Performance in the heat-physiological factors of importance for hyperthermia-induced fatigue.

This article presents a historical overview and an up-to-date review of hyperthermia-induced fatigue during exercise in the heat. Exercise in the heat is associated with a thermoregulatory burden which mediates cardiovascular challenges and influence the cerebral function, increase the pulmonary ventilation, and alter muscle metabolism; which all potentially may contribute to fatigue and impair the ability to sustain power output during aerobic exercise. For maximal intensity exercise, the performance impairment is clearly influenced by cardiovascular limitations to simultaneously support thermoregulation and oxygen delivery to the active skeletal muscle. In contrast, during submaximal intensity exercise at a fixed intensity, muscle blood flow and oxygen consumption remain unchanged and the potential influence from cardiovascular stressing and/or high skin temperature is not related to decreased oxygen delivery to the skeletal muscles. Regardless, performance is markedly deteriorated and exercise-induced hyperthermia is associated with central fatigue as indicated by impaired ability to sustain maximal muscle activation during sustained contractions. The central fatigue appears to be influenced by neurotransmitter activity of the dopaminergic system, but inhibitory signals from thermoreceptors arising secondary to the elevated core, muscle and skin temperatures and augmented afferent feedback from the increased ventilation and the cardiovascular stressing (perhaps baroreceptor sensing of blood pressure stability) and metabolic alterations within the skeletal muscles are likely all factors of importance for afferent feedback to mediate hyperthermia-induced fatigue during submaximal intensity exercise. Taking all the potential factors into account, we propose an integrative model that may help understanding the interplay among factors, but also acknowledging that the influence from a given factor depends on the exercise hyperthermia situation.

[1]  Tom M. McLellan,et al.  The Thermophysiology of Uncompensable Heat Stress , 2000, Sports medicine.

[2]  L. Nybo,et al.  Middle cerebral artery blood velocity is reduced with hyperthermia during prolonged exercise in humans , 2001, The Journal of physiology.

[3]  E. Newsholme,et al.  Tryptophan, 5-hydroxytryptamine and a possible explanation for central fatigue. , 1995, Advances in experimental medicine and biology.

[4]  N. Lassen,et al.  The luxury-perfusion syndrome and its possible relation to acute metabolic acidosis localised within the brain. , 1966, Lancet.

[5]  N. Lassen,et al.  Normal Average Value of Cerebral Blood Flow in Younger Adults is 50 ml/100 g/min , 1985, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[6]  N. Secher,et al.  Syncope, cerebral perfusion, and oxygenation. , 2003, Journal of applied physiology.

[7]  E. Coyle,et al.  Supine exercise restores arterial blood pressure and skin blood flow despite dehydration and hyperthermia. , 1999, The American journal of physiology.

[8]  A F Bennett,et al.  Thermal dependence of muscle function. , 1984, The American journal of physiology.

[9]  H Yonas,et al.  The Q10 ratio for basal cerebral metabolic rate for oxygen in rats. , 1996, Journal of neurosurgery.

[10]  J. González-Alonso.  Separate and Combined Influences of Dehydration and Hyperthermia on Cardiovascular Responses to Exercise , 1998, International journal of sports medicine.

[11]  J. Vogel,et al.  Effects of acute alterations of Vo2 max on endurance capacity of men. , 1973, Journal of applied physiology.

[12]  N. Gledhill,et al.  Endurance athletes' stroke volume does not plateau: major advantage is diastolic function. , 1994, Medicine and science in sports and exercise.

[13]  C B Wenger,et al.  Physiological Responses to Acute Exercise-Heat Stress , 1988 .

[14]  B. Saltin,et al.  Maximal perfusion of skeletal muscle in man. , 1985, The Journal of physiology.

[15]  R. Meeusen,et al.  A dopamine/noradrenaline reuptake inhibitor improves performance in the heat, but only at the maximum therapeutic dose , 2012, Scandinavian journal of medicine & science in sports.

[16]  M N Sawka,et al.  Skin temperature modifies the impact of hypohydration on aerobic performance. , 2010, Journal of applied physiology.

[17]  Romain Meeusen,et al.  Alterations in Central Fatigue by Pharmacological Manipulations of Neurotransmitters in Normal and High Ambient Temperature , 2010, Sports medicine.

[18]  Andrew J. Young,et al.  Influence of heat stress and acclimation on maximal aerobic power , 1984, European Journal of Applied Physiology and Occupational Physiology.

[19]  J. Davis,et al.  Possible mechanisms of central nervous system fatigue during exercise. , 1997, Medicine and science in sports and exercise.

[20]  A. Nehlig,et al.  Cerebral energy metabolism, glucose transport and blood flow: changes with maturation and adaptation to hypoglycaemia. , 1997, Diabetes & metabolism.

[21]  A. Dimarco,et al.  Endotoxin administration alters the force vs. pCa relationship of skeletal muscle fibers. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[22]  R. Meeusen,et al.  Exercise and Brain Neurotransmission , 1995, Sports medicine.

[23]  E. Newsholme,et al.  Effect of sustained exercise on concentrations of plasma aromatic and branched-chain amino acids and brain amines. , 1986, Biochemical and biophysical research communications.

[24]  R. Meeusen,et al.  No effect of caffeine on exercise performance in high ambient temperature , 2011, European Journal of Applied Physiology.

[25]  L. Nybo,et al.  Enhanced cerebral CO2 reactivity during strenuous exercise in man , 2006, European Journal of Applied Physiology.

[26]  Gary H. Glover,et al.  Changes of Cerebral Blood Flow, Oxygenation, and Oxidative Metabolism during Graded Motor Activation , 2002, NeuroImage.

[27]  J. M. Thomson,et al.  Oxygen transport and oxyhemoglobin dissociation during prolonged muscular work. , 1974, Journal of applied physiology.

[28]  John M. Johnson,et al.  Cardiovascular Adjustments to Heat Stress , 2011 .

[29]  M. Amann.  Significance of Group III and IV muscle afferents for the endurance exercising human , 2012, Clinical and experimental pharmacology & physiology.

[30]  C. Crandall,et al.  The cardiovascular challenge of exercising in the heat , 2008, The Journal of physiology.

