High-intensity exercise
8.5 Mechanisms of fatigue
Muscle fatigue may be defined as an exercise- induced reduction in the ability of muscle to produce force or power, whether or not the task can be sustained (Bigland-Ritchie & Woods, 1984). This may be demonstrated by examining the power output profile of an individual undergo- ing a 30-second Wingate test. The profile shows a peak in the first few seconds, followed by a steady decline over the subsequent 25 seconds or so. Why is the muscle unable to support energy production at a sufficient rate to maintain a continuous peak power? Indeed, why can an individual not sprint supra-maximally for two minutes or longer? There are a number of reasons for this, and although this section will briefly describe some of the factors, for a more detailed exploration of muscle fatigue you should read Allenet al. (2008) or Enoka & Duchateau (2008).
Examination of Figure 8.12 shows various sites which may contribute to fatigue in skeletal muscle. These include the action potential along the sarcolemma and the T-tubule, the release of Ca2+ and the re-uptake of Ca2+ from the endoplasmic reticulum, contractile events at the crossbridge and enzyme activation. This section will not explore changes associated with muscle glycogen or hydration, but will briefly report on factors such as reduced levels of ATP and PCr,
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ATP Ach Ach
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Ca2+ Ca2+
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ATP
ATP
Ca2+ Ca2+
1- Sarcolemma 2- T-tubule 3- Ca2+ release 4- Ca2+ re-uptake 5- Crossbridge
Figure 8.12 Possible sites of fatigue during HIE (adapted from Green, 1990)
increased cellular concentrations of Pi and ADP, reduced pH and changes in K+ and Na+.
8.5.1 Reduced ATP
Many studies have reported that cytoplasmic ATP concentration does not drop below ≈60% of the resting level during either electrical stimulation or dynamic exercise during HIE at the point of fatigue. ATP may decline from 24 to 12 mM, while ADP may increase from 10 to 200µM, yet maximum force production in skinned fibres is not reduced unless the concentration of ATP is ≈20µM (lower than normally found in intake fibres), and the rate of relaxation is reduced 2.5-fold when lowered to 0.5 mM. This is not due to an effect on the contractile apparatus, but instead is due to reduced Ca2+ uptake by the SR.
ATP also has a regulatory action on the pump at the SR such that if ATP decreases from 5 to 0.25 mM, the Ca2+ affinity of the pump is reduced
≈10-fold.
Having said that, it is possible that there may be ATP reduction in certain localized areas of
a muscle. One possible site of localized ATP depletion is the space between the T-tubule and the SR. ATP consumption in this region is substantial, due to the presence of calcium pumps on the SR terminal cisternae just outside the junction and Na+/K+ pumps and other ATPases in the T-system membrane. Approximately 50%
of all Na+/-K+ pumps are in the T system.
Glycolytic enzymes associated with this so- called triad junction support localized synthesis of ATP. The glycolytic enzymes are well placed to utilize glucose entering the fibre via the T system, as well as the glucose-6-phosphate from adjacent glycogen stores. Na+/-K+ pumps in muscle fibres preferentially use ATP derived from glycolysis.
In view of the high density of ATP-consuming and -generating processes in the vicinity of the triad junction, as well as the comparatively small percentage of the cell volume it encompasses, ATP in the triad junction quite likely differs considerably from that in the cytoplasm as a whole. This could therefore allow the triad region to play a major role in sensing and responding to changes in cellular energy status, particularly
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Lactic Acid ( ) (mM/kg)
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Figure 8.13 Depletion of muscle PCr and increases in lactate and Pi during intense exercise (adapted from Hultmanet al., 1990)
given that the triad junction is the key transduction zone regulating Ca2+ release and contraction.
Therefore, in HIE, the triad junction may play a key role by sensing depletion of cellular ATP levels and respond by reducing Ca2+release. This will decrease the rate of ATP use by reducing both crossbridge cycling and SR Ca2+ uptake, the two main sources of ATP hydrolysis. The cost of this is a reduction in power output, or muscle fatigue, but the benefit is that it ultimately prevents complete exhaustion of all cellular ATP and consequent rigor development and cellular damage.
8.5.2 Reduced PCr
We have already noted that PCr levels decrease significantly in response to HIE. Indeed, muscle PCr concentrations have been reported to decrease from 80 to 15 mM in a single strenuous bout of HIE. Figure 8.13 shows changes in PCr due to a series of maximal muscle contractions over a period of 102 seconds, and it reflects almost total depletion (Hultmanet al., 1990).
However, other evidence is available that has observed a dissociation between the rate of
recovery of PCr and the force-generating capacity of the muscle (McCartney et al., 1986). In other words, PCr recovery is faster than the recovery of muscle force. Furthermore, as ATP levels can remain high at the point of fatigue, it does not appear that PCr limits performance by limiting ATP resynthesis.
