its effect on GH release. Both of these factors may have led to lysine's inclusion in AA preparations promoted as increasing GH.35,36
For the most part, lysine has not been studied or tested alone as an ergogenic substance.
As is true for all essential amino acids (EAAs), the body's need for lysine increases during periods of intensive exercise training, and therefore it is generally included in AA blends designed to maximize exercise-induced protein synthesis (see Section 220.127.116.11).
Lysine's action in the body may also be modified in the presence of ARG, because ARG's proposed mechanism of action in the body is to inhibit secretion of somatostatin, which is a GH inhibitor.41 We therefore theorize lysine's action in combination with ARG to be an amplification of ARG's effects by attenuating NO production (which ARG supplementation enhances). NO production would otherwise inhibit the growth hormone-releasing hormone's (GHRH) effects on the pituitary release of GH.3746
Finally, if lysine and ARG together truly raise GH levels in combination more than separately, it may simply be the additive effect of stimulating the anterior pituitary (AP) by two different mechanisms: (1) ARG inhibition of somatostatin47 and (2) lysine stimulation of the GABA receptors.42-45
For more details on both studies and rationale for lysine and GH in exercise, see AA blends (Section 15.7) and GH sections (Section 18.104.22.168 and Section 22.214.171.124).
The AA aspartic acid participates in several biochemical pathways, such as the tricarboxylic acid (TCA) and urea cycles.48 It is involved in disposing excess metabolic nitrogen into the urea cycle, thus reducing elevated ammonia levels. Aspartic acid and oxalacetate are interchangeable by a transaminase reaction, which makes aspartic acid a glucogenic AA.
AA salts are hypothesized to be mineral transporters to subcellular sites. They thereby replenish electrolytes and aid in metabolism, including compartmentaliza-tion of energy production (e.g., sparing glycogen and increasing fatty acid utilization).49 The transport of potassium and magnesium by aspartate salts has been used to treat asthma and heart conditions with varying degrees of success.50-61 Potassium is the main cation of muscle and most other cells in the intracellular fluid. Potassium salts are widely used in medicine.50-61 Magnesium is a component of intra- and extracellular fluids and is required for the activity of many enzymes, particularly those involved in oxidative phosphorylation (energy production).62
Animal studies report conflicting results using aspartate salts. Trudeau et al. used 1 g/kg body weight of a potassium-aspartate salt formula in rats during swimming and found that it did not support the hypothesis of sparing muscle or liver glycogen. A similar content of glycogen remained in the muscles and liver of control rats after a 60-min swim, or after swimming to exhaustion.63 Marquezi et al. used 350 mM aspartate (ASP) and 400 mM asparagine (ASN) in rats and found that ASP + ASN supplementation might increase the contribution of oxidative metabolism in energy production and delay fatigue during exercise performed above the anaerobic threshold.64 The supplemented rats exercised approximately 27 min longer and had lower lactate levels than the rats receiving the distilled water placebo.
The conflicting results may be related to differences in formulas, meaning the aspartate/asparagine combination may have positively influenced oxidative metabolism, whereas potassium aspartate had no effect at the given dose.
Potassium and magnesium are important minerals for the body involved in sports/fitness activities because they are essential for enzyme activity involved in energy production in subcellular locations, such as the electron transport chain. In addition, they are important in the stabilization of cellular membranes by normalizing intracellular levels of the two minerals.49
Aspartate salts act as a mineral delivery system to specific cell sites, and the aspartate component is involved in the detoxification of ammonia,49,65-67 which can cause fatigue.
Aspartate also contributes to the TCA cycle via conversion to oxaloacetic acid.65,66 During exercise, fatigue may be caused by: (1) depleting potassium and magnesium, (2) increasing ammonia, and (3) decreasing TCA cycle intermediates. If one of these three conditions is the limiting factor in performance, a potassium magnesium aspartate (PMA) supplement may delay fatigue until another factor causes it (such as lactate accumulation in muscle or central fatigue due to increased serotonin levels in the brain).
Aspartate is thought to reduce ammonia or increase the TCA cycle flux, and then deliver the potassium and magnesium to the subcellular locations to normalize intracellular concentrations.496566 These conditions could increase fatty acid oxidation, spare glycogen, and reduce ammonia-induced fatigue — and thus increase the time to exhaustion. However, there are no proven action mechanisms.
