Antioxidant and Neurotropic Properties of Short Peptides

Antioxidant Effect of Short Peptides

A number of short peptides exhibit antioxidant and anti-inflammatory effects, countering the action of aggressive oxygen radicals, primarily oxygen, and the formation of pro-inflammatory cytokines (Zambrowicz A. et al., 2015; Ryder K. et al., 2016). As a result, the intensity of biochemical manifestations of oxidative stress of various origins is reduced. This includes the accumulation of toxic metabolites that damage cellular and subcellular membranes due to excessive oxygen intake in athletes and intense, prolonged aerobic physical activities in cyclic and team sports; and under glycolytic anaerobic loads due to the accumulation of lactate in the extracellular fluid, lymph, plasma (serum) — and the subsequent bodily reaction to it (psychological, physiological, and psychophysiological stress in athletes, particularly in the pre-competition mesocycle).

Neurotropic Properties of Short Peptides The neurotropic properties of short peptides have been studied in Russia and abroad since the 1970s and 1980s. Some peptides have a chemical structure similar to opioids and thus are called “opioid peptides.” When digesting various food products in the intestine, short opioid-like peptides, known as exorphins, can be formed (Chesnokova E.A. et al., 2015). Exorphins, similar in properties to endogenous opioid peptides like endorphins, enter the body with food and cause a complex of neuronal reactions. Among them, peptides containing 4 (tetrapeptides) to 6 amino acids often predominate, with proline and the Tyr-Pro sequence frequently found at the N-terminus of the peptide chain. Depending on the sources of intake into the body, the following exorphins are distinguished:

• Wheat (wheat gluten hydrolysate);
• Soy (soymorphins — derivatives of β-conglycinin of soy);
• From greens (spinach, lettuce, sorrel, parsley);
• Dairy (β-casomorphins — casein hydrolysis products).

As described above, short peptides can penetrate the blood-brain barrier (BBB) in their unchanged form, subsequently interacting with opioid receptors in various brain structures. Among the central physiological effects of exomorphins from the perspective of sports nutrition, their potential anxiolytic (reducing fear and anxiety) and analgesic properties may be of interest, although these currently lack sufficient clinical confirmation.

L-Glutamine Dipeptides

The emergence of “light” L-glutamine peptides (L-alanyl-L-glutamine – AG, glycyl-L-glutamine – GG) and their incorporation into the theory and practice of sports medicine over the past five years has significantly changed perceptions of the possibilities for metabolic correction of relative L-glutamine deficiency during physical exertion. Along with the well-known anabolic effects of L-glutamine, it has been established that the dipeptide AG can support the integrative function of the intestine, accelerating the absorption of water, electrolytes, macro- and micronutrients, thereby having a rehydrating effect and enhancing subsequent macronutrient absorption. There has emerged a conditional division of the effects of glutamine dipeptides into immediate (developing within an hour and mainly related to rehydration and improved function of excitable tissues) and delayed (developing hours and days after entering the body, manifested by stable anabolic and anticatabolic effects, enhanced immunity, increased muscle glycogen stores, etc.), necessitating a significant adaptation in the practical use of glutamine-containing mixtures in sports medicine.

In clinical and sports medicine, four main forms of L-glutamine are used: the amino acid L-glutamine itself, L-alanyl-L-glutamine, glycyl-L-glutamine, and the chelated magnesium compound of glycyl-L-glutamine (variants of dipeptides).

For the production of drugs containing L-glutamine and its dipeptides, as well as clinical applications, such indicators as solubility in water, stability at various temperatures, resistance in environments with different pH and enzymatic composition, and the formation and nature of degradation products in the GI tract are of great importance. Table 1 provides information on the solubility of L-glutamine and its dipeptides in water.

