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Skeletal Muscle and Exercise |
1 Institute for Biomedical Sciences, School of Medical Sciences, University of Sydney F13, NSW 2006, Australia
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Abstract |
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(Received 1 November 2005;
accepted after revision 1 December 2005;
first published online 8 December 2005)
Corresponding author D. G. Allen: Institute for Biomedical Sciences, School of Medical Sciences, University of Sydney F13, NSW 2006, Australia. Email: davida{at}physiol.usyd.edu.au
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Introduction |
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While a role for ROS in muscle fatigue is widely accepted, the details of how ROS are produced, which ROS have the most critical role and the cellular pathways of the action of ROS remain uncertain. A useful preliminary step in identification of the cellular pathway in muscle is to determine whether ROS affect (i) excitation–contraction coupling, (ii) the maximum Ca2+-activated force, or (iii) the Ca2+ sensitivity of the myofibrillar proteins. Studies of fatigue in isolated muscle fibres, with a Ca2+ indicator present to measure cytosolic calcium concentration ([Ca2+]i), allow the contributions of these three components to be identified (Westerblad & Allen, 1991).
There are a number of studies suggesting that ROS may affect excitation–contraction coupling. For instance Favero et al. (1995) showed that H2O2 could stimulate Ca2+ release from isolated sarcoplasmic reticulum (SR) vesicles and suggested that critical sulphydryl groups near the release site on the ryanodine receptor contribute to the regulation of Ca2+ release. In contrast Brotto & Nosek (1996) found that application of H2O2 to single skinned rat skeletal muscle fibres inhibited depolarization-induced release and suggest that this mechanism might contribute to muscle fatigue. However another study using a similar approach failed to identify any major effect of H2O2 on SR Ca2+ release (Posterino et al. 2003). A study on intact mouse muscle fibres also found that Ca2+ release was relatively insensitive to exogenous application of H2O2 (Andrade et al. 1998).
The contractile and regulatory proteins may also be sensitive to ROS. A number of studies on skinned muscle have sought to characterize how the myofibrillar function is affected by a variety of exogenous ROS. For instance, superoxide can reduce the maximum Ca2+-activated force in both cardiac and skeletal muscle (MacFarlane & Miller, 1992; Darnley et al. 2001; Callahan et al. 2001). However studies with H2O2 as the oxidant and DTT as reducing agent showed no effect on maximum force (Callahan et al. 2001; Lamb & Posterino, 2003). van der Poel & Stephenson (2002) heated intact skeletal muscle fibres to 43–46°C and subsequently skinned them and showed that maximum Ca2+-activated force was reduced. Importantly this reduction of force was prevented by the ROS scavenger 4,5-dihydroxy-1,3-benzene-disulphonic acid (Tiron) and these authors suggested that superoxide produced at elevated temperatures damaged the ability of the contractile proteins to produce maximal force.
Studies of the Ca2+ sensitivity of myofibrillar proteins have often suggested that exposure of skinned fibres to ROS has minimal effect on Ca2+ sensitivity (MacFarlane & Miller, 1992; Darnley et al. 2001; Callahan et al. 2001; van der Poel & Stephenson, 2002). One exception was a study of skinned rat muscle in which, after an initial increase in Ca2+ sensitivity, there was a slowly developing reduction of Ca2+ sensitivity, which was not reversed by dithiothreitol (Lamb & Posterino, 2003). However in intact cardiac muscle there is good evidence that the post-ischaemia–reperfusion contractile weakness (stunning) is partly due to reduced Ca2+ sensitivity as a consequence of oxidative damage to regulatory proteins (for review see Bolli & Marban, 1999). Studies of intact mouse muscle showed that prolonged application of H2O2 produced a fall in Ca2+ sensitivity which was reversed by dithiothreitol (Andrade et al. 1998). Thus it seems that ROS may affect Ca2+ sensitivity by pathways which are lost in skinned fibres.
