Scientific interest in the nature and causes of exercise-induced fatigue developed through the 19th century, culminating in the publication in 1891 of a monograph on the subject by Angelo Mosso (Mosso, 1891). Mosso had developed an ergographic method to quantify fatigue of the muscles of the middle finger in response to voluntary or electrically evoked contractions. Other methodological advances led to a focus on different exercise models and on specific aspects of the fatigue process. August Krogh developed a reliable cycle ergometer that has remained the standard laboratory exercise model and also an accurate method for the analysis of expired air (Krogh, 1913). The introduction of the needle biopsy method for obtaining samples of human muscle, by Jonas Bergstrom in the 1960s, shifted the focus to the role of substrate depletion and metabolite accumulation in the active muscles (Bergstrom, 1962). A working definition of fatigue was proposed by Richard Edwards at the 1981 Ciba Foundation symposium: ‘fatigue is a failure to maintain the required or expected work output’ (Edwards, 1981). The symposium covered aspects of fatigue from the perspectives of the central and peripheral neuromuscular system. Various international symposia dedicated to the topic of fatigue were held in the 1980s and 1990s, for example, the 1994 International Symposium on Neural and Neuromuscular Aspects of Muscle Fatigue (Gandevia et al., 1994). As part of its 2019 annual meeting, hosted in Aberdeen, The Physiological Society organised five satellite symposia on the day prior to the main conference. The theme of one of these satellite symposia was ‘Fatigue as a limitation to performance’, and it was based upon three separate but inter-related sessions that focused on the neuromuscular system and fatigue, the cardiovascular system and fatigue, and finally, muscle metabolism and fatigue.

The first session included an examination of the role of the brain in fatigue presented by Professor Romain Meeusen (Vrije University, Brussels, Belgium), who reviewed the evidence that manipulation of the activity of brain neurotransmitters during exercise could influence performance and the perception of fatigue (Meeusen et al., 2021). Wilson and Maughan (1992) showed that administration of paroxetine, an inhibitor of 5-hydroxytryptamine reuptake, significantly reduced endurance capacity during prolonged exercise. Oral administration of noradrenaline, dopamine and reuptake inhibitors of these central catecholamines before exercise led to the conclusion that administration of noradrenaline agonists (reboxetine) impaired performance, but inhibiting reuptake of dopamine had no effect on exercise performance. Furthermore, emerging evidence was provided to suggest a role of dopamine and adenosine in the process of mental fatigue, which from a performance perspective could negatively affect perceived exertion (Schiphof-Godart et al., 2018).

The consequences of exercising under conditions of heat stress were discussed by Dr Derek Ball (University of Aberdeen, UK). Using examples of direct heating and the consequences of exposure to hot environments, the acute and chronic effects of heat on locomotor capacity were discussed (Ball, 2021). Elevating muscle temperature by immersing limbs in hot water was shown to improve peak power production but this was at the expense of a greater rate of decline in power output. Using a similar method of heating muscle but measuring endurance capacity during static contractions was shown to reduce endurance capacity due to a higher cross-bridge turnover rate. Chronic exposure to hot environments and measuring subsequent locomotory capacity across a range of temperatures was shown to result in adaptation to the hot environment that results in an improvement in neuromuscular function in ectothermic animals (Fry & Hart, 1948). In humans, however, there appears to be a temperature of ∼10°C that is optimal for endurance at a moderate intensity of exercise (Galloway & Maughan, 1997). Increasing relative humidity (Maughan et al., 2012) or solar radiant heat load (Otani et al, 2016) or reducing air flow (Otani et al, 2018) also progressively impairs endurance capacity.

The first session concluded with a discussion from Professor Louise Burke (Australian Catholic University, Melbourne, Australia) of nutritional strategies that might offset fatigue. Laboratory-generated data indicate that the onset of fatigue can be delayed, either directly or indirectly and in some but not all exercise models, through the provision of carbohydrates, creatine, caffeine, nitrate, sodium bicarbonate, and fluids and electrolytes (Maughan et al., 2018). Professor Burke examined the dietary practices employed by athletes during competition and the efficacy of various nutritional manipulations in maintaining/enhancing performance; the available evidence highlighted the need for a personalised approach to nutrition (Burke, 2021). She also discussed the recent popularity of ketogenic diets in athletes, but concluded that a high-carbohydrate diet is a more effective strategy (Burke et al., 2017).

The second session discussion encompassed the role of the central cardiovascular system in the role of fatigue (presented by Professor Mike Joyner, Mayo Clinic, Rochester, USA) and the efficacy of pharmacological intervention to enhance performance (presented by Professor David Cowan, King's College London, UK). Endurance exercise performance is determined, in part, by the ability to sustain high rates of energy turnover, and Joyner emphasised that this would be primarily from oxidative substrate utilisation (Joyner & Dominelli, 2021). Professor Joyner discussed the central factors that limit as a function of the oxidative energy requirement and the demands made on an individual's aerobic capacity (); he observed that maximum heart rate is relatively constant across individuals, but an increased stroke volume can largely explain the higher cardiac output in elite endurance athletes (Lundby et al., 2017). The ability to utilise a high fraction of was illustrated using marathon running and events lasting between 15 and 30 min as examples with the emphasis that locomotory efficiency is also a determinant of endurance performance.

The third and final session discussed the role of muscle metabolism in fatigue. Dr Niels Ortenblad (University of Southern Denmark, Denmark) discussed the effect of glycogen availability on muscle function, with a focus on calcium handling and the inter-relationship between glycogen deposition and sarcoplasmic reticulum function. Using the model of intense intermittent training, Dr Martin Gibala (McMaster University, Canada) reported that 6 weeks of training does not appear to affect peak cardiac output but does result in a significant increase in maximum aerobic capacity (Gibala, 2021). Changes in mitochondrial function and muscle capillarity were observed following short-term interval training (Jacobs et al, 2013; Scribbans et al, 2014). In trained individuals, improvements in 10 km running performance have been observed following the incorporation of sprint training within the training regimen. However, Dr Gibala noted that in these individuals the adaptations appear to be related to changes in sodium and calcium transporter proteins rather than changes in enzymes related to mitochondrial expression (Gibala, 2021).

The roundtable discussion that summarised the presentations concluded that fatigue is a complex process: whether the ultimate limitation lies in the head, the heart or the muscles themselves depends on the intensity and duration of exercise, the exercise environment and the physiology of the individual. Fatigue can be delayed, and performance improved, by appropriate training and nutrition strategies as well as by pharmacological interventions. Addressing one limitation to exercise performance, however, simply introduces a new limitation: if the intensity and duration of exercise are sufficient, fatigue is an inevitable accompaniment to exercise.