[31]  R A Binkhorst,et al.  Maximal oxygen uptake during arm cranking and combined arm plus leg exercise. , 1974, Journal of applied physiology.

[32]  H. Stone,et al.  The effect of lowered body temperature on the cerebral hemodynamics and metabolism of man. , 1956, Surgery, gynecology & obstetrics.

[33]  L. Nybo,et al.  Physiological Responses and Physical Performance during Football in the Heat , 2012, PloS one.

[34]  B. Jones,et al.  Preparing Alberto Salazar for the Heat of the 1984 Olympic Marathon. , 1986, The Physician and sportsmedicine.

[35]  A. Jeukendrup,et al.  Relationship between gastro-intestinal complaints and endotoxaemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men. , 2000, Clinical science.

[36]  D. B. Dill,et al.  Metabolic reactions to work in the desert. , 1967, Journal of applied physiology.

[37]  R. Meeusen,et al.  The brain and fatigue: New opportunities for nutritional interventions? , 2006, Journal of sports sciences.

[38]  J D HARDY,et al.  Physiology of temperature regulation. , 1960, Physiological reviews.

[39]  109 – Disorders Due to Heat and Cold , 2012 .

[40]  L. Rowell,et al.  Hepatic clearance of indocyanine green in man under thermal and exercise stresses. , 1965, Journal of applied physiology.

[41]  The Commission for Thermal Physiology of the Internati Sciences.  Glossary of terms for thermal physiology , 2004, Pflügers Archiv - European Journal of Physiology.

[42]  M. Febbraio,et al.  Effects of heat stress on physiological responses and exercise performance in elite cyclists. , 2000, Journal of science and medicine in sport.

[43]  L. W. Eichna,et al.  Performance in relation to environmental temperature. Reactions of normal young men to hot, humid (simulated jungle) environment. , 1945 .

[44]  W G Hopkins,et al.  Variability of competitive performance of distance runners. , 2001, Medicine and science in sports and exercise.

[45]  G. Kenny,et al.  Current evidence does not support an anticipatory regulation of exercise intensity mediated by rate of body heat storage. , 2009, Journal of applied physiology.

[46]  Nadel Er.  Control of sweating rate while exercising in the heat. , 1979 .

[47]  Matthew R. Ely,et al.  Effect of ambient temperature on marathon pacing is dependent on runner ability. , 2008, Medicine and science in sports and exercise.

[48]  M. S. Ganio,et al.  Effect of caffeine on internal temperature , 2012, European Journal of Applied Physiology.

[49]  D. O'Leary,et al.  Effect of local warming on forearm reactive hyperaemia. , 1986, Clinical physiology.

[50]  B. Saltin,et al.  Muscle blood flow is not reduced in humans during moderate exercise and heat stress. , 1988, Journal of applied physiology.

[51]  Matthew R. Ely,et al.  Neither cloud cover nor low solar loads are associated with fast marathon performance. , 2007, Medicine and science in sports and exercise.

[52]  N. Secher,et al.  Cerebral carbohydrate cost of physical exertion in humans. , 2004, American journal of physiology. Regulatory, integrative and comparative physiology.

[53]  D. Low,et al.  Effects of graded heat stress on global left ventricular function and twist mechanics at rest and during exercise in healthy humans , 2011, Experimental physiology.

[54]  Lars Nybo,et al.  Hyperthermia and fatigue. , 2008, Journal of applied physiology.

[55]  L. Rowell,et al.  Human Cardiovascular Adjustments to Rapid Changes in Skin Temperature during Exercise , 1969, Circulation research.

[56]  N. B. Strydom,et al.  Circulatory and metabolic reactions to work in heat. , 1962, Journal of applied physiology.

[57]  Lars Nybo,et al.  Cerebral Changes During Exercise in the Heat , 2003, Sports medicine.

[58]  R. Maughan,et al.  Effects of ambient temperature on the capacity to perform prolonged cycle exercise in man. , 1997, Medicine and science in sports and exercise.

[59]  Samuel N Cheuvront,et al.  Mechanisms of aerobic performance impairment with heat stress and dehydration. , 2010, Journal of applied physiology.

[60]  K. Cureton,et al.  Relation of heart rate to percent VO2 peak during submaximal exercise in the heat. , 2003, Journal of applied physiology.

[61]  L. Nybo,et al.  Elevations in core and muscle temperature impairs repeated sprint performance. , 2005, Acta physiologica Scandinavica.

[62]  Gabrielle Todd,et al.  Hyperthermia: a failure of the motor cortex and the muscle , 2005, The Journal of physiology.

[63]  O. Girard,et al.  Markers of muscle damage and performance recovery after exercise in the heat. , 2013, Medicine and science in sports and exercise.

[64]  B. Nielsen,et al.  Metabolic and thermodynamic responses to dehydration‐induced reductions in muscle blood flow in exercising humans , 1999, The Journal of physiology.

[65]  B. Saltin,et al.  Muscle blood flow and muscle metabolism during exercise and heat stress. , 1990, Journal of applied physiology.

[66]  E. Asmussen,et al.  ON THE NERVOUS FACTORS CONTROLLING RESPIRATION AND CIRCULATION DURING EXERCISE. EXPERIMENTS WITH CURARIZATION. , 1965, Acta physiologica Scandinavica.

[67]  R. Meeusen,et al.  Exercise Performance is not Influenced by a 5-HT Reuptake Inhibitor , 2001, International journal of sports medicine.

[68]  J. Halliwill,et al.  Lactate threshold predicting time-trial performance: impact of heat and acclimation. , 2011, Journal of applied physiology.

[69]  B. Saltin,et al.  Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment. , 1993, The Journal of physiology.

[70]  C. R. Taylor,et al.  Heat storage in running antelopes: independence of brain and body temperatures. , 1972, The American journal of physiology.

[71]  R. Meeusen,et al.  No effect of a noradrenergic reuptake inhibitor on performance in trained cyclists. , 2002, Medicine and science in sports and exercise.

[72]  Carrie R. Vernieuw,et al.  Hypohydration and prior heat stress exacerbates decreases in cerebral blood flow velocity during standing. , 2006, Journal of applied physiology.