A characteristic finding of oxidative damage is that it can be prevented by pre-application of ROS scavengers and reversed by post-application of reducing agents. In this context dithiothreitol (DTT) is a membrane-permeant thiol-specific reducing agent which is capable of converting disulphide bridges in proteins to sulphydryl groups. Thus it is of particular interest that DTT was shown to improve recovery from fatigue in isolated diaphragm muscle at 37°C (Diaz et al. 1998).
We recently studied the fatiguability of isolated mouse skeletal muscle at both 22 and 37°C (Moopanar & Allen, 2005). We confirmed that mouse muscles fatigued more rapidly at 37°C and established that pre-application of the ROS scavenger, Tiron, slowed the rate of fatigue at 37°C but had no effect at 22°C. By measuring [Ca2+]i, we showed that the principal mechanism involved in the rapid onset of fatigue in single fibres at 37°C was a decline in Ca2+ sensitivity of the myofibrils. In the present study we have extended this work in two ways. We compare the decline in Ca2+ sensitivity at 37°C in fibres with minimal activity to fibres subjected to repeated stimulation leading to fatigue and show that intense muscle activity is necessary for the decline of Ca2+ sensitivity. We also show that the decline of Ca2+ sensitivity can be at least temporarily reversed by DTT. These results suggest that a specific protein in muscle can have sulphydryl groups converted to disulphide bridges in the oxidizing environment associated with muscle activity and that this change leads to a loss of Ca2+ sensitivity.
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Methods |
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Experimental protocol
Preliminary experiments were performed on small bundles without indo-1 injections to determine conditions under which recovery from fatigue would occur. Single fibre preparations were microinjected with indo-1 and allowed to rest at room temperature for 40 min. The preparations were stimulated intermittently at room temperature (0.4 s duration, 100 Hz frequency, 0.5 ms pulse duration, 1.2 x threshold) and only stable preparations used for the main experimental protocol.
The temperature in the muscle chamber was then raised to 37°C over a 2–3 min period. Ca2+ sensitivity, defined as the tetanic [Ca2+]i which produced 50% of maximum force (Ca50), and maximum Ca2+-activated force (Fmax) were assessed using the protocol described below which involved six tetani at 1 min intervals (see Fig. 1). The muscle preparation was then rested for 2 min before being fatigued by 0.4 s 100 Hz tetani repeated every 4 s until force was reduced to 50% of the initial level. Ca50 and Fmax were reassessed post-fatigue after a 1 min rest. The muscle fibre was then rested for 3 min during which 0.5 mM DTT was applied to the preparation for the last 2 min. DTT was removed just prior to the third determination of Ca50 and Fmax.
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A second set of control experiments were used to determine the effect of DTT on muscle properties in preparations which had not been fatigued, described as ‘DTT control’. In these experiments, after the first determination of Ca50 and Fmax at 37°C, the muscle was rested for 10 min, DTT (0.5 mM) was applied for 2 min, and then Ca50 and Fmax were redetermined.
The third control was used to determine how muscle properties changed with time after the fatigue protocol. This protocol was identical to the basic protocol except that DTT was not applied and is described as ‘Post-fatigue (ii)’. Only three experiments were completed in this series and there was only one successful caffeine application, so we do not report Fmax for this series.
Measurement of [Ca2+]i
[Ca2+]i was measured by microinjecting each preparation with the fluorescent Ca2+ indicator indo-1 (Westerblad & Allen, 1991). The injected preparation was allowed to rest for 40 min and was thereafter illuminated with monochromatic light at 360 nm wavelength. The light emitted at 405 and 505 nm was measured using two photomultiplier tubes and these signals were then passed to an analog divide circuit which produced a 405/505 nm ratio signal. Background signal was subtracted from each photomultiplier tube (PMT) measurement prior to ratio calculation. The fibre was protected from the exciting illumination by a shutter at all times except during each tetanus. The ratio (R) measurements were later converted to [Ca2+]i using the following equation:
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Determining Ca50 and Fmax
The protocol to determine Ca50 and Fmax involved 0.4 s tetani at a range of frequencies (20, 30, 50, 70, 100 Hz and 100 Hz in the presence of 10 mM caffeine) at 1 min intervals (Westerblad & Allen, 1991). Caffeine exposure was kept as brief as possible (
20 s) since the muscle fibres appeared to be more sensitive to caffeine at 37°C and some fibres developed an irreversible contracture in caffeine. [Ca2+]i and force during the tetani were estimated by taking an average of the last 200 ms of the tetanic record, by which time the force and [Ca2+]i appeared to have reached a steady state relationship.
