Michael Gleeson

The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease

Regular exercise reduces the risk of chronic metabolic and cardiorespiratory diseases, in part because exercise exerts anti-inflammatory effects. However, these effects are also likely to be responsible for the suppressed immunity that makes elite athletes more susceptible to infections. The anti-inflammatory effects of regular exercise may be mediated via both a reduction in visceral fat mass (with a subsequent decreased release of adipokines) and the induction of an anti-inflammatory environment with each bout of exercise. In this Review, we focus on the known mechanisms by which exercise — both acute and chronic — exerts its anti-inflammatory effects, and we discuss the implications of these effects for the prevention and treatment of disease.

Determination of the exercise intensity that elicits maximal fat oxidation

PURPOSE The aim of this study was to develop a test protocol to determine the exercise intensity at which fat oxidation rate is maximal (Fat(max)). METHOD Eighteen moderately trained cyclists performed a graded exercise test to exhaustion, with 5-min stages and 35-W increments (GE(35/5)). In addition, four to six continuous prolonged exercise tests (CE) at constant work rates, corresponding to the work rates of the GE test, were performed on separate days. The duration of each test was chosen so that all trials would result in an equal energy expenditure. Seven other subjects performed three different GE tests to exhaustion. The test protocols differed in stage duration and in increment size. Fat oxidation was measured using indirect calorimetry. RESULTS No significant differences were found in Fat(max) determined with the GE(35/5), the average fat oxidation of the CE tests, or fat oxidation measured during the first 5 min of the CE tests (56 +/- 3, 64 +/- 3, 58 +/- 3%VO(2max), respectively). Results of the GE(35/5) protocol were used to construct an exercise intensity versus fat oxidation curve for each individual. Fat(max) was equivalent to 64 +/- 4%VO(2max) and 74 +/- 3%HR(max). The Fat(max) zone (range of intensities with fat oxidation rates within 10% of the peak rate) was located between 55 +/- 3 and 72 +/- 4%VO(2max). The contribution of fat oxidation to energy expenditure became negligible above 89 +/- 3%VO(2max) (92 +/- 1%HR(max)). When stage duration was reduced from 5 to 3 min or when increment size was reduced from 35 to 20 W, no significant differences were found in Fat(max), Fat(min), or the Fat(max) zone. CONCLUSION It is concluded that a protocol with 3-min stages and 35-W increments in work rate can be used to determine Fat(max). Fat oxidation rates are high over a large range of intensities; however, at exercise intensities above Fat(max), fat oxidation rates drop markedly.

Prevention, diagnosis and treatment of the Overtraining Syndrome ECSS Position Statement 'Task Force'

Abstract Successful training must involve overload but also must avoid the combination of excessive overload plus inadequate recovery. Athletes can experience short term performance decrement, without severe psychological, or lasting other negative symptoms. This Functional Overreaching (FOR) will eventually lead to an improvement in performance after recovery. When athletes do not sufficiently respect the balance between training and recovery, Non-Functional Overreaching (NFOR) can occur. The distinction between NFOR and the Overtraining Syndrome (OTS) is very difficult and will depend on the clinical outcome and exclusion diagnosis. The athlete will often show the same clinical, hormonal and other signs and symptoms. A keyword in the recognition of OTS might be ‘prolonged maladaptation’ not only of the athlete, but also of several biological, neurochemical, and hormonal regulation mechanisms. It is generally thought that symptoms of OTS, such as fatigue, performance decline, and mood disturbances, are more severe than those of NFOR. However, there is no scientific evidence to either confirm or refute this suggestion. One approach to understanding the aetiology of OTS involves the exclusion of organic diseases or infections and factors such as dietary caloric restriction (negative energy balance) and insufficient carbohydrate and/or protein intake, iron deficiency, magnesium deficiency, allergies, etc. together with identification of initiating events or triggers. In this paper we provide the recent status of possible markers for the detection of OTS. Currently several markers (hormones, performance tests, psychological tests, biochemical and immune markers) are used, but none of them meets all criteria to make its use generally accepted. We propose a “check list” that might help the physicians and sport scientists to decide on the diagnosis of OTS and to exclude other possible causes of underperformance.

Markers to measure immunomodulation in human nutrition intervention studies

Normal functioning of the immune system is crucial to the health of man, and diet is one of the major exogenous factors modulating individual immunocompetence. Recently, nutrition research has focused on the role of foods or specific food components in enhancing immune system responsiveness to challenges and thereby improving health and reducing disease risks. Assessing diet-induced changes of immune function, however, requires a thorough methodological approach targeting a large spectrum of immune system parameters. Currently, no single marker is available to predict the outcome of a dietary intervention on the resistance to infection or to other immune system-related diseases. The present review summarises the immune function assays commonly used as markers in human intervention studies and evaluates their biological relevance (e.g. known correlation with clinically relevant endpoints), sensitivity (e.g. within- and between-subject variation), and practical feasibility. Based on these criteria markers were classified into three categories with high, medium or low suitability. Vaccine-specific serum antibody production, delayed-type hypersensitivity response, vaccine-specific or total secretory IgA in saliva and the response to attenuated pathogens, were classified as markers with high suitability. Markers with medium suitability include natural killer cell cytotoxicity, oxidative burst of phagocytes, lymphocyte proliferation and the cytokine pattern produced by activated immune cells. Since no single marker allows conclusions to be drawn about the modulation of the whole immune system, except for the clinical outcome of infection itself, combining markers with high and medium suitability is currently the best approach to measure immunomodulation in human nutrition intervention studies. It would be valuable to include several immune markers in addition to clinical outcome in future clinical trials in this area, as there is too little evidence that correlates markers with global health improvement.