[73]  N. Secher,et al.  Association between fatigue and failure to preserve cerebral energy turnover during prolonged exercise. , 2003, Acta physiologica Scandinavica.

[74]  J. Xing,et al.  Temperature modulates P2X receptor-mediated cardiovascular responses to muscle afferent activation. , 2006, American journal of physiology. Heart and circulatory physiology.

[75]  T. Nagasaka,et al.  Selective brain cooling in hyperthermia: the mechanisms and medical implications. , 1998, Medical hypotheses.

[76]  S. Shirreffs,et al.  The effect of acute branched-chain amino acid supplementation on prolonged exercise capacity in a warm environment , 2004, European Journal of Applied Physiology.

[77]  J. V. van Lieshout,et al.  Cerebral blood flow and metabolism during exercise: implications for fatigue. , 2008, Journal of applied physiology.

[78]  J. Leiper,et al.  Paroxetine administration to influence human exercise capacity, perceived effort or hormone responses during prolonged exercise in a warm environment , 2004, Experimental physiology.

[79]  S. Cheung.  Hyperthermia and voluntary exhaustion: integrating models and future challenges. , 2007, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[80]  R. Hellon.  Monoamines, pyrogens and cations: their actions on central control of bodytemperature. , 1974, Pharmacological reviews.

[81]  F. A. Bainbridge.  The Physiology of Muscular Exercise , 2010 .

[82]  P. Schrauwen,et al.  A new validated endurance performance test. , 2005 .

[83]  Santiago Lorenzo,et al.  Heat acclimation improves exercise performance. , 2010, Journal of applied physiology.

[84]  R. Meeusen,et al.  Acute dopamine/noradrenaline reuptake inhibition enhances human exercise performance in warm, but not temperate conditions , 2005, The Journal of physiology.

[85]  N. Secher,et al.  A reduced cerebral metabolic ratio in exercise reflects metabolism and not accumulation of lactate within the human brain , 2004, The Journal of physiology.

[86]  M E Raichle,et al.  Coupling between changes in human brain temperature and oxidative metabolism during prolonged visual stimulation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[87]  S. Ogoh,et al.  Differential blood flow responses to CO2 in human internal and external carotid and vertebral arteries , 2012, The Journal of physiology.

[88]  M. Febbraio,et al.  Effect of ambient temperature on human skeletal muscle metabolism during fatiguing submaximal exercise. , 1999, Journal of applied physiology.

[89]  J. Johnson,et al.  Nonthermoregulatory control of human skin blood flow. , 1986, Journal of applied physiology.

[90]  R. Meeusen,et al.  Central fatigue and neurotransmitters, can thermoregulation be manipulated? , 2010, Scandinavian journal of medicine & science in sports.

[91]  T. McLellan,et al.  Thermal regulation in the heat during exercise after caffeine and ephedrine ingestion. , 1999, Aviation, space, and environmental medicine.

[92]  G. Hodges,et al.  The involvement of norepinephrine, neuropeptide Y, and nitric oxide in the cutaneous vasodilator response to local heating in humans. , 2008, Journal of applied physiology.

[93]  James Pearson,et al.  Dehydration reduces left ventricular filling at rest and during exercise independent of twist mechanics. , 2011, Journal of applied physiology.

[94]  C D Deakin,et al.  Effects of changes in packed cell volume on the specific heat capacity of blood: implications for studies measuring heat exchange in extracorporeal circuits. , 2000, British journal of anaesthesia.

[95]  N. Secher,et al.  Inadequate heat release from the human brain during prolonged exercise with hyperthermia , 2002, The Journal of physiology.

[96]  L. Rowell,et al.  Forearm skin and muscle vascular responses to prolonged leg exercise in man. , 1975, Journal of applied physiology.

[97]  F. Pirnay,et al.  Maximal oxygen consumption in a hot environment. , 1970, Journal of applied physiology.

[98]  M. Cabanac,et al.  Enhanced brain protection during passive hyperthermia in humans , 2004, European Journal of Applied Physiology and Occupational Physiology.

[99]  E. Coyle,et al.  Stroke volume during exercise: interaction of environment and hydration. , 2000, American journal of physiology. Heart and circulatory physiology.

[100]  Y. Honda,et al.  Changes in arterial blood pressure elicited by severe passive heating at rest is associated with hyperthermia-induced hyperventilation in humans , 2012, European Journal of Applied Physiology.

[101]  C. Moraes,et al.  Mitochondrial dysfunction induced by heat stress in cultured rat CNS neurons. , 2012, Journal of neurophysiology.

[102]  M. Thompson.  CARDIOVASCULAR DRIFT AND CRITICAL CORE TEMPERATURE: FACTORS LIMITING ENDURANCE PERFORMANCE IN THE HEAT? , 2006 .

[103]  M. Sawka,et al.  Aerobic performance is degraded, despite modest hyperthermia, in hot environments. , 2010, Medicine and science in sports and exercise.

[104]  M. Febbraio.  Alterations in Energy Metabolism During Exercise and Heat Stress , 2001, Sports medicine.

[105]  J. Saboisky,et al.  Exercise Heat Stress does not Reduce Central Activation to non‐exercised Human Skeletal Muscle , 2003, Experimental physiology.

[106]  Samuel N Cheuvront,et al.  Evidence against a 40 degrees C core temperature threshold for fatigue in humans. , 2009, Journal of applied physiology.

[107]  E. Coyle,et al.  Interaction of hyperthermia and heart rate on stroke volume during prolonged exercise. , 2010, Journal of applied physiology.

[108]  E R Nadel,et al.  Interaction of local and reflex thermal effects in control of forearm blood flow. , 1985, Journal of applied physiology.

[109]  A. P. Gagge,et al.  THERMAL INTERCHANGES BETWEEN THE HUMAN BODY AND ITS ATMOSPHERIC ENVIRONMENT , 1937 .

[110]  G. Grudic,et al.  Use of advanced machine-learning techniques for noninvasive monitoring of hemorrhage. , 2011, The Journal of trauma.

[111]  Albertas Skurvydas,et al.  Heat acclimation does not reduce the impact of hyperthermia on central fatigue , 2010, European Journal of Applied Physiology.