The values of Fmax and Ca50 were determined by plotting peak tetanic force versus[Ca2+]i for each frequency of stimulation including 100 Hz + caffeine and the resting [Ca2+]i (see Fig. 3). These plots were fitted by a least squares minimization routine to the following Hill curve:
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Results are presented as means ±S.E.M. followed by the n value. Statistical significance was determined using Student's paired t test. Significance was accepted at P < 0.05.
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Results |
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Preliminary studies were performed on small muscle bundles as these were easier to dissect and were more resilient to the stresses of dissection and heat. Muscle bundles (5–10 fibres) were subjected to a similar stimulation protocol as single fibres. After the period of fatigue, the bundles were rested for 3 min before being re-stimulated at 100 Hz. In six experiments, the 100 Hz force after 3 min recovery was 56 ± 4% of pre-fatigue values.
In a second series of experiments, DTT was applied during the recovery period. In preliminary experiments we found that 
2 mM DTT caused the fibres to become inexcitable. Small concentrations of DTT (
0.25 mM) had only minimal effect on recovery. The optimal recovery was observed with 0.5 mM DTT, which was used for the main series of experiments. When 0.5 mM DTT was applied in the final 2 min of rest and removed before restimulation, the 3 min recovery force was 102 ± 6% (n= 6) of the initial force. We also experimented with longer duration applications of DTT but the muscle performance rapidly deteriorated if DTT was maintained during the recovery contractions. These results confirm the earlier observations of Diaz et al. (1998) but do not reveal the cellular mechanism involved.
Intracellular calcium measurements in single fibres
Single muscle fibres were subjected to the stimulation protocol described in the Methods and required 10 ± 1 tetani (40 s) to fatigue to 50% at 37°C. The 100 Hz force post-fatigue was similar to bundle experiments and the application of DTT caused a similar recovery of muscle function. In the following experiments we tested whether this recovery of force was caused by an action of DTT on (i) tetanic [Ca2+]i, (ii) Fmax or (iii) Ca50. The following experimental data show that the recovery of force triggered by DTT is not caused by changes in tetanic [Ca2+]i.
Figure 2 shows representative results from one experiment and it is clear that the tetanic [Ca2+]i at 100 Hz is minimally affected following the fatigue protocol and also unaffected by the DTT application. Figure 4A shows averaged data from all experiments and in none of these conditions was tetanic [Ca2+]i at 100 Hz significantly affected. In the pre-fatigue period, the 100 Hz tetanic [Ca2+]i was 960 ± 50 nM (n= 18). As in our earlier study (Moopanar & Allen, 2005), in the post-fatigue period when force was greatly reduced there was no significant reduction in tetanic [Ca2+]i, which was 870 ± 40 nM (n= 9). Finally, following DTT application, tetanic [Ca2+]i was unaffected (870 ± 60 nM, n= 6) even though there was a significant recovery of tetanic force.
