Sports and Immunity, from the recreational to the elite athlete.

The pivotal role of the immune system in physical activity is well-established. While interactions are complex, they tend to constitute discrete immune responses. Moderate intensity exercise causes leukocytosis with a mild anti-inflammatory cytokine profile and immunoenhancement. Above a threshold of intensity, lactate-mediated IL-6 release causes a proinflammatory state followed by a depressed inflammatory state, which stimulates immune adaptation and longer term cardiometabolic enhancement. Exercise-related immune responses are modulated by sex, age and immunonutrition. At all ability levels, these factors collectively affect the immune balance between enhancement or overload and dysfunction. Excessive training, mental stress or insufficient recovery risks immune cell exhaustion and hypothalamic pituitary axis (HPA) stress responses causing immunodepression with negative impacts on performance or general health. Participation in sport provides additional immune benefits in terms of ensuring regularity, social inclusion, mental well-being and healthier life choices in terms of diet and reduced smoking and alcohol, thereby consolidating healthy lifestyles and longer term health. Significant differences exist between recreational and professional athletes in terms of inherent characteristics, training resilience and additional stresses arising from competition schedules, travel-related infections and stress. Exercise immunology examines the central role of immunity in exercise physiology and straddles multiple disciplines ranging from neuroendocrinology to nutrition and genetics, with the aim of guiding athletes to train optimally and safely. This review provides a brief outline of the main interactions of immunity and exercise, some influencing factors, and current guidance on maintaining immune health.

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases.

The monoamine model of depression has long formed the basis of drug development but fails to explain treatment resistance or associations with stress or inflammation. Recent animal research, clinical trials of ketamine (a glutamate receptor antagonist), neuroimaging research, and microbiome studies provide increasing evidence of glutamatergic dysfunction in depression and other disorders. Glutamatergic involvement across diverse neuropathologies including psychoses, neurodevelopmental, neurodegenerative conditions, and brain injury forms the rationale for this review. Glutamate is the brain's principal excitatory neurotransmitter (NT), a metabolic and synthesis substrate, and an immune mediator. These overlapping roles and multiple glutamate NT receptor types complicate research into glutamate neurotransmission. The glutamate microcircuit comprises excitatory glutamatergic neurons, astrocytes controlling synaptic space levels, through glutamate reuptake, and inhibitory GABA interneurons. Astroglia generate and respond to inflammatory mediators. Glutamatergic microcircuits also act at the brain/body interface via the microbiome, kynurenine pathway, and hypothalamus-pituitary-adrenal axis. Disruption of excitatory/inhibitory homeostasis causing neuro-excitotoxicity, with neuronal impairment, causes depression and cognition symptoms via limbic and prefrontal regions, respectively. Persistent dysfunction reduces neuronal plasticity and growth causing neuronal death and tissue atrophy in neurodegenerative diseases. A conceptual overview of brain glutamatergic activity and peripheral interfacing is presented, including the common mechanisms that diverse diseases share when glutamate homeostasis is disrupted.

International Association of Athletics Federations Consensus Statement 2019: Nutrition for Athletics.

The International Association of Athletics Federations recognizes the importance of nutritional practices in optimizing an Athlete's well-being and performance. Although Athletics encompasses a diverse range of track-and-field events with different performance determinants, there are common goals around nutritional support for adaptation to training, optimal performance for key events, and reducing the risk of injury and illness. Periodized guidelines can be provided for the appropriate type, amount, and timing of intake of food and fluids to promote optimal health and performance across different scenarios of training and competition. Some Athletes are at risk of relative energy deficiency in sport arising from a mismatch between energy intake and exercise energy expenditure. Competition nutrition strategies may involve pre-event, within-event, and between-event eating to address requirements for carbohydrate and fluid replacement. Although a "food first" policy should underpin an Athlete's nutrition plan, there may be occasions for the judicious use of medical supplements to address nutrient deficiencies or sports foods that help the athlete to meet nutritional goals when it is impractical to eat food. Evidence-based supplements include caffeine, bicarbonate, beta-alanine, nitrate, and creatine; however, their value is specific to the characteristics of the event. Special considerations are needed for travel, challenging environments (e.g., heat and altitude); special populations (e.g., females, young and masters athletes); and restricted dietary choice (e.g., vegetarian). Ideally, each Athlete should develop a personalized, periodized, and practical nutrition plan via collaboration with their coach and accredited sports nutrition experts, to optimize their performance.

Nutrients, immune system, and exercise: Where will it take us?

