On an operational level, it has proven convenient to classify fatigue into different types, with these different forms of fatigue representing different biophysical mechanisms of fatigue development and with each type having different physiological characteristics (3). Several such classification schemes are possible, but a widely employed convention is to classify fatigue as either (1) central fatigue, (2) peripheral high-frequency fatigue, or (3) peripheral low-frequency fatigue. We review each of these types of fatigue in turn.
"Central fatigue" refers to a condition in which muscle force generation during sustained or repetitive contraction becomes limited owing to a decline in motoneuronal output. Central fatigue is judged to be present when a truly maximum voluntary effort produces less force than one generated by direct electrical stimulation.
A number of experiments have suggested that a form of central diaphragmatic "fatigue" may develop during respiratory loading (3-11). A study by Bellemare and Bigland-Ritchie (5) provided evidence that such a phenomenon can occur during the application of external resistive loads to normal human subjects. This study measured transdiaphragmatic pressure generation over time before, during, and after in-spiratory resistive loading, and employed superimposed electrical phrenic stimulation at various times during the experiment to determine whether subjects were capable of fully "activating" the diaphragm. This approach makes use of the observation that it is possible for well-motivated individuals to fully activate rested skeletal muscle during volitional contractions when making a maximal effort (i.e., superimposed elec trical stimulation of muscle during such maximal maneuvers does not result in an increase in force generation above that achieved volitionally) (3) (see Twitch Occlusion in Section 2 of this Statement). Although achievement of such "maximal" activation is difficult, and usually cannot be achieved with every attempted contraction even in motivated individuals, one study found that all research subjects could achieve at least one maximal contraction of a limb muscle (6). As a result, evidence that maximal activation of a given muscle during a maximal volitional effort can never be achieved after a period of exercise (i.e., the superimposed electrical stimulation can always evoke an increase in force generation) constitutes evidence of "central" fatigue.
At the start of the study by Bellemare and Bigland-Ritchie, no superimposed force could be detected during the imposition of electrical stimuli on maximum volitional efforts, indicating that these subjects were capable of maximally activating the diaphragm before respiratory loading. During the course of loading, however, the extent to which the diaphragm could be activated decreased progressively. Evidence of the development of central diaphragmatic fatigue during repeated maximal and submaximal diaphragmatic contractions has also been reported in a study by McKenzie and coworkers (7).
Other work has suggested that "central fatigue" may be the result of a decrease in central respiratory motor outflow in response to opioid elaboration in the central nervous system, with the latter generated, in turn, as a consequence of the stress of loaded breathing (4, 8, 9). In support of this concept, Santiago and coworkers (8) have shown that naloxone restores the load compensatory reflex in patients with chronic obstructive pulmonary disease in whom it is initially absent. Subsequently, this group demonstrated that resistive loading in unanesthetized goats resulted in a progressive reduction in tidal volume, which was partially reversed by administration of naloxone (4).
In keeping with the results of these animal studies, an experiment involving patients with asthma found that naloxone pretreatment alters the response to methacholine challenge. In these individuals, in whom methacholine induced severe reductions in FEV1, naloxone pretreatment resulted in an increased breathing frequency, occlusion pressure, and mean in-spiratory flow rate when compared with saline pretreatment (10). It has been postulated that similar central limitations of respiratory motor outflow may occur in patients with diseases that chronically load the respiratory system, contributing to the development of chronic hypercapnia.
Central fatigue is a failure to generate force as a result of a reduction in motor output from the central nervous system. Peripheral fatigue refers to failure at the neuromuscular junction or distal to this structure and is judged to be present when muscle force output or velocity falls in response to direct electrical stimulation. Peripheral fatigue can result because of alterations in the neuromuscular junction, changes in propagation of the action potentials along the sarcolemmal membrane or into the t-tubules, changes in excitation-contraction coupling, or because of other alterations within the muscle cell (e.g., alterations in metabolism, changes in contractile proteins). Peripheral fatigue can be further classified into high-frequency and low-frequency fatigue on the basis of the shape of the postfatigue muscle force-frequency relationship. If fa tigue results in depression of the forces generated by a muscle in response to high-frequency electrical stimulation (e.g., in humans, 50-100 Hz) then high-frequency fatigue is said to be present, whereas a reduction in force generation in response to low-frequency stimuli (i.e., 1-20 Hz) is taken as an indication of low-frequency fatigue. Studies have suggested that loss of force at low frequencies represents an impairment of muscle excitation-contraction coupling (i.e., a reduction in contractile protein activation in response to a given nonimpaired sarcolemmal action potential) (12). Reduction in high-frequency force generation is thought to indicate either an alteration in neuromuscular junction transmission, a reduction in sarcolemmal membrane excitability, or a reduction in action potential propagation into the t-tubular system (13, 14). Low-frequency fatigue can occur in isolation, but high-frequency fatigue is invariably associated with some alterations in muscle force generation at lower frequencies.
High-frequency fatigue has been demonstrated in the diaphragms of normal humans after a trial of high-intensity in-spiratory resistive loading (this was demonstrated using high-frequency electrical phrenic stimulation) (15). In this study high-frequency fatigue resolves extremely quickly after cessation of strenuous muscle contractions (i.e., after removal of the inspiratory resistive load; see Figure 1).
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