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Maximum Ca2+-activated force
Fmax and Ca50 were obtained for each stage of the experiment by fitting Hill curves to the tetanic data at the various frequencies. Figure 3 shows plots of [Ca2+]i and force for the experimental data shown in Fig. 2 and also shows the fitted curves from which Ca50 and Fmax were determined. Note that in the initial (pre-fatigue) series the 100 Hz force (rightmost unfilled circle), the 100 Hz + caffeine force (the filled circle), and Fmax (the value to which the fitted curve approaches asymptotically) are all quite similar in magnitude. This is similar to previous results and suggests that the [Ca2+]i during a normal 100 Hz tetanus is close to the level which produces maximum Ca2+-activated force (Allen & Westerblad, 1995). In contrast in the post-fatigue data, the 100 Hz force (rightmost open triangle) is greatly reduced and addition of caffeine produces a large increase in force. We have already established that the 100 Hz tetanic [Ca2+]i is unchanged by fatigue; thus the smaller force could either be because the Ca50 is increased or Fmax is reduced by fatigue. The fitting of the Hill curve clarifies the fact that Fmax is unchanged by fatigue but Ca50 increases substantially. Figure 4B shows average Fmax values from all experiments under the various conditions studied. The pre-fatigue value for Fmax was 117 ± 2% of the initial 100 Hz tetanus at 37°C (n= 18). After the muscle was fatigued, there was no significant difference in Fmax (116 ± 6%, n= 6). Finally, after DTT was applied, it was found that Fmax remained unchanged at 116 ± 5% (n= 4) of the initial.
In control experiments in which fatigue was omitted, the second determination of Fmax was not significantly different (110 ± 2% of control, n= 5). When DTT was applied without fatigue, Fmax was not significantly changed at 117 ± 2% of control (n= 4). The post-fatigue (ii) value is not estimated because the caffeine exposure was only successfully complete in one out of three experiments. These results suggest that the decline in muscle performance at 37°C post-fatigue and the improvement in muscle function associated with DTT application are not due to changes in Fmax.
Myofibrillar Ca2+ sensitivity
Figure 3 illustrates the results of plotting tetanic [Ca2+]i and force during the various stages of one experiment. The open circles represent force and [Ca2+]i for the initial stimulation protocol, and the fitted Hill curve (the continuous line) has a Ca50 of 561 nM. The open triangles represent stimulation just after the muscle was fatigued and the fitted line (long dashes) shows that Ca50 had increased to 728 nM. It is clear that, as in our earlier study (Moopanar & Allen, 2005), fatiguing stimulation at 37°C causes a substantial fall in Ca2+ sensitivity. The squares represent measurements of [Ca2+]i and force after DTT was applied, and the fitted line (short dashes) shows that the Ca2+ sensitivity had largely recovered (Ca50 577 nM).
Figure 4C shows a bar graph of Ca50 from all experiments including the various controls. The initial value of Ca50 was 650 ± 40 nM (n= 18). After fatigue, Ca50 was significantly increased to 870 ± 40 nM (n= 9) indicating a loss in myofibrillar Ca2+ sensitivity. After the DTT application to the fatigued muscle, the Ca50 recovered to 680 ± 40 nM (n= 6), which was not significantly different from the initial control value. In control experiments in which muscle preparations were stimulated 10 min apart, it was found that there was no significant difference in Ca50 (630 ± 110 nM, n= 5). Also, the application of DTT in unfatigued preparations had no significant effect on Ca2+ sensitivity (Ca50= 620 ± 20, n= 4). When the muscle was stimulated a second time after fatigue, Ca50 showed a significant further increase to 1050 ± 90 nM (n= 3), showing that there was an ongoing decline in Ca2+ sensitivity post-fatigue.
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Discussion |
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We also show that if the muscle was left resting for 10 min, instead of the fatiguing protocol, there was no significant change in Ca2+ sensitivity. This observation shows that the reduced sensitivity is not simply a consequence of time at 37°C but requires muscle contraction for its development. In fact although the preparation was rested for 10 min, it received 12 contractions spread over 20 min (6 tetani for each sensitivity determination) so that it appears that infrequent tetani do not induce the reduction in Ca2+ sensitivity. This strongly suggests that either rapidly repeated tetani, or perhaps fatiguing tetani, are required to induce this effect. This conclusion is consistent with our earlier observation that ROS scavengers prevent the reduced Ca2+ sensitivity, since it is known that the rate of production of ROS increases with frequency of activation (Reid et al. 1992a). It also fits well with the observation that this mechanism does not appear to operate at room temperature, since it is known that production of ROS is increased steeply by temperature (Zuo et al. 2000).