The immune system plays a key role in controlling infections, repairing injuries, and restoring homeostasis. Immune cells are bioenergetically expensive during activation, which requires a tightly regulated control of the metabolic pathways, which is mostly regulated by two cellular energy sensors: Adenosine monophosphate-activated protein kinase and mammalian target of rapamycin. The activation and inhibition of this pathways can change cell subtype differentiation. Exercise intensity and duration and nutrient availability (especially glucose and glutamine) tightly regulate immune cell differentiation and function through Adenosine monophosphate-activated protein kinase and mammalian target of rapamycin signaling. Herein, we discuss the innate and adaptive immune-cell metabolism and how they can be affected by exercise and nutrients.

Sports Foods and Dietary Supplements for Optimal Function and Performance Enhancement in Track-and-Field Athletes.

Athletes are exposed to numerous nutritional products, attractively marketed with claims of optimizing health, function, and performance. However, there is limited evidence to support many of these claims, and the efficacy and safety of many products is questionable. The variety of nutritional aids considered for use by track-and-field athletes includes sports foods, performance supplements, and therapeutic nutritional aids. Support for sports foods and five evidence-based performance supplements (caffeine, creatine, nitrate/beetroot juice, ß-alanine, and bicarbonate) varies according to the event, the specific scenario of use, and the individual athlete's goals and responsiveness. Specific challenges include developing protocols to manage repeated use of performance supplements in multievent or heat-final competitions or the interaction between several products which are used concurrently. Potential disadvantages of supplement use include expense, false expectancy, and the risk of ingesting banned substances sometimes present as contaminants. However, a pragmatic approach to the decision-making process for supplement use is recommended. The authors conclude that it is pertinent for sports foods and nutritional supplements to be considered only where a strong evidence base supports their use as safe, legal, and effective and that such supplements are trialed thoroughly by the individual before committing to use in a competition setting.

Biochemical markers of possible immunodepression in military training in harsh environments.

Prolonged, exhaustive exercise frequently leads to an increased incidence of upper respiratory tract illness (URTI) which is linked to transient immunodepression. We investigated potential biochemical markers of stress and fatigue, and URTI symptoms as a surrogate of immunodepression, in US Marines undergoing intensive winter training at altitude. Selected plasma amino acids and leptin (p[Lep]) were measured as possible markers of fatigue and immunodepression, together with nonesterified fatty acids (p[NEFA]) and total antioxidant capacity (p[TAC]). Changes were observed in plasma free tryptophan (p[FT]), p[Gln], p[Lep], p[NEFA], p[TAC] but not branched chain amino acids (p[BCAA]). p[FT] decreased markedly. Resting p[Gln] decreased overall after one month at altitude. p[Gln] routinely decreases 1-2 hrs after prolonged exercise. Importantly, we observed early morning decreases in p[Gln], suggesting a cumulative effect of prolonged activity, stress, and fatigue. Concomitantly, individuals with highest illness scores had the greatest p[Gln] decrease: low p[Gln] may therefore be associated with a diminished stress tolerance.

Effects of elevated plasma tryptophan on brain activation associated with the Stroop task.

RATIONALE: Central fatigue, such as that found in chronic fatigue syndrome, is a state in which cognition and action require increasing effort and performance is impaired without evidence for reduced peripheral motor responsiveness. Previous studies identified functional changes in subcortical regions in patients who experience central fatigue but did not address neural correlates of the subjective experience of fatigue. OBJECTIVES: This study investigated responses to acute tryptophan feeding (after administration of 30 mg/kg body mass) using functional magnetic resonance imaging to investigate neural correlates of central fatigue during a cognitively demanding exercise, the counting Stroop task. MATERIALS AND METHODS: In a double-blind, cross-over study, eight subjects ingested L: -tryptophan (Trp) or placebo (Plac) on two separate test days. Neutral (N) and interference (I) Stroop tasks were carried out. RESULTS: Plasma-free tryptophan (p[FT]) increased tenfold after L: -Trp administration (P < 0.01). Although reaction times were longer after Trp (mean+/-SD, Plac-Neut 669 +/- 163 ms, I 715 +/- 174 ms, P < 0.01; Trp-Neut 712 +/- 193 ms, I 761 +/- 198 ms, P < 0.05), the Stroop effect was not significantly different between Plac and Trp. L: -Trp administration was associated with relatively decreased activation in regions, including the left postcentral, angular, inferior frontal, and the lateral orbital gyri and the inferior frontal sulcus relative to Plac. Relatively increased activation was found after Trp in the left precuneus and in the posterior cingulate gyrus. CONCLUSIONS: Thus, Trp administration before the Stroop task caused distributed functional changes in primary sensory and in multimodal neocortex, including changes in a brain region, the activity of which has been shown previously to vary with conscious awareness (precuneus). Previous reports suggest that primary mechanisms of central fatigue may be predominantly subcortical. The present results demonstrate that neocortical activity changes are also found. Whether this activity contributes to the primary mechanisms underlying central fatigue or not, the neocortical activity changes may provide an index of the conscious experience.