[112]  K. Cureton,et al.  Cardiovascular Drift During Heat Stress: Implications for Exercise Prescription , 2012, Exercise and sport sciences reviews.

[113]  M. Febbraio,et al.  Effect of heat stress on muscle energy metabolism during exercise. , 1994, Journal of applied physiology.

[114]  D R Bassett,et al.  Limiting factors for maximum oxygen uptake and determinants of endurance performance. , 2000, Medicine and science in sports and exercise.

[115]  Ross Tucker,et al.  Impaired exercise performance in the heat is associated with an anticipatory reduction in skeletal muscle recruitment , 2004, Pflügers Archiv.

[116]  K. Cureton,et al.  Effect of ambient temperature on cardiovascular drift and maximal oxygen uptake. , 2008, Medicine and science in sports and exercise.

[117]  Shawnda Morrison,et al.  Passive hyperthermia reduces voluntary activation and isometric force production , 2004, European Journal of Applied Physiology.

[118]  P. A. Mason,et al.  Exercise in the heat is limited by a critical internal temperature. , 2000, Journal of applied physiology.

[119]  R. D. Myers,et al.  Effects on temperature of monoamines injected into the cerebral ventricles of anaesthetized dogs , 1966, The Journal of physiology.

[120]  Peter G. Martin,et al.  Reduced voluntary activation of human skeletal muscle during shortening and lengthening contractions in whole body hyperthermia , 2005, Experimental physiology.

[121]  Lisa R Leon,et al.  Integrated physiological mechanisms of exercise performance, adaptation, and maladaptation to heat stress. , 2011, Comprehensive Physiology.

[122]  Ross Tucker,et al.  The rate of heat storage mediates an anticipatory reduction in exercise intensity during cycling at a fixed rating of perceived exertion , 2006, The Journal of physiology.

[123]  J. Dempsey,et al.  Implications of group III and IV muscle afferents for high‐intensity endurance exercise performance in humans , 2011, The Journal of physiology.

[124]  B. Jacobs,et al.  Structure and function of the brain serotonin system. , 1992, Physiological reviews.

[125]  C. Caillaud,et al.  Central and peripheral fatigue during passive and exercise-induced hyperthermia. , 2011, Medicine and science in sports and exercise.

[126]  Samuel N. Cheuvront,et al.  High skin temperature and hypohydration impair aerobic performance , 2012, Experimental physiology.

[127]  T. Graham.  Caffeine and Exercise , 2001, Sports medicine.

[128]  C. Crandall,et al.  Cardiovascular function in the heat‐stressed human , 2010, Acta physiologica.

[129]  J A Dempsey,et al.  Effects of metabolic hyperthermia on performance during heavy prolonged exercise. , 1974, Journal of applied physiology.

[130]  R. Fitts,et al.  Cellular, molecular, and metabolic basis of muscle fatigue , 1996 .

[131]  N. Lassen,et al.  Middle cerebral artery blood velocity and cerebral blood flow and O2 uptake during dynamic exercise. , 1993, Journal of applied physiology.

[132]  P. Ainslie,et al.  Human cardiorespiratory and cerebrovascular function during severe passive hyperthermia: effects of mild hypohydration. , 2008, Journal of applied physiology.

[133]  Albert Gjedde,et al.  Cerebral Metabolic Response to Low Blood Flow: Possible Role of Cytochrome Oxidase Inhibition , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[134]  C. Dejong,et al.  Physiology and pathophysiology of splanchnic hypoperfusion and intestinal injury during exercise: strategies for evaluation and prevention. , 2012, American journal of physiology. Gastrointestinal and liver physiology.

[135]  G. Lamb,et al.  Point:Counterpoint: Lactic acid accumulation is an advantage/disadvantage during muscle activity , 2006 .

[136]  J. Davis,et al.  Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue. , 1993, Journal of applied physiology.

[137]  E. Stöhr,et al.  Left ventricular mechanical limitations to stroke volume in healthy humans during incremental exercise. , 2011, American journal of physiology. Heart and circulatory physiology.

[138]  L. Nybo,et al.  Heat induced fatigue and changes of the EEG is not related to reduced perfusion of the brain during prolonged exercise in humans , 2004 .

[139]  C. Sunderland,et al.  The Effect of Ambient Temperature on the Reliability of a Preloaded Treadmill Time-Trial , 2008, International journal of sports medicine.

[140]  L. Nybo,et al.  Hyperthermia and central fatigue during prolonged exercise in humans. , 2001, Journal of applied physiology.

[141]  W. Willis,et al.  Mitochondrial function during heavy exercise. , 1994, Medicine and science in sports and exercise.

[142]  E. Coyle,et al.  Dehydration markedly impairs cardiovascular function in hyperthermic endurance athletes during exercise. , 1997, Journal of applied physiology.

[143]  L. Romer,et al.  Severity of arterial hypoxaemia affects the relative contributions of peripheral muscle fatigue to exercise performance in healthy humans , 2007, The Journal of physiology.

[144]  M. Sawka,et al.  Branched-chain amino acid supplementation and human performance when hypohydrated in the heat. , 2004, Journal of applied physiology.

[145]  J. Oksa,et al.  Temperature and neuromuscular function , 2010, Scandinavian journal of medicine & science in sports.

[146]  T M McLellan,et al.  Heat acclimation, aerobic fitness, and hydration effects on tolerance during uncompensable heat stress. , 1998, Journal of applied physiology.

[147]  Ronald G. Knowlton,et al.  Thermal and circulatory responses to repeated bouts of prolonged running. , 1979, Medicine and science in sports.

[148]  R. Meeusen,et al.  Performance and thermoregulatory effects of chronic bupropion administration in the heat , 2009, European Journal of Applied Physiology.

[149]  V. Quaresima,et al.  Influence of heat stress and exercise intensity on vastus lateralis muscle and prefrontal cortex oxygenation , 2012, European Journal of Applied Physiology.

[150]  K B Pandolf,et al.  Hypohydration and exercise: effects of heat acclimation, gender, and environment. , 1983, Journal of applied physiology: respiratory, environmental and exercise physiology.