Table 1. Chemical-Physical Characteristics of L-Glutamine and Its Dipeptides (cited from: Furst P., 2001; modified by authors)

The application of L-glutamine in ready-made commercial mixes is hindered by two circumstances: weak solubility and partial decomposition in an aqueous environment during production, resulting in ammonia release. The solubility of GG is approximately 4 times, and AG — 15 times higher than that of L-glutamine itself. These factors are compounded by the low resistance of L-glutamine to the acidic and enzymatic environment of the stomach and its relatively slow and incomplete absorption in the intestine. Thus, in terms of its physicochemical properties, L-glutamine is less attractive for practical use compared to its dipeptides.

There are a number of methods for producing L-glutamine dipeptides (particularly AG), among which two main ones are:

1. Chemical or enzymatic condensation of protected L-amino acids of glutamine and alanine (Yokozeki K., Hara S., 2005; Nozaki H. et al., 2006);
2. The chemical synthesis process using D-2-chloropropionyl-glutamine (Sano T. et al., 2000). However, these methods are not satisfactory for two reasons: low economy and lack of quality (for example, the parallel formation of by-products — D-alanyl-glutamine, derivatives of glutamic acid, glutamine tripeptides, etc.) (Sano T. et al., 2000; Yokozeki K., Hara S., 2005). A new method of enzymatic bioengineering synthesis (enzymatic production) of AG (Tabata K., Hashimoto S., 2007) using Escherichia coli microorganisms was proposed relatively recently, allowing for the production of the purest form of this dipeptide.

Currently, AG is included as a supplement in multi-component dry mixes for long-term use together with macronutrients, as well as one of the main components for preparing rehydration solutions (product information, Kyowa Hakko U.S.A. Inc., 2013). At normal body temperature (36.6°C), 50% of L-glutamine is destroyed within the first hour, whereas AG remains stable for at least four hours, which is sufficient for complete absorption in the intestine. AG also exhibits increased thermal stability, which is important in manufacturing processes and during storage.

Single Dose of AG in Conditions of Short-term High-intensity Physical Activity and Moderate Hydration Stress (Hoffman J.R. et al., 2010). The influence of hydration stress on hormonal, immunological, and inflammatory responses to physical exertion has been studied in a number of works (Maresh C.M. et al., 2006; Penkman M.A. et al., 2008; Judelson D.A. et al., 2007, 2008; Hoffman J.R. et al., 2010). A moderate level of athlete’s hypohydration (2-3% body mass loss) enhances the hormonal and immune response of the body, leads to an increase in cortisol concentration, weakens the testosterone response to stress. Changes of this kind can slow down the recovery process after training and competitive loads and form a so-called hypohydration status.

The results of the study by J.R. Hoffman and co-authors were performed on 10 male volunteers (age 20.8±0.6 years; height 176.8±7.2 cm; total body mass 77.4±10.5 kg; fat mass 12.3±4.6%). During all studies, a preliminary load (walking on a treadmill at a 2% incline at a speed of 3.4 miles per hour in closed clothing) was given until the target body mass loss indicator (2.5%) was reached, i.e., achieving a hypohydration status. Then four groups of subjects were formed. In the first study (group T2), subjects reached the target figure (2.5%) of body mass loss and then rested directly on the bicycle for 45 minutes before the start of the training session (without rehydration). In the three other studies, after reaching the same target weight loss indicator (2.5%), subjects were rehydrated to 1.5% of body mass before the test task by consuming fluids: only water (group T3); water with the addition of a low dose of AG (group T4 — 0.05 g×kg-1); water with the addition of a high dose of AG (group T5 — 0.20 g×kg-1). The subsequent training protocol (testing physical load) consisted of ten 10-second sprints on a bicycle ergometer with a one-minute break between them. Blood samples for full analysis were taken: after initial hypohydration, immediately before the testing physical load, immediately after it, and also after 24 hours.

