What is fatigue?
Fatigue is a temporary and reversible reduction in exercise performance (often measured as a reduction in maximum strength, but it can alternatively involve reductions in endurance capacity or maximum velocity) as a result of a previous bout of exercise. Although fatigue is usually discussed as a single concept, it can be separated out into multiple mechanisms inside the central nervous system (CNS) and inside the muscle itself.
One of those mechanisms is glycogen depletion.
Glycogen depletion is one mechanism that can cause fatigue inside the muscle itself. It tends to cause fatigue mainly after endurance exercise, but arguably it could also be relevant after high volume strength training workouts.
Nevertheless, the way in which this fatigue mechanism works is widely misunderstood.
Indeed, it is common for fitness industry commentators to assume that the fatiguing effect of glycogen depletion involves muscle fibers running out of fuel (during exercise) or requiring time to replenish fuel (after exercise). Yet, glycogen depletion probably does not work like that, either during exercise or afterwards. It is more likely that glycogen depletion simply provokes a greater degree of excitation-contraction coupling failure, which has very important practical implications. Let’s look more closely at the way in which glycogen depletion causes fatigue during exercise.
How does glycogen depletion cause fatigue during exercise?
Several studies in the 1960s and 1970s assessed the reductions in muscle glycogen immediately after aerobic exercise bouts in humans as well as in animals. They found that muscle glycogen reduces substantially over the course of a sustained bout of exercise (which indicates that the availability of fuel does reduce over time). And they found that the consumption of dietary carbohydrate in the hours or days prior to exercise affects muscle glycogen content, such that a lower level of muscle glycogen content can reduce the time to exhaustion during an aerobic exercise test (which suggests that a lack of muscle glycogen can indeed cause fatigue).
As a result of findings of this kind, researchers have since accepted that the depletion of muscle glycogen can cause fatigue during aerobic exercise. Yet, subsequent studies have not been able to establish any clear mechanistic link between the depletion of muscle glycogen and fatigue by means of a reduction in fuel availability. So let’s look more closely at the research linking muscle glycogen levels with fatigue and see what we can deduce.
Does running out of muscle glycogen cause fatigue? (part one)
While completely running out of fuel would certainly cause very severe fatigue (if it ever happened), the fatigue that is experienced when muscle glycogen reduces starts much sooner than that. This suggests that the link between low muscle glycogen levels and fatigue is somewhat complex, and not as simple as running out of fuel. Indeed, if your car has ever run out of fuel on the road, you will know that the effect is not gradual but rather sudden.
Nevertheless, there are a small number of studies that partially support the idea that glycogen depletion causes fatigue simply by reducing the availability of fuel. Such studies typically involve initial, fatiguing bouts of exercise in single muscle fibers or bundles of muscle fibers such that glycogen is depleted. Recovery is then allowed either in the presence or absence of a glucose solution before a second series of muscular contractions is performed. These studies typically show that the rate of fatigue is faster in the second bout of exercise when the muscle fibers are left to recover in the absence of glucose. Yet, if we are more rigorous in our analysis, these studies only really provide further evidence of a connection between muscle glycogen depletion and the presence of fatigue, since some glycogen is always present at task failure.
Indeed, no studies have recorded the complete absence of muscle glycogen at the end of a fatiguing bout of exercise, which indicates that running out of fuel cannot be the real mechanism by which fatigue arises. To resolve this problem, some researchers have suggested that glycogen stored in certain, key parts of the muscle fiber may be depleted more rapidly than the glycogen that is stored in other parts. Specifically, it is possible that glycogen stored near to the sarcoplasmic reticulum may be depleted more quickly than in other parts of the muscle fiber, such that excitation-contraction coupling stops working before complete muscle fiber glycogen depletion can occur.
While early research identified up to five different cellular locations for glycogen within muscle fibers, most subsequent research has identified three, being the subsarcolemmal, intermyofibrillar, and intramyofibrillar locations. It is intramyofibrillar glycogen that is most commonly preferentially depleted during exhaustive exercise. Given that myofibrils are relatively close to the sarcoplasmic reticulum, it could be argued that this source of glycogen is the source that the sarcoplasmic reticulum draws upon in order to produce the excitation-contraction process, and that running out of glycogen in this area could cause excitation-contraction coupling failure through a different mechanism from the way in which it normally occurs during strength training (which is the accumulation of calcium ions inside the cytoplasm, leading to calpain release and triadic junction damage). Even so, it is feasible that low muscle glycogen in this area simply triggers signaling processes that cause excitation-contraction coupling failure in more conventional ways.
So is it possible to deduce which of these mechanisms is correct?
Does running out of muscle glycogen cause fatigue? (part two)
Importantly, many studies have linked muscle glycogen depletion with calcium ion-related fatigue. Indeed, some research has shown changes in calcium ion release in tandem with glycogen depletion during fatiguing exercise in animal models. Other research has shown that glycogen depletion affects calcium ion release in human experiments. Therefore, there are good reasons to assume that glycogen depletion may cause fatigue not directly by the lack of fuel being available for the crossbridge cycle but by impairing the excitation-contraction coupling process in some way.
Additionally, further research has indicated that localized glycogen stores may well be the critical link that connects low muscle glycogen levels with calcium ion-related fatigue mechanisms. Indeed, some research performed into the localized regions of muscle fiber glycogen depletion after exhaustive exercise has shown that [A] intramyofibrillar glycogen is preferentially depleted during exercise, and that [B] such reductions in intramyofibrillar glycogen are associated with the extent of fatigue and with impairments in sarcoplasmic reticulum function and the release of calcium ions. This confirms that glycogen depletion does cause calcium ion-related fatigue in general, and most likely excitation-contraction coupling failure in particular.