Human exercise studies have used 2 to 13 g of potassium and magnesium D or L aspartate. They employed exercise endurance (aerobic and anaerobic) testing protocols. Results have been mixed. Five studies found between a 14 and 50% increase in performance (increased time to exhaustion).62,67-70 A more recent study found a decrease in blood lactate and blood ammonia levels compared to the placebo group.67 In five other studies, aspartate salts produced no benefit.71-75
A deeper look into the study designs reveals the following: In four of six studies with trained subjects, there was no significant improvement in performance. In three of four studies with untrained subjects, there was a significant performance enhancement. In addition, higher dosages of 6 to 13 g were used in the studies finding benefits; 2 g per dose was ingested in four of the five studies reporting no effect, suggesting a dose-response. There also may have been differences between the D and L aspartate salts of potassium and magnesium on resynthesis of ATP, indicating the forms were critical.76 D, L aspartate was used consistently in the positive studies.62,65-70 Only one study showed no benefit when used in this form.72
This closer look at study designs and protocols suggests reasons why individuals may experience different effects when using supplementation. The dosage, form, and condition of athletes may have played a significant role in the results of the studies.
Lancha et al.77 tested the effect of aspartate, ARG, and carnitine supplementation on metabolism of skeletal muscle during exercise. The group receiving the supplement was able to exercise 40% longer than the control group, and blood analysis determined a greater glycogen preservation and free fatty acid utilization.77 These dramatic results would need to be confirmed by a better designed study that included a placebo group in order to be credited. See also Section 15.6.2.
Typical dosages, extrapolated from studies that suggest benefit and indicate safety, include 7 to 12 g per day of potassium and magnesium aspartate split over a 24-h period and administered acutely (5-day to 4-week periods). Chronic use for longer periods is not recommended. When ingested during intense training or before competition, performance may improve, especially with the novice to intermediate athlete.
Glycine is a nonessential AA, but during periods of rapid growth glycine requirements increase. Creatine can be formed from glycine and ARG contributing to the creatine pool in skeletal muscle. Ingestion of glycine in combination with ARG has been shown to increase creatine synthesis.78,79 Glycine's unique structure allows it to bind to various substances that are then excreted in bile or urine. Important pools for glycine in the body are the extracellular protein, collagen, and skeletal muscle. In fact, practically one third of the AAs found in collagen fibers are glycine. Pharmacological doses of intravenous glycine, in a dose-dependent manner, have been shown to significantly raise GH levels in humans.80 Additionally, glycine is a significant contributor to cell volumization (see data on cell volume and glycine's role in Section 126.96.36.199), which is a major control point for protein metabolism. These properties of glycine have created some rationale for its investigation as a potential ergogenic agent.
Glycine alone has not been studied as a supplement for improving athletic outcomes.
In combination with ARG and a-ketoisocaproic acid, it has been shown to be a potential application in sport according to two studies:
Cysteine is a principal source of sulfur in the diet, which is necessary for the production of coenzyme A and taurine. Cysteine is also utilized in PS, especially in the formation of hair and skin. It supports wound healing and stimulates white blood cell activity. The N-acetyl derivative of cysteine is N-acetyl cysteine (NAC), which is more stable and is the preferred form of cysteine for oral ingestion and infusion.81 NAC has been shown to protect the liver from the effects of alcohol, acetaminophen, and cancer drugs.82 NAC provides significant free radical protection and may be beneficial in reducing oxidative damage from exercise.83
At this time there are no published reports of the sole use of cysteine for the purpose of increasing sports or fitness performance. However, intravenous NAC has been shown to attenuate fatigue in male cyclists84,85 and is commonly incorporated as an antioxidant into many commercially available products.