[151]  José González-Alonso,et al.  Limitations to systemic and locomotor limb muscle oxygen delivery and uptake during maximal exercise in humans , 2005, The Journal of physiology.

[152]  Lars Nybo,et al.  Effects of hyperthermia on cerebral blood flow and metabolism during prolonged exercise in humans. , 2002, Journal of applied physiology.

[153]  M. Amann,et al.  On the contribution of group III and IV muscle afferents to the circulatory response to rhythmic exercise in humans , 2011, The Journal of physiology.

[154]  M. Sawka,et al.  No effect of nutritional adenosine receptor antagonists on exercise performance in the heat. , 2009, American journal of physiology. Regulatory, integrative and comparative physiology.

[155]  L. Rowell,et al.  Altered control of skin blood flow during exercise at high internal temperatures. , 1977, Journal of applied physiology: respiratory, environmental and exercise physiology.

[156]  S. Ogoh,et al.  Interaction between the ventilatory and cerebrovascular responses to hypo‐ and hypercapnia at rest and during exercise , 2008, The Journal of physiology.

[157]  R. Gaudio,et al.  Heat-induced hyperventilation. , 1968, Journal of applied physiology.

[158]  J A Faulkner,et al.  Temperature, skeletal muscle mitochondrial functions, and oxygen debt. , 1971, The American journal of physiology.

[159]  C. Kleeman,et al.  MECHANISMS OF ACCLIMATIZATION TO HEAT IN MAN , 1955, Medicine.

[160]  N. Secher,et al.  Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[161]  F. Jensen,et al.  Influence of body temperature on the development of fatigue during prolonged exercise in the heat. , 1999, Journal of applied physiology.

[162]  M A Gleser,et al.  Effects of hypoxia and physical training on hemodynamic adjustments to one-legged exercise. , 1973, Journal of applied physiology.

[163]  M. Sawka,et al.  Control of thermoregulatory sweating is altered by hydration level and exercise intensity. , 1995, Journal of applied physiology.

[164]  P. G. Iatridis,et al.  Human Circulation: Regulation During Physical Stress , 1987 .

[165]  R. F. Goldman,et al.  Predicting sweat loss response to exercise, environment and clothing , 2004, European Journal of Applied Physiology and Occupational Physiology.

[166]  E. Coyle,et al.  Influence of graded dehydration on hyperthermia and cardiovascular drift during exercise. , 1992, Journal of applied physiology.

[167]  R. G. Knowlton,et al.  Effect of prolonged running on physiological responses to subsequent exercise. , 1979, Journal of human ergology.

[168]  J. Dempsey,et al.  Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans. , 2010, Journal of applied physiology.

[169]  D. Costill,et al.  Leg muscle metabolism during exercise in the heat and cold , 1975, European Journal of Applied Physiology and Occupational Physiology.

[170]  N. Lassen,et al.  Average Blood Flow and Oxygen Uptake in the Human Brain during Resting Wakefulness: A Critical Appraisal of the Kety—Schmidt Technique , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[171]  Toby Mündel,et al.  The independent roles of temperature and thermal perception in the control of human thermoregulatory behavior , 2011, Physiology & Behavior.

[172]  S. Ogoh,et al.  Onset responses of ventilation and cerebral blood flow to hypercapnia in humans: rest and exercise. , 2009, Journal of applied physiology.

[173]  Albert Gjedde,et al.  Capillary-Oxygenation-Level-Dependent Near-Infrared Spectrometry in Frontal Lobe of Humans , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[174]  L. Nybo,et al.  Perceived exertion is associated with an altered brain activity during exercise with progressive hyperthermia. , 2001, Journal of applied physiology.

[175]  M. White.  Components and mechanisms of thermal hyperpnea. , 2006, Journal of applied physiology.

[176]  C T Davies,et al.  Influence of skin temperature on sweating and aerobic performance during severe work. , 1979, Journal of applied physiology: respiratory, environmental and exercise physiology.

[177]  Effect of body temperature on the ventilatory response to exercise. , 1970, Respiration physiology.

[178]  O B Paulson,et al.  Cerebral autoregulation. , 1984, Stroke.

[179]  S. Robinson,et al.  TEMPERATURE REGULATION IN EXERCISE. , 1963, Pediatrics.

[180]  R. Maughan,et al.  Serotonin2C receptor blockade and thermoregulation during exercise in the heat. , 2005, Medicine and science in sports and exercise.

[181]  M. Febbraio,et al.  Limits to Exercise Performance in the Heat , 1998, International journal of sports medicine.

[182]  N. Secher,et al.  Effect of carbohydrate ingestion on brain exchange of amino acids during sustained exercise in human subjects. , 2005, Acta physiologica Scandinavica.

[183]  R. Meeusen,et al.  Caffeine, dopamine and thermoregulation , 2012, European Journal of Applied Physiology.

[184]  M. Amann.  Central and peripheral fatigue: interaction during cycling exercise in humans. , 2011, Medicine and science in sports and exercise.

[185]  M. Pourcyrous,et al.  Hyperthermia increases cerebral metabolic rate and blood flow in neonatal pigs. , 1988, The American journal of physiology.

[186]  J. Dempsey,et al.  Effects of respiratory muscle work on cardiac output and its distribution during maximal exercise. , 1998, Journal of applied physiology.

[187]  W. C. Adams,et al.  Effects of airflow and work load on cardiovascular drift and skin blood flow. , 1984, Journal of applied physiology: respiratory, environmental and exercise physiology.

[188]  N. Secher,et al.  Sympathetic influence on cerebral blood flow and metabolism during exercise in humans , 2011, Progress in Neurobiology.

[189]  P. Seth,et al.  Exertional heat stroke in a marathon runner with extensive healed deep burns: a case report , 2011, International journal of emergency medicine.

[190]  Toby Mündel,et al.  Skin temperature as a thermal controller of exercise intensity , 2010, European Journal of Applied Physiology.

[191]  M. Febbraio,et al.  Influence of elevated muscle temperature on metabolism during intense, dynamic exercise. , 1996, The American journal of physiology.

[192]  C. Wenger,et al.  Control of forearm venous volume during exercise and body heating. , 1980, Journal of applied physiology: respiratory, environmental and exercise physiology.