Serum levels of L-glutamine, potassium, sodium, aldosterone, arginine, vasopressin, C-reactive protein, interleukin-6, malondialdehyde, testosterone, cortisol, adrenocorticotropic hormone (ACTH), and growth hormone were registered. It was found that L-glutamine levels in group T5 were significantly higher than in groups T2, T3, T4. Additionally, AG increased the time to exhaustion during bicycle sprints in a dose-dependent manner compared to group T2 (group T4 saw an increase of 130.2 ± 340.2 seconds; group T5 saw an increase of 157.4 ± 263.1 seconds). Plasma sodium concentration was higher (P < 0.05) in group T2 compared to the other three groups, and aldosterone concentration in groups using AG was lower than in group T2. The authors concluded that adding AG to the athlete’s hydration fluid provides a significant ergogenic advantage by extending the endurance time under moderate hypohydration stress.

However, using just water (as in this study) as a base for adding AG to counteract hypohydration is not a modern strategy for athletes’ fluid and electrolyte balance (FEB) recovery. Therefore, several studies have been conducted on the combined effects of AG and electrolytes in sports drinks on FEB indicators during physical activities.

The aim of the study by G.J. Pruna (2014) was to investigate the effectiveness of two different doses of AG in a commercial electrolyte drink compared to the effects of the base electrolyte drink alone in terms of reaction time changes and cognitive functions during endurance training. A double-blind, placebo-controlled, crossover study was conducted on 12 trained male runners (age 23.5±3.7 years; height 175.5±5.4 cm; body weight 70.7±7.6 kg). The standard test for all study groups was a 60-minute run at 75% VO2max followed by a run to exhaustion at 90% VO2max. The study examined VO2 (oxygen uptake and assimilation capacity); RPE (Rating of Perceived Exertion), which allows the evaluation of training intensity on a scale from 6 to 20, where 6 is no exertion, 13 is somewhat heavy, 17 is very heavy, and 20 is maximum exertion; blood lactate levels, and electromyography (EMG). Weight loss in all participants during the first test (without replenishment) was ≥ 1.3 L×hour-1. In the three subsequent tests, participants consumed 250 ml of fluid every 15 minutes (a total of one liter over an hour). Randomization of groups was double-blind: ED — electrolyte sports drink; LD — sports drink + 300 mg AG (per 250 ml); HD — sports drink + 1000 mg AG (per 250 ml). In the control run (DHY without rehydration), subjects lost 1.7±0.23 kg of total body weight in 60 minutes, amounting to 2.4%. All three drink variants significantly and substantially reduced these losses, with a tendency for greater effectiveness in the drink with low AG content. Changes in motor and visual reaction times, physical reaction time were assessed before and after the run. The most positive changes were observed in the low AG content group (LD), where there was a decrease in visual and physical reaction time and the least increase in motor reaction time. Thus, it was shown that both low and high doses of AG, unlike other study variants, enhance cognitive function in the post-load period, as evidenced by an increase in the frequency of successful results in the special CAVE test (Cave Automatic Virtual Environment) – identification of proposed visual combinations of colored balls on the wall with changing configurations (NeuroTracker system, CogniSens, Montreal, Quebec), and also in the successful completion of simple mathematical computer digital tasks (Serial Sevens Test), performed according to A. Smith, 1967. The author concludes that AG in low and high doses as part of an electrolyte sports drink positively influences the physical preparedness of athletes for prolonged high-intensity exercise, reduces body mass loss due to rehydration, maintains high motor and visual reaction, and cognitive function. According to the authors of the study, this is primarily related to the enhancement of water and electrolyte absorption under the influence of AG, and possibly, to the normalizing effect of AG and L-glutamine on the central nervous system (CNS).

The literature presents results regarding the effectiveness of solutions containing AG and GG in athletes from different sports and training with various energy provision mechanisms.