Manipulation of systemic oxygen flux by acute exercise and normobaric hypoxia: implications for reactive oxygen species generation.

Maximal exercise in normoxia results in oxidative stress due to an increase in free radical production. However, the effect of a single bout of moderate aerobic exercise performed in either relative or absolute normobaric hypoxia on free radical production and lipid peroxidation remains unknown. To examine this, we randomly matched {according to their normobaric normoxic VO2peak [peak VO2 (oxygen uptake)]} and assigned 30 male subjects to a normoxia (n = 10), a hypoxia relative (n = 10) or a hypoxia absolute (n = 10) group. Each group was required to exercise on a cycle ergometer at 55% of VO2peak for 2 h double-blinded to either a normoxic or hypoxic condition [FiO2 (inspired fraction of O2) = 0.21 and 0.16 respectively]. ESR (electron spin resonance) spectroscopy in conjunction with ex vivo spin trapping was utilized for the direct detection of free radical species. The main findings show that moderate intensity exercise increased plasma-volume-corrected free radical and lipid hydroperoxide concentration (pooled rest compared with exercise data, P < 0.05); however, there were no selective differences between groups (statexgroup interaction, P > 0.05). The delta change in free radical concentration was moderately correlated with systemic VO2 (r2 = 0.48, P < 0.05). The hyperfine coupling constants recorded from the ESR spectra [aN = 13.8 Gauss, and a(H)beta = 1.9 Gauss; where 1 Gauss = 10(-4) T (telsa)] are suggestive of oxygen-centred free radical species formed via the decomposition of lipid hydroperoxides. Peripheral leucocyte and neutrophil cells and total CK (creatine kinase) activity all increased following sustained exercise (pooled rest compared with exercise data, P < 0.05), but no selective differences were observed between groups (state x group interaction, P > 0.05). We conclude that a single bout of moderate aerobic exercise increases secondary free radical species. There is also evidence of exercise-induced muscle damage, possibly caused by the increase in free radical generation.

Granule localization of glutaminase in human neutrophils and the consequence of glutamine utilization for neutrophil activity.

The provision of glutamine in vivo has been observed to reduce to normal levels the neutrophilia observed after exhaustive exercise and to decrease the neutrophil chemoattractant, interleukin-8. Thus, the role for glutamine in the regulation of inflammatory mediators of human neutrophil activation was investigated. The study sought to establish whether glutamine supplementation in vitro affects neutrophil function at rest and whether glutaminase, the major enzyme that metabolizes glutamine, is present in human polymorphonuclear neutrophils (PMN). During in vitro studies, the addition of 2 mm glutamine increased the respiratory burst of human PMN stimulated with both phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenylalanine. These observations were made using a highly sensitive, real time chemiluminescent probe, Pholasin. Glutamine alone did not stimulate the release of reactive oxygen species. In a novel finding using glutaminase-specific antibodies in combination with flow cytometry and confocal microscopy, glutaminase was shown to be present on the surface of human PMN. Subcellular fractionation revealed that the enzyme was enriched in the secondary granules and could be released into cell culture medium upon stimulation with PMA. In conclusion, human PMN appeared to utilize glutamine and possess the appropriate glutaminase enzyme for metabolizing glutamine. This may depress some pro-inflammatory factors that occur during prolonged, exhaustive exercise.

Symptoms of infection and acute mountain sickness; associated metabolic sequelae and problems in differential diagnosis.