[193]  J. Volek,et al.  Effect of ambient temperature on caffeine ergogenicity during endurance exercise , 2011, European Journal of Applied Physiology.

[194]  M. Febbraio,et al.  Muscle metabolism during exercise and heat stress in trained men: effect of acclimation. , 1994, Journal of applied physiology.

[195]  R A Bruce,et al.  Reductions in cardiac output, central blood volume, and stroke volume with thermal stress in normal men during exercise. , 1966, The Journal of clinical investigation.

[196]  I Vuori,et al.  Man in the sauna. , 1986, Annals of clinical research.

[197]  W. Feldberg.  The role of monoamines in the hypothalamus for temperature regulation. , 1969, Journal of neuro-visceral relations.

[198]  N. Secher,et al.  Neurohumoral responses during prolonged exercise in humans. , 2003, Journal of applied physiology.

[199]  Y. Michotte,et al.  Influence of brain catecholamines on the development of fatigue in exercising rats in the heat , 2008, The Journal of physiology.

[200]  N. Secher,et al.  Are the arms and legs in competition for cardiac output? , 2006, Medicine and science in sports and exercise.

[201]  Nicolas Caesar Petersen,et al.  Reduced muscle activation during exercise related to brain oxygenation and metabolism in humans , 2010, The Journal of physiology.

[202]  Gagge Ap,et al.  Physiological bases of warm discomfort for sedentary man. , 1973 .

[203]  M. Febbraio,et al.  Effect of Temperature on Muscle Metabolism During Submaximal Exercise in Humans , 1999, Experimental physiology.

[204]  Stephen S. Cheung,et al.  Lowering of skin temperature decreases isokinetic maximal force production independent of core temperature , 2004, European Journal of Applied Physiology.

[205]  M. Febbraio,et al.  Blunting the rise in body temperature reduces muscle glycogenolysis during exercise in humans , 1996, Experimental physiology.

[206]  R. Meeusen,et al.  Hormonal responses during prolonged exercise are influenced by a selective DA/NA reuptake inhibitor , 2004, British Journal of Sports Medicine.

[207]  C. R. Taylor,et al.  Temperature regulation and heat balance in running cheetahs: a strategy for sprinters? , 1973, The American journal of physiology.

[208]  Albert Gjedde,et al.  Cerebral Blood Flow Change in Arterial Hypoxemia Is Consistent with Negligible Oxygen Tension in Brain Mitochondria , 2002, NeuroImage.

[209]  M. Haykowsky,et al.  Reductions in cerebral blood flow during passive heat stress in humans: partitioning the mechanisms , 2011, The Journal of physiology.

[210]  N. Secher,et al.  Middle cerebral artery blood velocity depends on cardiac output during exercise with a large muscle mass. , 1998, Acta physiologica Scandinavica.

[211]  M. Febbraio,et al.  Effect of epinephrine on muscle glycogenolysis during exercise in trained men. , 1998, Journal of applied physiology.

[212]  F. Brouns,et al.  Effect of dehydration on gastrointestinal function at rest and during exercise in humans , 2000, European Journal of Applied Physiology.

[213]  N. Secher,et al.  The intent to exercise influences the cerebral O2/carbohydrate uptake ratio in humans , 2002, The Journal of physiology.

[214]  J. Bangsbo,et al.  Counterpoint: lactic acid accumulation is a disadvantage during muscle activity. , 2006, Journal of applied physiology.

[215]  L. Rowell,et al.  Human metabolic responses to hyperthermia during mild to maximal exercise. , 1969, Journal of applied physiology.

[216]  R. Fitts.  Cellular mechanisms of muscle fatigue. , 1994, Physiological reviews.

[217]  O. Girard,et al.  Neuromuscular failure is unlikely to explain the early exercise cessation in hot ambient conditions. , 2012, Psychophysiology.

[218]  Romain Meeusen,et al.  Acute norepinephrine reuptake inhibition decreases performance in normal and high ambient temperature. , 2008, Journal of applied physiology.

[219]  J. Johnson,et al.  Graded cutaneous vascular responses to dynamic leg exercise. , 1988, Journal of applied physiology.

[220]  J. Johnson,et al.  Exercise in a hot environment: the skin circulation , 2010, Scandinavian journal of medicine & science in sports.

[221]  W C Adams,et al.  INFLUENCE OF EXERCISE MODE AND SELECTED AMBIENT CONDITIONS ON SKIN TEMPERATURE * , 1977, Annals of the New York Academy of Sciences.

[222]  J. Cloudsley-Thompson,et al.  Life in Deserts , 1965 .

[223]  An extrapolation procedure for determination of oxygen debt repayment , 1980, European Journal of Applied Physiology and Occupational Physiology.

[224]  G. Sleivert,et al.  Multiple Triggers for Hyperthermic Fatigue and Exhaustion , 2004, Exercise and sport sciences reviews.

[225]  Shigehiko Ogoh,et al.  Cerebral blood flow during exercise: mechanisms of regulation. , 2009, Journal of applied physiology.

[226]  K. Brück,et al.  Body temperature related factors diminishing the drive to exercise. , 1987, Canadian journal of physiology and pharmacology.

[227]  Alan St Clair Gibson,et al.  Evidence for neuromuscular fatigue during high-intensity cycling in warm, humid conditions , 2001, European Journal of Applied Physiology.

[228]  M. S. Malhotra,et al.  Alterations in aerobic-anaerobic proportions of metabolism during work in heat , 2004, European Journal of Applied Physiology and Occupational Physiology.

[229]  Jean-François Perrier,et al.  Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation , 2013, Proceedings of the National Academy of Sciences.

[230]  G. Ferretti,et al.  Superficial shell insulation in resting and exercising men in cold water. , 1982, Journal of applied physiology: respiratory, environmental and exercise physiology.

[231]  N. Secher,et al.  Cerebral Metabolism is Influenced by Muscle Ischaemia During Exercise in Humans , 2003, Experimental physiology.

[232]  E Kamon,et al.  Physiological and biophysical limits to work in the heat for clothed men and women. , 1978, Journal of applied physiology: respiratory, environmental and exercise physiology.