Influence of Oral Administration of AG and Electrolytes on Plasma Electrolyte Concentration, Physiological Indicators, and Neuromuscular Fatigue during Endurance Training (McCormack W.P., 2014; McCormack W.P. et al., 2015). The effectiveness of AG as a commercial sports drink compared to a standard sports drink on exhaustion time and physiological indicators during prolonged endurance exercises was investigated. Twelve endurance-trained men (age 23.5±3.7 years; height 175.5±5.4 cm; body weight 70.7±7.6 kg) performed four tasks. Each task consisted of a one-hour treadmill run at 75% VO2peak followed by a run to exhaustion at 90% VO2peak. In one study, no hydration was provided (NHY), in another, a standard sports drink was given (ED), and in two other studies, a low dose (LD; 300 mg AG per 500 ml) and high dose (HD; 1000 mg AG per 500 ml) of AG were added to the standard sports drink. During the study, 250 ml of the specified fluids were consumed every 15 minutes (one liter over an hour). L-glutamine, glucose, electrolytes in plasma, and osmolarity were measured before running and at 30, 45, and 60 minutes after starting. VO2, respiratory quotient (RQ), and heart rate (HR) were measured every 15 minutes. The exhaustion time was significantly longer in the LD and HD groups compared to the non-hydrated group. No differences were found between the non-hydrated group and the group hydrated with a standard sports drink (NHY and ED). In the LD and HD groups, glutamine concentrations were significantly increased at 45 minutes and then maintained at the reached level until 60 minutes in the HD group. Plasma sodium concentration increased from the beginning of the run and remained stable throughout the hour of running. At 60 minutes, plasma sodium concentration was significantly lower in all hydration groups compared to the non-hydrated group. The authors concluded that consuming AG in a sports drink, both in small and large doses, significantly and dose-dependently prolongs the time to exhaustion during high-intensity training, enhancing athletes’ endurance.

L-Glutamine Peptides in Maintaining Performance in Football (Favano A. et al., 2008). In football, as in other sports games, motor activity has its specifics: multifaceted mechanical activity; high variability of neuromuscular efforts; continuous change of working motor modes; high intensity of efforts in crucial game moments; increased stress of vegetative functions; complex manifestation of motor qualities in short time intervals. Together, these qualities of a footballer are characterized as resistance to alternating periods of load and relative relaxation, requiring the involvement of all energy supply systems. On average, footballers cover a distance of 10 to 14 km per game. The study was conducted on 9 Brazilian footballers of a high level from the professional São Paulo team (average age 18.4±1.1 years; body weight 69.2±4.6 kg; height 175.5±7.3 cm; VO2MAX 57.7±4.8 ml×kg-1×min-1). The load proposed was a special treadmill test, simulating the rhythm and alternating intensity of movements with changes in speeds during the game with corresponding physical load. During the study, the following were continuously monitored: lung ventilation (VE), oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER), electrocardiogram parameters. Athletes were given two variants of drinks 30 minutes before the start of the test, which was repeated twice with a weekly interval:

1. main group — 50 g maltodextrin + 3.5 g glutamine peptide in 250 ml of water;
2. control group — 50 g maltodextrin in 250 ml of water. The main result of the study was a very significant increase in the distance run by athletes during the test under the influence of the solution with glutamine peptide: 12750± 4037 m in the control group and 15571±4184 m in the main group (with the use of the solution containing glutamine peptide; an increase of 22.1%). The total duration of tolerating loads, in turn, reached 73±23 minutes in the control group and 88±24 minutes in the group with glutamine peptide (+20.5%). The authors concluded that the introduction of glutamine peptide into a carbohydrate solution increases work capacity and tolerance to intermittent (acyclic) types of physical loads in football players, reduces the feeling of fatigue and allows for longer exercise durations compared to the use of a standard carbohydrate solution.The effective use of solutions containing AG and GG in athletes from various sports and during training sessions with different energy provision mechanisms is well documented.Influence of Oral Administration of AG and Electrolytes on Plasma Electrolyte Concentration, Physiological Indicators, and Neuromuscular Fatigue During Endurance Training (McCormack W.P., 2014; McCormack W.P. et al., 2015). The study explored the efficacy of AG in a commercial sports drink compared to a standard sports drink on time to exhaustion and physiological indicators during prolonged endurance exercises. Twelve endurance-trained men (age 23.5±3.7 years; height 175.5±5.4 cm; body weight 70.7±7.6 kg) performed four tasks. Each task involved a one-hour treadmill run at 75% VO2peak followed by running to exhaustion at 90% VO2peak. In one study, no hydration was provided (NHY), in another, a standard sports drink was given (ED), and in two other studies, low (LD; 300 mg AG per 500 ml) and high doses (HD; 1000 mg AG per 500 ml) of AG were added to the standard sports drink. Participants consumed 250 ml of the specified fluids every 15 minutes during the study (one liter over an hour). L-glutamine, glucose, electrolytes in plasma, and osmolarity were measured before running and at 30, 45, and 60 minutes after starting. VO2, respiratory quotient (RQ), and heart rate (HR) were measured every 15 minutes. Exhaustion time was significantly longer in the LD and HD groups compared to the non-hydrated group. No differences were found between the non-hydrated group and the group hydrated with a standard sports drink (NHY and ED). In the LD and HD groups, glutamine concentrations were significantly increased at 45 minutes and then maintained at the reached level until 60 minutes in the HD group. Plasma sodium concentration increased from the start of the run and remained stable throughout the hour of running. At 60 minutes, plasma sodium concentration was significantly lower in all hydration groups compared to the non-hydrated group. The authors concluded that consuming AG in a sports drink, both in small and large doses, significantly and dose-dependently prolongs the time to exhaustion during high-intensity training, enhancing athletes’ endurance.L-Glutamine Peptides in Maintaining Performance in Football (Favano A. et al., 2008). In football, as in other sports games, motor activity is specific: multifaceted mechanical activity, high variability of neuromuscular efforts, continuous change of working motor modes, high intensity of efforts in crucial game moments, increased stress of vegetative functions, and complex manifestation of motor qualities in short time intervals. These qualities of a footballer are characterized as resistance to alternating periods of load and relative relaxation, requiring

   the involvement of all energy supply systems. On average, footballers cover a distance of 10 to 14 km per game. The study was conducted on 9 Brazilian footballers of a high level from the professional São Paulo team (average age 18.4±1.1 years; body weight 69.2±4.6 kg; height 175.5±7.3 cm; VO2MAX 57.7±4.8 ml×kg-1×min-1). The load offered was a special treadmill test, simulating the rhythm and alternating intensity of movements with changes in speeds during the game with corresponding physical exertion. Throughout the study, lung ventilation (VE), oxygen consumption (VO2), carbon dioxide output (VCO2), and the respiratory exchange ratio (RER), and electrocardiogram parameters were continuously monitored. Athletes were given two types of drinks 30 minutes before starting the test, which was repeated twice with a weekly interval:

   1. main group — 50 g maltodextrin + 3.5 g glutamine peptide in 250 ml of water;
   2. control group — 50 g maltodextrin in 250 ml of water. The main result of the study was a very significant increase in the distance run by athletes during the test under the influence of the solution with glutamine peptide: 12750± 4037 m in the control group and 15571±4184 m in the main group (using the solution containing glutamine peptide, an increase of 22.1%). The total duration of load tolerance, in turn, reached 73±23 minutes in the control group and 88±24 minutes in the group with glutamine peptide (+20.5%). The authors concluded that introducing glutamine peptide into a carbohydrate solution enhances performance and endurance to intermittent (acyclical) types of physical loads in football players, reduces fatigue sensation, and allows for longer exercise durations compared to the use of a standard carbohydrate solution.

