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Symposium Reports |
1 Copenhagen Muscle Research Centre, Department of Anaesthesia, Rigshospitalet2 Department of Exercise and Sport Sciences, The Panum Institute, University of Copenhagen, Denmark
(Received 18 December 2006;
accepted after revision 3 January 2007; first published online 4 January 2007)
Corresponding author P. Rasmussen: Rigshospitalet, AN2041, Blegdamsvej 9, DK2100 Copenhagen, Denmark. Email: peter{at}prec.dk
Intense exercise challenges the capability of most organs of the body, and even the vital functions of the heart and the respiratory system become affected. In that regard, the brain has an interesting position, and in this volume of Experimental Physiology, Ross et al. (2007) demonstrate that central fatigue, relative to the neuromuscular junction, develops following a marathon run. The brain activates the muscles but, on the other hand, the muscles represent a potent competitor (‘the sleeping giant’, L. B. Rowell) for continuous provision of oxygen and substrate upon which the brain relies. Central fatigue has been demonstrated for especially slow muscle contractions during very intense exercise of short duration with lowering of the oxygen tension in the brain (Rasmussen et al. 2007) and central fatigue is not confined to predictable situations, such as when exercise provokes an elevated brain temperature or a low blood glucose level (Nybo & Secher, 2004). Although the mechanism(s) involved in central fatigue remains unknown, elucidation of how, when and why central fatigue develops during exercise is important. Central fatigue can be considered a safety precaution for the active organism to balance the function of various organs. Conversely, an important effect of training is to alleviate central fatigue during intense exercise. Furthermore, insight into mechanisms responsible for central fatigue may be relevant for the treatment of patients suffering from diseases associated with chronic fatigue.
It is fascinating how the brain, for hours, can stress the body even after ‘hitting the wall’ during a marathon run. This is even more impressive in a laboratory environment. The marathon run has fascinated physiologists since the beginning of the modern Olympic Games, as the example of extreme exercise. It is a classical observation that the running speed declines markedly when the muscle glycogen level decreases to a critical level requiring that the activation strategy needs to change accordingly. The breakdown of running style suggests that the muscles are no longer activated ideally and, using electrophysiological techniques, Ross et al. (2007) provide a first insight into the phenomena within the central nervous system (CNS) that, without doubt, are affected by long-lasting exercise.
Ross et al. (2007) use twitch interpolation to express the central activation efficacy in recruitment of the muscles. Until Gandevia and colleagues carefully introduced transcranial magnetic stimulation (TMS) for twitch interpolation (Todd et al. 2003), measurement of voluntary activation was evaluated by electrical stimulation of the motor nerve (Merton, 1954). The TMS provides the advantage of access to cells within the motor cortex in awake humans and, thereby, an estimate of the activity in the motoneuronal pathways. Although the effect of TMS is complex (Petersen et al. 2003), TMS does open a window for evaluation of muscle fibre recruitment; however, there remains a need for careful interpretation of the results.
The motor nerve to the tibialis anterior muscle lies in proximity to the branch of the common peroneal nerve, and electrical stimulation aimed to activate the tibialis anterior muscle may activate the peroneal muscles (Gandevia & McKenzie, 1988) so that interpretation of its role in torque production around the ankle joint will be complex. Ross et al. (2007) stimulated the peripheral nerve with magnetic stimulation, and it remains to be established how this stimulus includes various branches of the common peroneal nerve.
The advantage of using TMS for activation of the tibialis anterior muscle is that it has a low threshold and, importantly, a lower threshold than the antagonist (soleus muscle). This is relevant, especially when the extra force induced by the stimulus, compared with a voluntary effort, is assessed. The voluntary activation of the tibialis anterior muscle was less than 90% of its TMS-induced strength, which is lower than what has been found in studies using electrical stimulation. Nevertheless, the marathon significantly reduced the ability to activate the muscle to a maximum performance. It should be pointed out that central fatigue, as measured with the twitch interpolation technique, recovers quickly after exercise (Gandevia et al. 1996). Nonetheless, Ross et al. (2007) found a clear reduction in voluntary activation of the tibialis anterior within 20 min after the marathon that disappeared after 4 h, demonstrating a change in cortical output.