Our experiments also confirm the earlier observation that intermediate concentrations of DTT are capable of reversing the force deficit after fatigue at 37°C (Diaz et al. 1998). Diaz et al. showed that the beneficial effects of DTT were not apparent at 0.1 mM or 5 mM and were not apparent in unfatigued muscle, and we confirm both these observations. Diaz et al. applied 0.5–1.0 mM DTT continuously after fatigue and observed an improvement in performance over at least 90 min. However in our experiments the improved performance only lasted 10–20 min after which performance deteriorated (data not shown). We are unsure of the reason for this difference. Single fibres seem to be particularly susceptible to ROS at 37°C, possibly because intense illumination of cells required for [Ca2+]i measurements is capable of generating additional ROS (King & Oh, 2004). If this is the case, it might be more difficult for DTT to reverse this process in our single fibre preparation.
An important novel finding in our study is that the mechanism of action of dithiothreitol is a reversal of the reduced Ca2+ sensitivity which characterizes this type of fatigue. In the post-fatigue (ii) condition Ca50 was 1050 ± 90 nM. At the same time in the DTT treated muscle fibres Ca50 was 680 ± 40 nM. Diaz et al. speculated that ‘endogenously produced ROS down-regulate force production during fatigue by oxidizing critical sulphydryl groups on important redox-sensitive proteins’. Our findings strongly suggest that the protein(s) affected are involved in regulating Ca2+ sensitivity.
Cellular site of action
Many different protein modifications have been identified as a consequence of oxidative stresses. Methionine residues are particularly susceptible and can be reversibly oxidized to methionine sulphoxide (Vogt, 1995; Davies, 2005). Cysteine residues are also susceptible and may be subject to S-glutathiolation, S-nitrosolation, as well as disulphide formation both within proteins and between proteins (Hogg, 2003; Davies, 2005). It is also known that oxidative damage makes proteins more susceptible to breakdown both by proteasome and by Ca2+-activated proteases (Nakashima et al. 2004). While other possibilities are not excluded, the development of disulphide bonds seems an important possibility because of the reversal by DTT. Disulphide bonds are particularly common in extracellular proteins where they help stabilize proteins but may also be cleaved as part of the regulatory pathway for a particular protein (Hogg, 2003). Under most circumstances intracellular proteins are thought to be protected from disulphide bridge formation by the reducing environment of the cell but it seems that the oxidative stresses of intense muscle activity could be sufficient to allow this reaction to occur (Brennan et al. 2004).
The fact that myofibrillar Ca2+ sensitivity seems to be a target for oxidative damage suggests that troponin, tropomyosin, actin, myosin or myosin light chains may be possible targets. Cardiac troponin can form both inter- and intramolecular disulphide bonds and this process leads to an increase in Ca2+ sensitivity (Putkey et al. 1993). However skeletal troponin C does not have cysteines at the same location and it requires a mutant skeletal troponin C to form an intradomain disulphide bond (Grabarek et al. 1990). Brotto et al. (2000) and de Paula Brotto et al. (2001) have shown that hypoxic fatigue in diaphragm muscle at 22°C causes a loss of Ca2+ sensitivity which is associated with damage to troponin C and I; it is not clear how this relates to oxidative damage at 37°C but points to troponins as possible targets. Oxidative damage to tropomyosin and actin have been demonstrated in the heart following reperfusion damage (Canton et al. 2004). Evidence for disulphide bridges in myosin comes from application of 5,5-dithiobis(2-nitrobenzoic acid) (DTNB), an oxidizing agent which produces disulphide links between appropriately positioned cysteines. DTNB applied to skinned skeletal fibres caused force to fall rapidly to zero but force recovery occurred with DTT (Wilson et al. 1991). Thus currently, while troponins are the most obvious target, there is little evidence of oxidative damage to skeletal troponins and it remains possible that a variety of proteins might be involved in the loss of Ca2+ sensitivity.