Role of AG in Maintaining Physical Fitness in Basketball (Hoffman J.R. et al., 2012). The purpose of this study was to investigate the effect of AG in a water solution on physical fitness in basketball, including jump strength, reaction time, shooting accuracy, and fatigue. Ten women participated in the study (age 21.2±1.6 years; height 177.8±8.7 cm; body weight 73.5±8.0 kg; all athletes were volunteers from Division I of the National Basketball Association in the USA). Four studies were conducted, each including a 40-minute basketball game with controlled timeouts for rehydration. In the first study (DHY), no rehydration was carried out, and the data obtained on weight loss were used for the other three studies as a control to determine the necessary volume of fluid replacement. In the first of these three studies, subjects received only water (group W). In the remaining two studies, subjects received AG supplements in water at a low dose (AG1 at a dose of 1 g per 500 ml) or a higher dose (AG2 – 2 g per 500 ml). All data recorded before and after the game were converted into points (post-game results – pre-game results). Data was statistically processed using variance analysis. Without rehydration (group DHY), players lost 1.72±0.42 kg, which is 2.3% of body weight. In the groups with rehydration, there were no differences in fluid consumption (1.55±0.43 liters). An increase in shooting accuracy of 12.5% (P = 0.016) was found in group AG1 compared to the non-rehydration group and 11.1% (P = 0.029) in this group compared to group W (water intake). Visual reaction time was also shorter in group AG1 (P = 0.014) compared to group DHY. Significant differences in fatigue (P = 0.045), determined by the player’s load, were found only between groups AG2 and DHY in favor of group W. No differences in jump power were found between the groups. The authors concluded that in basketball, rehydration using a solution containing AG, compared to regular water, much better supports physical and functional preparedness, as well as the psychophysiological characteristics of athletes.

Influence of L-Glutamine Dipeptides on Athletes’ Physical Condition During Anaerobic Exercises Anaerobic training (with a glycolytic lactate mechanism of energy supply) is a type of physical load (weightlifting, sprint running, etc.) characterized by high intensity over a very short period (tens of seconds), during which muscle movements are powered by energy obtained through anaerobic glycolysis and stored in muscle and other tissues, after which anaerobic power sharply decreases. For this type of load, two indicators are used: maximum anaerobic power and maximum anaerobic capacity, for which the maximum value of oxygen debt (MVD) is used as a measure, manifesting after work at peak power (Wilmore J.H., Costill D.L., 2004). In this context, the effects of any studied compound during anaerobic exercises are a separate characteristic. The influence of AG dipeptide on the physiological indicators of healthy individuals (athletes and non-athletes) in this type of exercise was the focus of a study by M. Khorshidi-Hosseini & B. Nakhostin-Roohi (2013). The study aimed to use a solution for oral intake (sports drink) containing carbohydrates and glutamine dipeptide to prevent a decline in anaerobic power during repeated loads. Twenty-eight physically fit male students participated in the study, who were randomized into four groups based on their maximum power (Max Power) and the drink consumed 2 hours before the study:

1. G-group (oral intake of glutamine dipeptide at a dose of 0.25 g×kg-1 body weight in 250 ml of water),
2. M-group (50 g of maltodextrin in 250 ml of water),
3. GM-group (50 g of maltodextrin + glutamine dipeptide at a dose of 0.25 g×kg-1 body weight in 250 ml of water),
4. P-group (placebo, 250 ml of water with 30 g of sweetener).

Each participant underwent a three-time running-based anaerobic sprint test (RAST) with a 60-minute interval. Max power and Min power were registered, as well as fatigue. The main results of this study were, firstly, no changes in the placebo group compared to the baseline in all three exercise series with a tendency to decrease results from series to series; secondly, a tendency to maintain both types of power in groups with maltodextrin and glutamine dipeptide; thirdly, a significant preservation of both types of power — minimal and maximal — in the group with the combined use of maltodextrin and glutamine dipeptide, and exceeding this effect compared to the groups with separate use of glutamine dipeptide and maltodextrin in the third exercise session. The authors concluded that a single intake 2 hours before anaerobic physical exertion of a sports drink containing L-glutamine dipeptide and maltodextrin is an effective method to prevent a fall in anaerobic power during three repeated exercises over a relatively short interval between them.

Neuroprotective and Analgesic Properties of L-Glutamine Dipeptides

As demonstrated in 2011 by V. Pires and co-authors in a model of acute cerebral ischemic/reperfusion injury, AG penetrates the brain with any peripheral route of administration. The L-glutamine dipeptide reduces degeneration of neuronal nuclei and prevents cell death in brain tissue. The protective mechanism of AG in relation to brain tissue may be an enhancement of the release of reduced glutathione (GSH), which reduces the impact of oxygen free radicals on the body. The authors suggested that such a mechanism could be important in preventing and reducing fatigue of CNS structures, maintaining reaction time, and increasing the ability to adequately and enduringly respond to various external stressors.