Although the results presented are impressive, the underlying mechanisms for the development of central fatigue are not elucidated. It is tempting to address such possible mechanisms. Activation of the brain increases cerebral blood flow because neural metabolism is enhanced, as expressed by the cerebral metabolic rates of oxygen (CMRO2) and carbohydrate (CMRCHO). A decrease in the ratio between CMRO2 and CMRCHO, being 
6 at rest, is a characteristic of cerebral activation, and strenuous exercise increases the carbohydrate uptake relative to that of oxygen (Dalsgaard, 2006). The reduced ratio between CMRO2 and CMRCHO developed during exercise identifies exercise as a powerful activator of cerebral metabolism and illustrates that exercise causes a marked perturbation of cerebral metabolism. Considering that the brain has little capacity for anaerobic metabolism, the fate for the surplus carbohydrate taken up during activation is most probably that it is metabolized, although ammonia clearance may account for some 10% of the surplus carbohydrate taken up (Dalsgaard, 2006).
During exercise, the muscles release and the brain takes up ammonia. The brain has no effective urea cycle and depends on the synthesis of glutamine from glutamate for removal of ammonia. Elimination of ammonia may reduce the concentration of the excitatory neurotransmitters glutamate and 
-aminobutyric acid, and such disturbance could underlie cerebral dysfunction and chronic fatigue in hepatic diseases, suggesting that ammonia may be a ‘fatiguing agent’ during exercise (Nybo & Secher, 2004). Also of interest are the serotonergic and dopaminergic systems (Newsholme et al. 1987). Serotonin has a role in arousal, sleepiness and mood and, while the kinetics of serotonin metabolism cannot be assessed through arteriovenous differences for the brain, its precursor, tryptophan, may provide such information. Dopamine is involved in the control of movement, and regional cerebral dopamine metabolism is enhanced during exercise in animals. Similarly, the arterial concentration of dopamine increases during strenuous exercise; however, no change in release across the brain was observed (Nybo & Secher, 2004).
The illustration of central fatigue as a change in cortical excitation is a large step forward. However, the applicable methods, such as TMS, arteriovenous differences and imaging techniques, need to be combined in order to link changes in cortical excitability to those in cerebral carbohydrate, amino acid and neurotransmitter metabolism, as well as to metabolite and hormonal signalling between the brain and the muscles. The question is then, what is the chicken and what is the egg? Therefore, to elucidate the cause and effect relationships, the descriptive work has to shift to experimental physiology and integrative physiological studies involving humans.
References
Gandevia SC, Allen GM, Butler JE & Taylor JL (1996). Supraspinal factors in human muscle fatigue: evidence for suboptimal output from the motor cortex. J Physiol 490, 529–536.[Medline]
Gandevia SC & McKenzie DK (1988). Activation of human muscles at short muscle lengths during maximal static efforts. J Physiol 407, 599–613.
Merton PA (1954). Voluntary strength and fatigue. J Physiol 123, 553–564.
Newsholme EA, Acworth I & Blomstrand E (1987). Amino-acids, brain neurotransmitters and a functional link between muscle and brain that is important in sustained exercise. In Advances in Biochemistry, ed. Benzi G, pp. 127–133. John Libbey Eurotext Ltd, London.
Nybo L & Secher NH (2004). Cerebral perturbations provoked by prolonged exercise. Prog Neurobiol 72, 223–261.[CrossRef][Medline]
Petersen NT, Pyndt HS & Nielsen JB (2003). Investigating human motor control by transcranial magnetic stimulation. Exp Brain Res 152, 1–16.[CrossRef][Medline]
Rasmussen P, Dawson EA, Nybo L, Van Lieshout JJ, Secher NH & Gjedde A (2007). Capillary-oxygenation-level-dependent near-infrared spectrometry in frontal lobe of humans. J Cereb Blood Flow Metab. DOI: 10.1038/sj.jcbfm.9600416.
Ross EZ, Middleton N, Shave R, George K & Nowicky A (2007). Corticomotor excitability contributes to neuromuscular fatigue following marathon running in man. Exp Physiol 92, 417–426.
Todd G, Taylor JL & Gandevia SC (2003). Measurement of voluntary activation of fresh and fatigued human muscles using transcranial magnetic stimulation. J Physiol 551, 661–671.
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