Exercise, Nutrition, and Immune Function

Strenuous bouts of prolonged exercise and heavy training are associated with depressed immune cell function. Furthermore, inadequate or inappropriate nutrition can compound the negative influence of heavy exertion on immunocompetence. Dietary deficiencies of protein and specific micronutrients have long been associated with immune dysfunction. An adequate intake of iron, zinc and vitamins A, E, B6 and B12 is particularly important for the maintenance of immune function, but excess intakes of some micronutrients can also impair immune function and have other adverse effects on health. Immune system depression has also been associated with an excess intake of fat. To maintain immune function, athletes should eat a well-balanced diet sufficient to meet their energy requirements. An athlete exercising in a carbohydrate-depleted state experiences larger increases in circulating stress hormones and a greater perturbation of several immune function indices. Conversely, consuming 30–60 g carbohydrate · h−1 during sustained intensive exercise attenuates rises in stress hormones such as cortisol and appears to limit the degree of exercise-induced immune depression. Convincing evidence that so-called ‘immune-boosting’ supplements, including high doses of antioxidant vitamins, glutamine, zinc, probiotics and Echinacea, prevent exercise-induced immune impairment is currently lacking.

Salivary IgA as a risk factor for upper respiratory infections in elite professional athletes.

UNLABELLED The relationship between physiological and psychological stress and immune function is widely recognized; however, there is little evidence to confirm a direct link between depressed immune function and incidence of illness in athletes. PURPOSE To examine the relationship between salivary immunoglobulin A (s-IgA) and upper respiratory infections (URI) in a cohort of professional athletes over a prolonged period. METHODS Thirty-eight elite Americas Cup yacht racing athletes were studied over 50 wk of training. Resting, unstimulated saliva samples were collected weekly (38 h after exercise, consistent time of day, fasted) together with clinically confirmed URI, training load, and perceived fatigue rating. RESULTS s-IgA was highly variable within (coefficients of variation [CV] = 48%) and between subjects (CV = 71%). No significant correlation was found between absolute s-IgA concentration and the incidence of URI among athletes (r = 0.11). However, a significant (28%, P < 0.005) reduction in s-IgA occurred during the 3 wk before URI episodes and returned to baseline by 2 wk after a URI. When an athlete did not have, or was not recovering from URI, a s-IgA value lower than 40% of their mean healthy s-IgA concentration indicated a one in two chance of contracting an URI within 3 wk. CONCLUSION On a group basis, relative s-IgA determined a substantial proportion of the variability in weekly URI incidence. The typical decline in an individuals relative s-IgA over the 3 wk before a URI appears to precede and contribute to URI risk, with the magnitude of the decrease related to the risk of URI, independent of the absolute s-IgA concentration. These findings have important implications for athletes and coaches in identifying periods of high URI risk.

The effects of high-intensity intermittent exercise on saliva IgA, total protein and alpha-amylase

The aim of this study was to assess the effect of an acute bout of high-intensity intermittent exercise on saliva IgA concentration and alpha-amylase activity, since this type of training is commonly incorporated into the training programmes of endurance athletes and games players. Eight well-trained male games players took part in the study. They reported to the laboratory after an overnight fast and performed a 60-min cycle exercise task consisting of twenty 1-min periods at 100% VO2max, each separated by 2 min recovery at 30% VO2max. Unstimulated whole saliva was collected over a 5-min period into pre-weighed tubes and analysed for total protein, saliva IgA and alpha-amylase. The saliva flow rate ranged from 0.08 to 1.40 ml x min(-1) at rest and was not significantly affected by the exercise. The performance of the intermittent exercise bout did not affect the saliva IgA concentration, but caused a five-fold increase in alpha-amylase activity (P<0.01 compared with pre-exercise) and a three-fold increase in total protein concentration (P<0.01). These returned to pre-exercise values within 2.5 h post-exercise. It has been suggested that IgA concentration should be expressed as the ratio to total protein concentration, to correct for any concentrating effect due to evaporative loss of saliva water when breathing through the mouth (as in strenuous exercise). The present study clearly demonstrates that this is not appropriate, since there is an increase in salivary protein secretion rate immediately after exercise (571+/-77 microg x min(-1) compared with 218+/-71 microg x min(-1) pre-exercise; P<0.05). The increased saliva alpha-amylase activity after exercise may improve the protective effect of saliva, since this enzyme is known to inhibit bacterial attachment to oral surfaces. The saliva alpha-amylase secretion rate was lower immediately pre-exercise than at any other instant, which may have been due to anticipatory psychological stress, although the subjects were all familiar with interval exercise. This emphasizes the need for true resting non-stressed control conditions in future studies of the effects of exercise on saliva constituents.