Another aspect of the positive neurotropic action of L-glutamine dipeptides (specifically, GG) is their potential analgesic activity. GG is a derivative of beta-endorphin (C-terminal fragment) and the main product of endorphin metabolism in the CNS (Cavun S. et al., 2005). The analgesic action of this compound has been studied for 30 years (1983-2014), and it has been established that GG is the predominant metabolite of β-endorphin in a number of brain structures and in peripheral tissues, although its physiological role remains unclear (Parish D.C. et al., 1983; Owen M.D. et al., 2000). As a “light” peptide, GG crosses the blood-brain barrier, reduces hypotension and cardiorespiratory depression caused by opiates, but does not alter their analgesic activity even at doses more than 100 times the necessary amount to alleviate respiratory depression following morphine administration (Owen M.D. et al., 2000). S. Cavun and co-authors (2005) consider GG a highly selective opioid antagonist with its own analgesic action, which acts as a neurotransmitter in the CNS and a circulating hormone in the periphery. Such an action of GG may have significant practical importance in all situations of increased physical exertion combined with painful traumatic phenomena.

Influence of Long-Term Intake of L-Glutamine Dipeptides on Metabolic Processes in the Body During Intense Physical Exertion (Delayed or Deferred Effects) With chronic use of AG and GG, their ability to stimulate the intake and metabolism of macronutrients, primarily proteins, and thus exhibit anabolic and anticatabolic effects, comes to the forefront. These effects are extended over time, provided by both the dipeptide molecule itself and individual amino acids after their hydrolysis in the body (L-glutamine and L-alanine), requiring adherence to different dosages and application schemes, including recommendations for combined administration with other nutrients. Systematic study of changes in L-glutamine metabolism, conducted at the Surgical Research Laboratory of the Vienna Medical University (Austria) under the direction of E.M. Strasser, has led to the formulation of the concept of “nutritive” and “non-nutritive” effects of L-glutamine as the basis for further use of glutamine and its derivatives as means to correct metabolic processes (Strasser E.M. et al., 2007; Roth E., 2008). Nutritive effects of glutamine imply its ability to form conditions for adequate nutritional support (pre-, current, and post-nutrition) to prevent the threat of nutritional deficiency or reduced nutrient absorption, stimulate an increase in lean body mass and decrease fat mass. Non-nutritive effects refer to maintaining normal immune function, cellular metabolic processes in excitable tissues, and the ability to counteract the impact of physiological and pathological stress.

Nutritive Effects of Long-term Use of L-Glutamine Dipeptides Intensive physical exertion constitutes a powerful physiological stressor that during the period of stressor action limits and even halts the intestine’s ability to fully absorb proteins, fats, and carbohydrates, reducing their maximum tolerable volume. Prolonged intense physical exertion leads to a range of gastrointestinal tract (GIT) disorders, especially in sports requiring enhanced endurance. This topic has been the subject of a vast number of studies, the results of which are summarized and analyzed in the review by E.P. de Oliveira and colleagues (2014). GIT issues themselves are the most common and general reason for insufficient physical, as well as functional, preparedness in athletes. Specifically, 30-90% of long-distance runners experience intestinal function disturbances during training (Jeukendrup A.E. et al., 2000). In 37-89% of ultra-long-distance runners, nausea, vomiting, abdominal cramps, and diarrhea have been observed (Hoffman M.D., Fogard K., 2011; Stuempfle K.J. et al., 2013).

In conclusion, L-glutamine and its dipeptides play essential roles in various aspects of sports nutrition and athlete performance. These include promoting muscle recovery and growth, supporting immune function, and potentially mitigating the adverse effects of intense physical training on the gastrointestinal tract. L-glutamine supplementation is a well-established practice in sports medicine, with numerous studies supporting its benefits. However, it’s essential to use L-glutamine and its dipeptides in appropriate dosages and under the guidance of sports nutrition professionals to maximize their effectiveness while avoiding unnecessary risks.