Physiological significance
Single fibres are a useful model for identifying mechanisms of fatigue but they obviously differ in many ways from intact muscles. The time course of fatigue in single fibres at 37°C is very fast and they fail to fully recover; both features suggest that some aspect of their performance is unphysiological. It is probable that either endogenous ROS production is increased or ROS scavenging is reduced since addition of the ROS scavenger Tiron improves both these features (Moopanar & Allen, 2005). Thus it is important to stress that although in the single fibre model at 37°C changes in Ca2+ sensitivity due to oxidative damage appear to be the principal mechanism of fatigue, we suspect this mechanism may only be one contributor in intact muscles. Furthermore, it is generally accepted that there are many mechanisms of fatigue and the relative importance of a particular mechanism, such as oxidative damage, is likely to vary according to the fatigue protocol.
Persistent muscle weakness following intense exercise, or even relatively normal daily activities, is a common complaint whose cellular basis, if any, is poorly understood. Edwards et al. (1977) described a form of weakness in humans following intense muscle activity which could persist for several days. Part of the explanation for this type of weakness may be a persistent reduction in SR Ca2+ release (Westerblad et al. 1993), possibly triggered by Ca2+-activated proteases acting on the ryanodine receptor (Lamb et al. 1995; Chin & Allen, 1996; Verburg et al. 2005). It is interesting to speculate whether reduced Ca2+ sensitivity secondary to oxidative damage might also contribute to this type of weakness. Westerblad et al. measured Ca2+ sensitivity 30 min after a fatiguing protocol and by that time Ca2+ sensitivity had returned to normal; however, the Westerblad et al. study was at room temperature so the kinds of changes seen in the present study would not be expected. We have been unable to find studies in which muscles are fatigued in vivo or at least at 37°C, and skinned fibres subsequently studied for changes in Ca2+ sensitivity. Thus two important goals for the future are to identify the target proteins for oxidative damage and to assess whether this mechanism operates in intact muscles during fatigue.
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 J. N. Edwards, W. A. Macdonald, C. van der Poel, and D. G. Stephenson O2bullet production at 37{degrees}C plays a critical role in depressing tetanic force of isolated rat and mouse skeletal muscle Am J Physiol Cell Physiol, August 1, 2007; 293(2): C650 - C660. [Abstract] [Full Text] [PDF]
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C. Cifelli, F. Bourassa, L. Gariepy, K. Banas, M. Benkhalti, and J.-M. Renaud KATP channel deficiency in mouse flexor digitorum brevis causes fibre damage and impairs Ca2+ release and force development during fatigue in vitro J. Physiol., July 15, 2007; 582(2): 843 - 857. [Abstract] [Full Text] [PDF]
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C. van der Poel and D. G. Stephenson Effects of elevated physiological temperatures on sarcoplasmic reticulum function in mechanically skinned muscle fibers of the rat Am J Physiol Cell Physiol, July 1, 2007; 293(1): C133 - C141. [Abstract] [Full Text] [PDF]
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T. Yamada, T. Mishima, M. Sakamoto, M. Sugiyama, S. Matsunaga, and M. Wada Myofibrillar protein oxidation and contractile dysfunction in hyperthyroid rat diaphragm J Appl Physiol, May 1, 2007; 102(5): 1850 - 1855. [Abstract] [Full Text] [PDF]
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M. J. McKenna, I. Medved, C. A. Goodman, M. J. Brown, A. R. Bjorksten, K. T. Murphy, A. C. Petersen, S. Sostaric, and X. Gong N-acetylcysteine attenuates the decline in muscle Na+,K+-pump activity and delays fatigue during prolonged exercise in humans J. Physiol., October 1, 2006; 576(1): 279 - 288. [Abstract] [Full Text] [PDF]
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, before fatigue; •, 100 Hz + caffeine before fatigue; 
, post-fatigue; 
, 100 Hz + caffeine post-fatigue; 
, after DTT in the post-fatigue state. Lines show fits of the Hill equation to the data points; continuous line, pre-fatigue; long dashes, post-fatigue; short dashes, after DTT in the post-fatigue state. The line fitted to the DTT in the post-fatigue state data points has been fitted on the assumption that Fmax was unchanged (see Methods).