Infections and acute mountain sickness (AMS) are common at high altitude, yet their precise etiologies remain elusive and the potential for differential diagnosis is considerable. The present study was therefore designed to compare clinical nonspecific symptoms associated with these pathologies and basic changes in free radical and amino-acid metabolism. Nineteen males were examined at rest and after maximal exercise at sea level before (SL(1)/SL(2)) and following a 20 +/- 5 day ascent to Kanchenjunga base camp located at 5100 m (HA). Four subjects with symptoms consistent with an ongoing respiratory and recent gastrointestinal infection were also diagnosed with clinical AMS on the evening of day 1 at HA. These and six other subjects recovering from symptoms consistent with a respiratory infection presented with a greater increase (HA minus SL(1)) in AMS scores and resting venous concentration of lipid hydroperoxides (LH) and in total creatine phosphokinase and ratio of free tryptophan/branched chain amino acids, and greater decrease in glutamine (Gln) compared to healthy controls (n = 9, p < 0.05). The decrease in Gln was consistently related to the altitude/exercise-induced increase in LH (r = -0.69/r = -0.45; p < 0.05) and altitude-induced increase in myoglobin (r = -0.73, p < 0.05). These findings highlight the potential for the misdiagnosis of altitude illness due to the similarity of nonspecific constitutional symptoms associated with infection and AMS. Both conditions were characterized by parallel changes in peripheral biomarkers related to free-radical, skeletal muscle damage and amino acid metabolism. While clearly not establishing cause and effect, free radical-mediated changes in peripheral amino acid metabolism known to influence immune and cerebral serotoninergic function may enhance susceptibility to and/or delay recovery from altitude illness.

Biochemical markers for post-operative fatigue after major surgery.

OBJECTIVE: To establish a link between tryptophan (a precursor for 5-hydroxytryptamine (5-HT) or serotonin, involved in sleep and fatigue) and post-operative fatigue after major surgery. BACKGROUND: There is a link between tryptophan (the precursor for the neurotransmitter 5-hydroxytryptamine), and its competitive binding with non-esterified fatty acids (NEFA) to albumin in the blood. An increase in the plasma concentration of free tryptophan can lead to an increased rate of synthesis of 5-HT in the brain. Free tryptophan competes with the branched chain amino acids (BCAA) for the same port of entry across the blood-brain barrier. It is suggested that the plasma concentration of these amino acids could be a marker of post-operative fatigue. In a previous study undertaken in this laboratory on patients undergoing two different types of major surgery, similar post-operative increases were observed in the plasma concentration of free tryptophan and the plasma concentration ratio of free tryptophan to branched chain amino acids. However, the study was retrospective and no measure of fatigue had been made. METHODS: In the present study, this deficiency has been addressed by administering a modified Profile of Mood States questionnaire to patients undergoing reconstructive or colorectal surgery. In addition, blood samples were measured for plasma free tryptophan, albumin, NEFA and branched chain amino acids before and on 2 days after surgery. RESULTS: There was a significant correlation between fatigue scores and plasma free tryptophan (P<0.000), and the plasma concentration ratio of free tryptophan/BCAA (P<0.016) after surgery in all the patients studied (n=34). This correlation was more marked in the colorectal-surgery patients, in whom surgery was more severe. In the three categories of patients receiving elective reconstructive surgery (n=24), those having breast reductions (n=6) had a lower plasma concentration of NEFA and appeared to recover from fatigue more quickly than those with pre-tibial lacerations or malignant melanoma. CONCLUSIONS: These data provide further evidence of a possible biochemical mechanism for central fatigue which involves a precursor of 5-HT. The provision of branched chain amino acids may help to combat the surge in free tryptophan that occurs during stress such as major surgery.

Glutamine supplementation in vitro and in vivo, in exercise and in immunodepression.

In situations of stress, such as clinical trauma, starvation or prolonged, strenuous exercise, the concentration of glutamine in the blood is decreased, often substantially. In endurance athletes this decrease occurs concomitantly with relatively transient immunodepression. Glutamine is used as a fuel by some cells of the immune system. Provision of glutamine or a glutamine precursor, such as branched chain amino acids, has been seen to have a beneficial effect on gut function, on morbidity and mortality, and on some aspects of immune cell function in clinical studies. It has also been seen to decrease the self-reported incidence of illness in endurance athletes. So far, there is no firm evidence as to precisely which aspect of the immune system is affected by glutamine feeding during the transient immunodepression that occurs after prolonged, strenuous exercise. However, there is increasing evidence that neutrophils may be implicated. Other aspects of glutamine and glutamine supplementation are also addressed.

Can glutamine modify the apparent immunodepression observed after prolonged, exhaustive exercise?

Glutamine is an important fuel for some cells of the immune system. In situations of stress, such as clinical trauma, starvation, or prolonged, strenuous exercise, the concentration of glutamine in blood is decreased, often substantially. In endurance athletes this decrease occurs concomitantly with relatively transient immunodepression. Provision of glutamine or a glutamine precursor has been found to decrease the incidence of illness in endurance athletes. To date, it has not been established precisely which aspect of the immune system is affected by glutamine feeding during the transient immunodepression that occurs after prolonged, strenuous exercise. However, there is increasing evidence that neutrophils may be implicated.