Tyrosine, a nonessential AA, is created from the hydroxylation of phenylalanine. Catecholamine neurotransmitters such as dopamine, epinephrine, and norepine-phrine are produced from it, and it is also a precursor of the hormones thyroxine and triiodothyronine. Fumarate, a TCA cycle intermediate, and acetoacetate are formed in the catabolism of tyrosine, making it both glucogenic and ketogenic.86 Performance-related stress during intense military operations has been shown to be attenuated or reversed by exogenous tyrosine, apparently by increasing norepine-phrine levels in the brain.87-89
There is great interest in tyrosine supplementation for preventing environmental stresses (cold and heat) from impairing cognitive behavior.93,94 It remains to be seen if tyrosine's ability to attenuate cognition-related stress (as noted during military operations) would translate to a benefit to athletes. Long-term use of large doses of tyrosine (>5 g) may have adverse health effects, based on its ability to alter sympathetic nervous system activity.95
Glutamic acid or glutamate is one of the most abundant AAs found in natural proteins (approximately 20%)96 and a major excitatory transmitter within the brain. It mediates fast synaptic transmission and is active in approximately one third of all central nervous system (CNS) synapses.97,98 It is also a precursor to gamma-aminobutyric acid (GABA), which is an inhibitory neurotransmitter important in brain metabolism. Glutamic acid readily participates in transamination reactions to produce other AAs and is converted to the TCA cycle intermediate a-ketoglutarate. The transport rate of glutamate from blood to brain in mature animals is much lower than that for neutral or basic AAs.99
The sodium salt form of glutamic acid is monosodium glutamate (MSG). The neurotoxic levels of MSG have been studied extensively in animal and human models. The available data indicate that, under normal conditions, mammals have the metabolic capacity to handle large oral doses of MSG. Glutamate salts have also been tested in exercise.
During the first 15 min of exercise, TCA intermediates increase 300%, while intramuscular glutamate decreases approximately 60%.100 This decrease makes glutamate essential to several transamination reactions that affect the production of ammonia, alanine, glutamine, and TCA cycle intermediates during exercise.101 Intensive exercise increases ammonia levels, a factor in fatigue, and can lead to a decrease in performance,102 giving rise to the potential for glutamate salts to function as ergogenic aids.
Both studies appear to suggest that supplemental salt forms of glutamate may play a positive role in nitrogen and energy metabolism.
The end product of histidine catabolism is glutamate, making histidine one of the glucogenic AAs. Bacterial decarboxylation of histidine in the intestine gives rise to histamine. Similarly, histamine appears in many tissues through the decarboxylation of histidine, which in excess causes constriction or dilation of various blood vessels. The general symptoms are those of asthma and various allergic reactions. Histidine is generally considered to be an essential AA, although this has been a subject of debate. Kriengsinyos et al. investigated histidine's essentiality in healthy adult humans consuming a histidine-free diet for 48 days. They discovered a gradual decrease in protein turnover and a substantial decrease in plasma protein concentrations, including albumin, hemoglobin, and transferrin. So, although histidine deficiency may not affect nitrogen equilibrium, it can impact other important health parameters.104 Histidine, like cysteine, also may have antioxidant properties.105
In regard to sports/fitness applications, histidine alone has not been studied as a supplement for improving athletic outcomes. Carnosine is related metabolically to histidine and histamine. It is a naturally occurring histidine-containing dipeptide present in muscle tissue. Being immunoprotective, carnosine has been shown to detoxify free radical species, protect cell membranes, and act as a buffer against lactic acid and hydrogen ions.106 This is especially important in athletic events where lactic acid buildup (metabolic acidosis) can affect performance by causing fatigue.107 Intracellular buffering agents such as phosphates and histidine-containing peptides may help delay fatigue by buffering hydrogen ions, reducing oxidative damage, and maintaining cell membrane integrity.108-110
Histidine appears to be one of the more toxic AAs. Unusually large doses (24 to 64 g/day) have been shown to have adverse effects.111
The nonessential AA proline is especially prevalent in connective tissue. Proline's structure contains a pyrrole ring such as that which forms the porphyrin component of hemoglobin and the cytochromes. Under extreme conditions, such as are found in severely traumatized patients or premature neonates, it has been suggested that proline may be a conditionally essential AA.112-115
During prolonged endurance events, serum proline is oxidized in skeletal muscle like the BC AAs. One study found that the increase in serum free fatty acids in postexercise subjects, compared to those at rest, was correlated to the decrease in the concentrations of alanine and proline.116 Therefore, although proline is considered to be dispensable, it may have an increased requirement under certain conditions.
In regard to sports/fitness applications, since proline levels decrease significantly during prolonged intense exercise, it may be prudent for energy-restricted athletes to maintain proline intake in line with their elevated needs for the essential AAs. Proline is often not included in specific AA blends designed to maximize exercise-induced protein synthesis (see data on AA blends in Section 188.8.131.52). It has not been tested alone as an ergogenic substance.