[233]  C. Nicol,et al.  Combined effect of heat stress, dehydration and exercise on neuromuscular function in humans , 2001, European Journal of Applied Physiology.

[234]  L. Nybo.  Brain temperature and exercise performance , 2012, Experimental physiology.

[235]  L. Nybo,et al.  Cycling in the heat: performance perspectives and cerebral challenges , 2010, Scandinavian journal of medicine & science in sports.

[236]  W. L. Kenney,et al.  Control of skin blood flow during exercise. , 1992, Medicine and science in sports and exercise.

[237]  R. Meeusen,et al.  Endurance Performance in Humans: The Effect of a Dopamine Precursor or a Specific Serotonin (5-HT2A/2C) Antagonist , 1997, International journal of sports medicine.

[238]  B. Saltin,et al.  Body temperatures and sweating during exhaustive exercise. , 1972, Journal of applied physiology.

[239]  S Racinais,et al.  Hyperthermia impairs short-term memory and peripheral motor drive transmission , 2008, The Journal of physiology.

[240]  K. Cureton,et al.  Cardiovascular drift is related to reduced maximal oxygen uptake during heat stress. , 2005, Medicine and science in sports and exercise.

[241]  K. Cureton,et al.  Fluid ingestion attenuates the decline in VO2peak associated with cardiovascular drift. , 2006, Medicine and science in sports and exercise.

[242]  M. B. Ducharme,et al.  A three-compartment thermometry model for the improved estimation of changes in body heat content. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[243]  W. Roberts.  Exercise-Associated Collapse Care Matrix in the Marathon , 2007, Sports medicine.

[244]  E R Nadel,et al.  Circulatory regulation during exercise in different ambient temperatures. , 1979, Journal of applied physiology: respiratory, environmental and exercise physiology.

[245]  S. M. Horvath,et al.  RAPID ACCLIMATIZATION TO WORK IN HOT CLIMATES , 1943 .

[246]  K. Klausen,et al.  Central and regional circulatory effects of adding arm exercise to leg exercise. , 1977, Acta physiologica Scandinavica.

[247]  T. Orszulak,et al.  Nitrous oxide method of measuring cerebral blood flow during hypothermic cardiopulmonary bypass. , 1997, The Annals of thoracic surgery.

[248]  S. Mortensen,et al.  Thigh oxygen uptake at the onset of intense exercise is not affected by a reduction in oxygen delivery caused by hypoxia. , 2012, American journal of physiology. Regulatory, integrative and comparative physiology.

[249]  C. Caillaud,et al.  Cardiovascular strain impairs prolonged self‐paced exercise in the heat , 2011, Experimental physiology.

[250]  Kojiro Ide,et al.  CEREBRAL BLOOD FLOW AND METABOLISM DURING EXERCISE , 1999 .

[251]  Nisha Charkoudian,et al.  Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans. , 2010, Journal of applied physiology.

[252]  J. Weil,et al.  Influence of exercise hyperthermia on exercise breathing pattern. , 1979, Journal of applied physiology: respiratory, environmental and exercise physiology.

[253]  R. Meeusen,et al.  The effects of acute dopamine reuptake inhibition on performance. , 2008, Medicine and science in sports and exercise.

[254]  José González-Alonso,et al.  Reductions in Systemic and Skeletal Muscle Blood Flow and Oxygen Delivery Limit Maximal Aerobic Capacity in Humans , 2003, Circulation.

[255]  B. Nielsen,et al.  Muscle blood flow is reduced with dehydration during prolonged exercise in humans , 1998, The Journal of physiology.

[256]  M. Sawka,et al.  Influence of hydration level and body fluids on exercise performance in the heat. , 1984, JAMA.

[257]  Santiago Lorenzo,et al.  Heat acclimation improves cutaneous vascular function and sweating in trained cyclists. , 2010, Journal of applied physiology.

[258]  M. Febbraio.  Does Muscle Function and Metabolism Affect Exercise Performance in the Heat? , 2000, Exercise and sport sciences reviews.

[259]  M. Raichle,et al.  Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[260]  N. Secher,et al.  Both acute and prolonged administration of EPO reduce cerebral and systemic vascular conductance in humans , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[261]  Markus Amann,et al.  Arterial oxygenation influences central motor output and exercise performance via effects on peripheral locomotor muscle fatigue in humans , 2006, The Journal of physiology.

[262]  M. Caputa,et al.  Effects of brain and trunk temperatures on exercise performance in goats , 2004, Pflügers Archiv.

[263]  E. Nadel.  Control of sweating rate while exercising in the heat. , 1979, Medicine and science in sports.

[264]  E. Adolph.  THE EFFECTS OF EXPOSURE TO HIGH TEMPERATURES UPON THE CIRCULATION IN MAN , 1924 .

[265]  D. Ingvar,et al.  Brain regions involved in voluntary movements as revealed by radioisotopic mapping of CBF or CMR-glucose changes. , 1990, Revue neurologique.

[266]  L. Rowell,et al.  Human cardiovascular adjustments to exercise and thermal stress. , 1974, Physiological reviews.

[267]  N. Lassen,et al.  Cerebral blood flow and oxygen consumption in man. , 1959, Physiological reviews.

[268]  S. Bailey,et al.  Branched-chain amino acids prolong exercise during heat stress in men and women. , 1998, Medicine and science in sports and exercise.

[269]  K B Pandolf,et al.  Thermoregulatory and blood responses during exercise at graded hypohydration levels. , 1985, Journal of applied physiology.

[270]  M. Kaufman,et al.  Reflex Autonomic Responses Evoked by Group III and IV Muscle Afferents , 2010 .

[271]  Michael N. Sawka,et al.  Thermoregulatory Responses to Acute Exercise‐Heat Stress and Heat Acclimation , 2011 .

[272]  K B Pandolf,et al.  Physiological responses of men and women to humid and dry heat. , 1980, Journal of applied physiology: respiratory, environmental and exercise physiology.

[273]  M. Cabanac,et al.  Natural selective cooling of the human brain: evidence of its occurrence and magnitude. , 1979, The Journal of physiology.

