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

For more than a century, applied physiologists have investigated the complex nature of fatigue and its implications for exercise performance. Long before the term “systems biology ” entered the biomedical lexicon, physiologists appreciated the need to understand fatigue at various levels of integration and across multiple organ systems, a point eloquently highlighted in a recent editorial (13) In his early 20th century text Physiology of Muscular Exercise, Bainbridge noted that It has long been recognized that the main seat of fatigue after muscular exercise is in the central nervous system. Mosso long ago stated that “nervous fatigue is the preponderating phenomenon and muscular fatigue is also at the bottom of the nervous system”. There appear, however, to be two types of fatigue, one arising entirely within the central nervous system, the other in which fatigue of the muscles themselves is superadded to that of the nervous system. In the intervening years, physiologists have employed a vast array of experimental procedures and protocols to understand the fundamental mechanisms of fatigue and potential limitations to exercise performance. The key sites in neuromuscular activation that have been central to understanding fatigue mechanisms are summarized in the elegant figure from Brenda Bigland-Ritchie (2; Figure 1). Of course, one cannot forget the crucial role of those systems responsible for oxygen delivery to vital organs an