Resolving fatigue mechanisms determining exercise performance: integrative physiology at its finest!

THE ORIGINS OF FATIGUE during exercise have intrigued scientists for well over a century and have proven to be a rich, but complex, area of investigation. Understanding fatigue and the consequent exercise limitation is not just an intellectual curiosity, but has far-reaching implications that traverse the broad spectrum of our communities. In chronically diseased or acutely ill patients, fatigue and exercise limitation can profoundly restrict daily activities and thus impair quality of life. In healthy individuals, fatigue can restrict performance in diverse occupational duties such as firefighting, the military, construction, and laboring, as well as limiting participation in recreational activities and sports. Most readers would link fatigue and exercise limitation to the grand stage of national and international sporting competition, adversely affecting elite athletic performance, with implications for medals, glory, and the sports industry. Fatigue and exercise limitation also impact on the young through to the aged, thus affecting all persons at multiple stages of our lives. It is therefore not surprising that investigation into the underlying causes of fatigue and exercise limitation has attracted special attention of scientists from clinical, basic, and applied science specializations. Early investigations on fatigue mechanisms focused on metabolic fuel availability or accumulation of “waste products.” Prolonged exercise was thus considered to be limited by reduced muscle glycogen availability and/or hypoglycemia. Fatigue during intense exercise was typically portrayed as a consequence of phosphocreatine depletion and lactic acidosis. With evidence that action potential transmission across the neuromuscular junction was not impaired, fatigue was ascribed as largely occurring within the active muscles. Hence, the term “muscle fatigue” is now firmly entrenched within the general scientific vocabulary. This series of nine mini-reviews, all by experts in their respective fields, first demonstrate the tremendous recent advances in understanding the complex phenomenon known as fatigue. Second, these reviews clearly indicate that “fatigue” rather than “muscle fatigue” is much more appropriate for voluntary exercise, since fatigue limiting exercise involves mechanisms within the contracting peripheral or locomotive muscles and encompasses the respiratory muscles, muscle perfusion, other inactive skeletal muscle and organs regulating fuel, metabolite, or ionic homeostasis and, most importantly, within the central nervous system itself. Furthermore, fatigue can be understood not as a failure of regulation, “the bad guy,” but as a highly regulated strategy conserving cellular integrity, function and, indeed, survival. These stateof-the-art reviews reinforce the concept that understanding fatigue is integrative physiology at its finest. Each review integrates existing knowledge and importantly, includes a focus on new directions for the field, ensuring each is obligatory reading for all interested in fatigue and exercise. The first six reviews focus on the mechanisms and importance of what have been labeled as peripheral muscle fatigue and central fatigue. The first two reviews have a cellular or “myo-site” focus of fatigue. Drs. Allen, Westerblad, and Lamb (1) review evidence for a failure of sarcoplasmic reticulum Ca release as a major causative factor in fatigue in muscle. The review draws heavily on elegant single-fiber experiments, which have used intact or mechanically skinned fibers and which clearly link insufficient Ca release to a reduction in force. They focus on the role of inorganic phosphate sequestration of Ca within the sarcoplasmic reticulum, rather than changes in action potential amplitude, as a primary factor responsible for the fatigue-induced decline in cytosolic Ca concentration and force. Drs. McKenna, Bangsbo, and Renaud (5) examine exercise effects on muscle ionic homeostasis and their essential role in fatigue, integrating findings from human exercise studies and in vitro studies of ionic effects on muscle function. Marked intracellular-interstitial perturbations in K and Na concentrations and impaired Na -K pump activity are presented as causative factors in fatigue, via cellular membrane depolarization and inexcitability; whereas Cl conductance changes oppose these effects. Hence regulation of each of these ions, and of the Na -K pump, must be considered in understanding fatigue. The review by Drs. Secher, Seifert, and van Lieshout (8) goes to the top end, investigating the role of cerebral metabolism in fatigue. They show that exercise increases cerebral perfusion when perfusion is analyzed appropriately. Furthermore, arteriovenous studies across the brain indicate that glucose and lactate uptake are increased with exercise, but that cerebral oxygenation and cerebral metabolic ratio [O2 uptake/(glucose and 1⁄2lactate uptake)] are in fact decreased. As a consequence, oxygenation of the brain is challenged during exercise and may be a vital factor in what has been defined as central fatigue. Continuing the focus on the central nervous system, Drs. Taylor and Gandevia (9) review the supraspinal and spinal mechanisms contributing to fatigue during both maximal and submaximal voluntary contractions. They summarize results Address for reprint requests and other correspondence: M. J. McKenna, School of Human Movement, Recreation and Performance, Centre for Ageing, Rehabilitation, Exercise and Sport, Victoria Univ., PO Box 14428, Melbourne, 8001 Victoria, Australia (e-mail: [email protected]). J Appl Physiol 104: 286–287, 2008; doi:10.1152/japplphysiol.01139.2007.