8.5.3 Increased Pi
The exchange of phosphate between ATP and PCr is catalysed by CK. During periods of high energy demand, the ATP concentration initially remains almost constant, while PCr breaks down to Cr and Pi. While Cr has little effect on contractile function, Pi may cause a decrease of myofibrillar force production and Ca2+ sensitivity, as well as SR Ca2+release (Allenet al., 2008). Accordingly, increased Pi is considered to be a major cause of fatigue.
A causative role of increased Pi has also been implied in other situations with impaired muscle function. For instance, in a study where participants were followed during rehabilitation after immobilization in a cast, there was an
observed significant inverse relationship between resting Pi and specific force production (Pathare et al., 2005).
A fatigue-induced increase in Pi can reduce myofibrillar Ca2+ sensitivity, which may a have large impact on force production. Furthermore, increased Pi can inhibit force production by direct action on crossbridge function, and this is a likely mechanism underlying the decrease in tetanic force occurring early during fatigue in type IIx fibres. The magnitude of this Pi-induced decrease in crossbridge force production is probably rather small (≈10% of maximum force) in mammalian muscle.
8.5.4 Lactate and H+
The accumulation of lactic acid in muscle has historically been suggested to be the major cause
of muscle fatigue. Lactate and H+ are produced in muscles during HIE and the intracellular lactate concentration may reach 30 mM or more while the intracellular pH (pHi)decreases by≈0.5 pH units.
A close temporal relationship is often observed between decreased muscle force and increased intracellular concentrations of lactate, and particu- larly H+. However, such correlations break down in many cases, and although increased intracellu- lar levels of H+ may reduce muscle performance to some degree, it now appears that its deleterious effects have been considerably overestimated.
In humans, muscle pHi at rest is ≈7.05, and after exhaustive exercise it may drop to as low as
≈6.5. In some studies, however, pHi decreases only to ≈6.8 or 6.9 at the point of exhaustion, showing that muscle fatigue in humans often occurs without there being any large increase in concentration of H+i. Importantly, in cases where
Transmission of the Action Potential along Sarcolemma
- deleterious effect of ↑K+o and ↑Na+l
Inward conduction of the Action Potential in T-tubule
- deleterious effect of ↑K+o and ↑Na+l
Ca2+ reuptake by Sarcoplasmic reticulum - reuptake inhibited by
↑Pi, ↑ADP, ↓ATP, and ↑ROS
Ca2+ release by Sarcoplasmic reticulum - reduced by CaPi precipitation - inhibition by ↑Mg2+ and ↓ATP - directs effects of Pi on RyR
- direct effects of RyR phosphorylation or oxidation
Ca2+-sensitivity of myofibrillar proteins
- reduced by ↑Pi, ↓pH, and
↑ROS
Maximum Ca2+ activated force - reduced by ↑Pi
Shortening velocity - reduced by ↑ADP Ca2+
Figure 8.14 Possible fatigue sites and likely causes (adapted from Allen, 2008)
pHi does drop to low levels in a fatigued muscle, then upon ceasing the exercise or stimulation, force typically recovers much faster than pHi
(Allenet al., 2008).
Another way in which low pH previously was thought to reduce force responses was by inhibiting Ca2+ release from the SR. Low pH does reduce direct activation of the Ca2+ release channel to stimulation by Ca2+ and caffeine.
However, activation of Ca2+ release, the normal physiological mechanism, is not noticeably inhibited even at pH 6.2. Therefore, when pHi
is lowered in intact fibres, maximum tetanic force is reduced by no more than the amount expected.
In summary, under physiological circumstances, low pH has a far less inhibitory effect on the activation of the contractile apparatus and Ca2+
release than previously assumed, and its effects on the SR Ca2+ pump actually favour force develop- ment. Therefore, raised H+i is notper sethe main cause of muscle fatigue, with its direct effects on force production being quite small.
Having said that, could a reduction in pHi cause decreased activation of key enzymes associated with energy production, i.e. phosphorylase, PFK, CK and even ATPases? This premise is based on the fact that all enzymes have an optimum pH for maximum activity, and invariably in cells this optimum pH is ≈7.0. Since skeletal muscle pH can decrease to values as low as 6.4, there is some suggestion that this lowering of pH by≈0.5 units is sufficient to inhibit the above key enzymes and thereby reduce ATP production (MacLarenet al., 1989). Although this is an interesting point, the findings are not conclusive and so, although this remains a consideration, muscle fatigue during HIE could be (in part) due to enzyme activity affected by pH.
In conclusion, in intense exercise, the triad junction may play a key role by sensing depletion of cellular ATP levels and respond by reducing Ca2+ release. This will decrease the rate of ATP usage by reducing both crossbridge cycling and SR Ca2+ uptake, the two main sources of ATP hydrolysis. The cost of this is a reduction in power output, or in other words muscle fatigue, but the
benefit is that it ultimately prevents complete exhaustion of all cellular ATP and consequent rigor development and cellular damage. Figure 8.14 summarizes these points.