Phenylalanine (P) is an essential AA that participates in protein synthesis. It is converted to tyrosine via hydroxylation (see Section 15.6.7). Phenylalanine is both glucogenic and ketogenic.4 Phenylketonuria (PKU) is a rare disease (generally diagnosed at birth) caused by an inborn error in the ability to metabolize P (lacking the enzyme phenylalanine hydroxylase). In affected people, if the diet is not controlled by severe restriction of P intake, PKU can lead to serious irreversible neurological disorders, such as mental retardation.
Sports drinks that contain a mixture of carbohydrate and free-form AAs, including P, can result in a greater insulin response than carbohydrate by itself.117118 Phenylalanine has not been studied or tested alone as an ergogenic substance. As is true for all essential AAs, the body's requirement for P increases during periods of intensive exercise training, and it is therefore generally included in AA blends designed to maximize exercise-induced PS (see data on AA blends in Section 184.108.40.206).
Tryptophan (TRP) is a glucogenic and ketogenic essential AA that serves as a precursor for the synthesis of serotonin (5-hydroxytryptamine [5HT]) and melatonin. TRP's precursor potential has created interest in its use as a natural alternative to traditional antidepressants, used to treat unipolar depression and dysthymia.119 Besides 5HT's involvement in mood, the chemical also helps to induce drowsiness and may play a role in CNS-related fatigue. Little is known about central fatigue in physical activity, but it has been suggested that changes in plasma AA concentrations (e.g., TRP and BCAA) during exercise may play a role by influencing the synthesis of neurotrans-mitters such as 5HT, which may in turn affect the perception of fatigue. It has also been proposed that the increase in nonesterified fatty acid (NEFA) mobilization that accompanies exercise, and the resulting rise in serum NEFA concentrations, indirectly promotes the entry of TRP into the brain, increasing the brain TRP pool. This process stimulates the synthesis and release of the neurotransmitter 5HT. Because increased 5HT release is associated with sleep and drowsiness, the notion is that such increases in 5HT promote central fatigue, and thereby impair athletic performance.120123 This is often referred to as the central fatigue hypothesis.124
BCAA competes with TRP for transport across the blood-brain barrier. Therefore, high doses of BCAA before and during exercise may slow TRP entry into the brain, decreasing the production of 5HT and therefore increasing time to exhaustion. This has been tested with equivocal results.125-129
As is the case for all essential AAs, TRP is generally included in AA blends designed to maximize exercise-induced PS (see AA blends information in Section 220.127.116.11).
Note: TRP was linked to eosinophilia-myalgia syndrome (EMS) during the late 1980s and early 1990s, leading the FDA to ban the sale of TRP products. It has since been generally accepted that the problem was not TRP itself, but a contaminated batch produced by a specific manufacturer.132,133
A nonessential AA, serine participates in protein synthesis and is an important energy substrate during high-protein diets.134 Serine contributes to the biosynthesis of purines and pyrimidines and, along with two fatty acids, is an important component of phosphatidylserine (PS). PS is a fat-like substance that may be important in determining neuronal membrane surface potential (the electrical potential at the membrane).135 Animal studies have found that the use of PS can attenuate the neuronal effects of aging. Consequently, researchers have been testing the ability of PS supplementation to stave off age-related cognitive decline in humans.135,136 PS has recently been studied for its anticatabolic effects. Administration of PS has been shown to blunt the cortisol response to exercise,137,138 giving rise to its potential as an ergogenic aid. Theoretically, the anabolic response to exercise may be enhanced through the PS process of decreasing exercise-induced cortisol.