Effects of exercise intensity on salivary antimicrobial proteins and markers of stress in active men

Abstract In the present study, we assessed the effects of exercise intensity on salivary immunoglobulin A (s-IgA) and salivary lysozyme (s-Lys) and examined how these responses were associated with salivary markers of adrenal activation. Using a randomized design, 10 healthy active men participated in three experimental cycling trials: 50% maximal oxygen uptake ([Vdot]O2max), 75%[Vdot]O2max, and an incremental test to exhaustion. The durations of the trials were the same as for a preliminary incremental test to exhaustion (22.3 min, s x = 0.8). Timed, unstimulated saliva samples were collected before exercise, immediately after exercise, and 1 h after exercise. In the incremental exhaustion trial, the secretion rates of both s-IgA and s-Lys were increased. An increase in s-Lys secretion rate was also observed at 75%[Vdot]O2max. No significant changes in saliva flow rate were observed in any trial. Cycling at 75%[Vdot]O2max and to exhaustion increased the secretion of α-amylase and chromogranin A immediately after exercise; higher cortisol values at 75%[Vdot]O2max and in the incremental exhaustion trial compared with 50%[Vdot]O2max were observed 1 h immediately after exercise only. These findings suggest that short-duration, high-intensity exercise increases the secretion rate of s-IgA and s-Lys despite no change in the saliva flow rate. These effects appear to be associated with changes in sympathetic activity and not the hypothalamic – pituitary – adrenal axis.

Glutamine, exercise and immune function : Links and possible mechanisms

Glutamine is the most abundant free amino acid in human muscle and plasma and is utilised at high rates by rapidly dividing cells, including leucocytes, to provide energy and optimal conditions for nucleotide biosynthesis. As such, it is considered to be essential for proper immune function.During various catabolic states including surgical trauma, infection, starvation and prolonged exercise, glutamine homeostasis is placed under stress. Falls in the plasma glutamine level (normal range 500 to 750 μmol/L after an overnight fast) have been reported following endurance events and prolonged exercise. These levels remain unchanged or temporarily elevated after short term, high intensity exercise. Plasma glutamine has also been reported to fall in patients with untreated diabetes mellitus, in diet-induced metabolic acidosis and in the recovery period following high intensity intermittent exercise. Common factors among all these stress states are rises in the plasma concentrations of cortisol and glucagon and an increased tissue requirement for glutamine for gluconeogenesis. It is suggested that increased gluconeogenesis and associated increases in hepatic, gut and renal glutamine uptake account for the depletion of plasma glutamine in catabolic stress states, including prolonged exercise.The short term effects of exercise on the plasma glutamine level may be cumulative, since heavy training has been shown to result in low plasma glutamine levels (<500 μmol/L) requiring long periods of recovery. Furthermore, athletes experiencing discomfort from the overtraining syndrome exhibit lower resting levels of plasma glutamine than active healthy controls. Therefore, physical activity directly affects the availability of glutamine to the leucocytes and thus may influence immune function. The utility of plasma glutamine level as a marker of overtraining has recently been highlighted, but a consensus has not yet been reached concerning the best method of determining the level.Since injury, infection, nutritional status and acute exercise can all influence plasma glutamine level, these factors must be controlled and/or taken into consideration if plasma glutamine is to prove a useful marker of impending overtraining.

The physiological regulation of toll‐like receptor expression and function in humans

Eleven mammalian toll‐like receptors (TLRs 1–11) have been identified to date and are known to play a crucial role in the regulation of immune responses; however, the factors that regulate TLR expression and function in vivo are poorly understood. Therefore, in the present study, we investigated the physiological regulation of TLR expression and function in humans. To examine the influence of diurnal rhythmicity on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers (n= 8) at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration. While no diurnal rhythmicity in the expression of TLRs 1, 2, 4 or 9 was observed, the upregulation of costimulatory (CD80 and CD86) and antigen‐presenting (MHC class II) molecules on CD14+ monocytes following activation with specific TLR ligands was greater (P < 0.05) in samples obtained in the evening compared with the morning. To examine the influence of physical stress on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers (n= 11) at rest and following 1.5 h of strenuous exercise in the heat (34°C). Strenuous exercise resulted in a decrease (P < 0.005) in the expression of TLRs 1, 2 and 4 on CD14+ monocytes. Furthermore, the upregulation of CD80, CD86, MHC class II and interleukin‐6 by CD14+ monocytes following activation with specific TLR ligands was decreased (P < 0.05) in samples obtained following exercise compared with at rest. These results demonstrate that TLR function is subject to modulation under physiological conditions in vivo and provide evidence for the role of immunomodulatory hormones in the regulation of TLR function.