[274]  Heather E. Wright,et al.  Mild endotoxemia, NF-kappaB translocation, and cytokine increase during exertional heat stress in trained and untrained individuals. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[275]  D. Low,et al.  Effect of elevated local temperature on cutaneous vasoconstrictor responsiveness in humans. , 2009, Journal of applied physiology.

[276]  R J Roman,et al.  Functional hyperemia in the brain: hypothesis for astrocyte-derived vasodilator metabolites. , 1998, Stroke.

[277]  R. Meeusen,et al.  No Effect of a Selective Serotonergic/Noradrenergic Reuptake Inhibitor on Endurance Performance , 2002 .

[278]  L. Rowell,et al.  Interactions between local and reflex influences on human forearm skin blood flow. , 1976, Journal of applied physiology.

[279]  M. Sawka,et al.  Skeletal muscle metabolism during exercise is influenced by heat acclimation. , 1985, Journal of applied physiology.

[280]  M. Cabanac,et al.  Tympanic temperatures during hemiface cooling , 2004, European Journal of Applied Physiology and Occupational Physiology.

[281]  P. Blumberg,et al.  High-affinity partial agonists of the vanilloid receptor. , 2003, Molecular pharmacology.

[282]  B. Nielsen,et al.  Body temperature during work at different environmental temperatures. , 1962, Acta physiologica Scandinavica.

[283]  Lars Nybo,et al.  Counterpoint: humans do not demonstrate selective brain cooling during hyperthermia. , 2011, Journal of applied physiology.

[284]  P. Clifford,et al.  Elevated temperature decreases sensitivity of P2X purinergic receptors in skeletal muscle arteries. , 2005, Journal of applied physiology.

[285]  Shigehiko Ogoh,et al.  The distribution of blood flow in the carotid and vertebral arteries during dynamic exercise in humans , 2011, The Journal of physiology.

[286]  Matthew R. Ely,et al.  Impact of weather on marathon-running performance. , 2007, Medicine and science in sports and exercise.

[287]  Lars Nybo,et al.  Inadequate Cerebral Oxygen Delivery and Central Fatigue during Strenuous Exercise , 2007, Exercise and sport sciences reviews.

[288]  F. S. Lee,et al.  THE ACTION OF TEMPERATURE AND HUMIDITY ON THE WORKING POWER OF MUSCLES AND ON THE SUGAR OF THE BLOOD , 1916 .

[289]  N. Secher,et al.  Cerebral oxygenation is reduced during hyperthermic exercise in humans , 2010, Acta physiologica.

[290]  Melissa M. Thomas,et al.  Voluntary muscle activation is impaired by core temperature rather than local muscle temperature. , 2006, Journal of applied physiology.

[291]  G. Brengelmann,et al.  Independence of brain and tympanic temperatures in an unanesthetized human. , 1988, Journal of applied physiology.

[292]  G. Atkinson,et al.  Effects of environmental heat stress (35 degrees C) with simulated air movement on the thermoregulatory responses during a 4-km cycling time trial. , 2009, International journal of sports medicine.

[293]  L. Rowell,et al.  Venomotor responses to local and remote thermal stimuli to skin in exercising man. , 1971, Journal of applied physiology.

[294]  R. G. Knowlton,et al.  Body temperature, respiration, and acid-base equilibrium during prolonged running. , 1980, Medicine and science in sports and exercise.

[295]  Loring B. Rowell,et al.  Cardiovascular Adjustments to Thermal Stress , 2011 .

[296]  L. Nybo,et al.  Effects of marked hyperthermia with and without dehydration on VO(2) kinetics during intense exercise. , 2001, Journal of applied physiology.

[297]  J A Stolwijk,et al.  Development and application of a mathematical model of human thermoregulation. , 1973, Archives des sciences physiologiques.

[298]  C T Davies,et al.  Temperature regulation during severe exercise with some observations on effects of skin wetting. , 1976, Journal of applied physiology.

[299]  L. W. Eichna,et al.  Performance in relation to Environmental Temperature. Reactions of Normal Young Men to Simulated Desert Environment. , 1943 .

[300]  E. Coyle,et al.  Stroke volume decline during prolonged exercise is influenced by the increase in heart rate. , 1999, Journal of applied physiology.

[301]  L. Hartley.  CENTRAL CIRCULATORY FUNCTION DURING PROLONGED EXERCISE , 1977, Annals of the New York Academy of Sciences.

[302]  K B Pandolf,et al.  Physiological responses and warm discomfort during heat strain. , 1973, Archives des sciences physiologiques.

[303]  M. Sawka,et al.  Efficacy of intermittent, regional microclimate cooling. , 2003, Journal of applied physiology.

[304]  M. Sawka,et al.  Gastric emptying during exercise: effects of heat stress and hypohydration , 2004, European Journal of Applied Physiology and Occupational Physiology.

[305]  N. Secher,et al.  Cerebral perturbations provoked by prolonged exercise , 2004, Progress in Neurobiology.

[306]  L. Rowell,et al.  Splanchnic blood flow and metabolism in heat-stressed man. , 1968, Journal of applied physiology.

[307]  Jane A. Kent-Braun,et al.  Central and peripheral contributions to muscle fatigue in humans during sustained maximal effort , 1999, European Journal of Applied Physiology and Occupational Physiology.

[308]  S. Kety,et al.  THE EFFECTS OF ALTERED ARTERIAL TENSIONS OF CARBON DIOXIDE AND OXYGEN ON CEREBRAL BLOOD FLOW AND CEREBRAL OXYGEN CONSUMPTION OF NORMAL YOUNG MEN. , 1948, The Journal of clinical investigation.

[309]  S. Fortney,et al.  Exercise, Performance and Temperature Control: Temperature Regulation during Exercise and Implications for Sports Performance and Training , 1985, Sports medicine.

[310]  R. Meeusen,et al.  Time trial performance in normal and high ambient temperature: is there a role for 5-HT? , 2009, European Journal of Applied Physiology.

[311]  M. Polkey,et al.  HIGHLIGHTED TOPIC Fatigue Mechanisms Determining Exercise Performance Exercise-induced respiratory muscle fatigue : implications for performance , 2008 .