In regard to sports/fitness applications, serine has not been tested alone as an ergogenic substance, but PS has been studied for its effects on exercise-induced cortisol with a surprising outcome. Kingsley et al., in two recent studies using 750 mg/day of PS, found an improvement in exercise capacity in the supplemented group vs. the placebo group. Ironically, neither study found a reduction in the cortisol response from exercise at this dose.139,140
Methionine (M) is a major source of sulfur in human diets and is an essential AA for normal growth and development. It is considered glucogenic, due to its conversion to pyruvic acid via succinyl CoA. It is a major methyl donor and is important in the metabolism of phospholipids. It is also prominent in methylation reactions and as a precursor for cysteine, which is the rate-limiting AA for glutathione synthesis. High levels of M are associated with hyperhomocysteinemia and endothelial dysfunction, which are risk factors for cardiovascular disease.141 Deficiency of M produces hepatic steatosis similar to that seen with ethanol,142 and supplementation with this lipotrope can prevent ethanol-induced fatty liver.142
Besides M's role in methyl group metabolism, and in serving as a substrate for PS, its other functions include participation in the synthesis of polyamines, catecholamines, nucleic acids, carnitine, and creatine.143-145 Because of its many functions, M has a high intracellular turnover.146 147 It may be the AA that is most rate limiting for the building of body proteins, including maintaining nitrogen balance and the effective reutilization of the other AAs.148 149 Therefore, the requirement for M increases significantly during times of high protein turnover, such as is seen in burn and trauma patients.150151
Intravenous doses of M have also been shown to increase GH,41152 but oral doses below pharmacological amounts have not been effective in raising GH levels in athletes.153
M has not been studied or tested alone as an ergogenic substance. As is true for all essential AAs, the requirement for M increases during periods of intensive exercise training, and it is therefore generally included in AA blends designed to maximize exercise-induced protein synthesis (see AA blends information in Section 18.104.22.168).
Harden et al. tested an L-methionine combination (with B6, B12, folate, and magnesium) supplement for its effects on symptoms of upper respiratory tract infections and on performance in 21 ultramarathon runners before, during, and after exercise. They found no significant differences between the experimental and placebo groups. However, they did conclude that benefits may be found using a greater number of participants.154
Because homocysteinemia is linked with cardiovascular disease, long-term use of M supplements may be of concern.95
Threonine is an essential AA often low in vegetarian diets. Aminotransferases exist for all AAs except threonine and lysine. Its main routes of catabolism lead to both ketogenic and glucogenic metabolites.10 The human requirement for threonine set by FAO/WHO/UNU at 7 mg/kg/day155 has been challenged by more recent data suggesting a level more than twice this amount to maintain AA homeostasis156,157 in healthy adults. The Institute of Medicine recently established a threonine RDA for adults at 27 mg/kg/day.158
Threonine has not been studied or tested alone as an ergogenic substance. As is the case with all essential AAs, the requirement for threonine increases during periods of intensive exercise training, and it is therefore generally included in AA blends designed to maximize exercise-induced protein synthesis (see AA blends information in Section 22.214.171.124).
Due to their association with muscle PS, AAs attract the interest of athletes, and thus have a colorful history in the athletic community. Researchers and athletes have been well aware that specific combinations of AAs, especially high intakes or infusions of one or more of the AA, can lead to changes in behavior, hormone production, and rates of PS (specifically muscle).159 This knowledge has led them in search of AA solutions to the "performance holy grail."
Various supplementation schemes have demonstrated safety and success in enhancing certain types of performance or increasing muscle size when compared to a nonsupplemented state.160161 Examples of such schemes are carbohydrate and creatine loading for specific athletes (endurance and strength, respectively). In healthy exercisers, under various conditions, AA supplementation, singular or in combinations, has been shown to positively alter the anabolic environment. Specific acute effects have included reducing muscle damage, increasing or indirectly decreasing specific related hormone levels (e.g., increased insulin and GH and decreased cortisol), increasing the rate of PS, and shortening time of recovery from intense exercise bouts. This has led many to the proverbial leap of faith that regular utilization of such acutely successful practices can enhance long-term training outcomes beyond that obtainable by following normal food intake patterns. Despite the preponderance of evidence in favor of various acute effects of AA supplementation, the answer to the question of ongoing benefits has been elusive.
This section attempts to correlate a wide variety of study results having to do with AA supplementation and sport, and thereby tease out some relevance to healthy athletes attempting to improve performance or increase muscle size. It also tries to develop some, albeit limited, practical recommendations based on current evidence. Additional data are continually becoming available, however, and this snapshot view is likely to need revision fairly soon.
Though it is currently difficult to support claims for long-term benefits from chronic AA supplementation in healthy, well-fed (nondieting) athletes, certain training conditions may warrant dietary supplementation with specific AAs or AA mixtures. The following sections present some of the purported scientific evidence in support of AA supplementation by athletes, discuss related studies in different populations (e.g., healthy, aging, exercising/sport, dieting, etc.), and attempt to present some potential practical applications for individual competitive exercisers.
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