Even so, this research does not address whether the cause of the calcium ion-related fatigue is the temporary absence of fuel for the sarcoplasmic reticulum or the stimulation of conventional calcium ion-related fatigue mechanisms.
To answer this question, it may help to look at what happens in the days after a workout, since a temporary absence of fuel for the sarcoplasmic reticulum caused by extremely low or even zero intramyofibrillar glycogen levels should not cause very sustained fatigue (or if it does, then the low muscle glycogen levels should be linked to the presence of sustained fatigue). In contrast, if the excitation-contraction coupling failure is caused by conventional mechanisms, then it should cause quite extensive sustained fatigue (and there should be no link between the muscle glycogen levels and the presence of that fatigue).
And indeed, research has shown that the rate of strength recovery after exercise is largely unrelated to the rate of muscle glycogen replenishment in the post-workout period (as modified by carbohydrate consumption). This suggests that low muscle glycogen stimulates excitation-contraction coupling failure by conventional calcium ion-related fatigue mechanisms. In other words, low muscle glycogen probably does not cause fatigue directly, but instead contributes to an accelerated accumulation of normal excitation-contraction coupling failure.
What does this mean in practice?
In practice, it seems likely that low muscle glycogen levels during exercise provoke fatigue through conventional calcium ion-related mechanisms (including excitation-contraction coupling failure).
This has two main practical implications.
Firstly, it means that exercising in a state of low muscle glycogen is likely to cause calcium ion-related fatigue earlier in the workout than would normally occur. This will reduce the effectiveness of the workout for stimulating muscle growth because excitation-contraction coupling failure substantially reduces the capacity of individual muscle fibers to produce and therefore experience mechanical tension.
Secondly, it means that the sustained fatigue that will be produced by a workout that involves exercising in a state of low muscle glycogen will be much greater than would normally occur. This will impact on training frequency and also on the ability to engage in other activities, such as sports practice. Moreover, supplying extra carbohydrate in the days after the workout does not fix the problem, because the sustained fatigue is now calcium ion-related and not muscle glycogen-related.
How does muscle damage cause glycogen depletion after exercise?
After exercise, muscle glycogen levels are usually replenished relatively quickly (within 24 hours). However, when a workout causes a lot of muscle damage (due to excess calcium ion accumulation during exercise), this can dramatically increase the amount of time that it takes for muscle glycogen levels to return to normal.
Indeed, eccentric training workouts (which are often used to study the effects of muscle-damaging exercise because eccentric contractions cause stretch-activated ion channels to open, which causes an excess of additional calcium ions to enter the cytoplasm of the working muscle fibers) can cause extremely prolonged muscle glycogen depletion for more than a week afterwards.
Effects of eccentric training workouts on sustained fatigue
By causing a large influx of calcium ions into the cytoplasm through stretch-activated ion channels (which stimulates the production of proteases called calpains), eccentric contractions cause a lot of damage to the cytoskeleton, muscle cell membrane, and the actin and myosin myofilaments of single muscle fibers. This damage impairs the ability of the muscle fiber to produce force by preventing or impairing the generation and transmission of forces exerted by the formation of actin-myosin crossbridges.
Similarly, by causing an influx of calcium ions that triggers calpain release, eccentric contractions also cause extensive localized damage to the minor triadic proteins that link the voltage sensor of the transverse tubules to the sarcoplasmic reticulum. This causes the two sides of the junction to drift apart, thereby causing excitation-contraction coupling failure. For this reason, excitation-contraction coupling failure can actually be viewed as a highly specific and localized form of muscle damage, although the fatigue is not caused by an inability to transmit forces but rather by an inability to produce crossbridge formation subsequent to muscle fiber activation.
Subsequent to muscle damage, there is an increase in oxidative stress as well as an increase in inflammatory mediators. The inflammatory response to muscle damage is responsible for central nervous system (CNS) fatigue, since it causes afferent feedback to the brain. Thus, all three main sustained fatigue mechanisms (muscle damage, excitation-contraction coupling failure, and CNS fatigue) ultimately arise from an excessive influx of calcium ions into the muscle fiber cytoplasm during a bout of exercise.
Effects of eccentric training workouts on glycogen recovery
After eccentric training workouts (which cause a large amount of muscle damage, excitation-contraction coupling failure and CNS fatigue, as well as a lot of oxidative stress, and a large inflammatory response), muscle glycogen is replenished extremely slowly. Indeed, researchers have observed impairments in muscle glycogen for up to 10 days after an eccentric training workout. After conventional strength training workouts or after aerobic exercise, muscle glycogen is typically replenished within 24–48 hours.
Importantly, while the actual reduction in muscle glycogen during exercise is usually very similar (when volume of exercise is similar), the rate at which muscle glycogen is replenished afterwards is slower after eccentric training workouts than after concentric training workouts. Consequently, we can deduce that slow replenishment of muscle glycogen after exercise is not caused by using a lot of glycogen during exercise but rather by some key feature of eccentric contractions.
The mechanism that causes the slower rate of muscle glycogen replenishment after eccentric training workouts is not clear. Some studies have reported a reduction in glycogen synthase activity, while others have not. Researchers have identified reductions in GLUT4 after eccentric training workouts, and this seems to be a more consistent finding. GLUT4 is a glucose transporter, and it is stimulated by the presence of insulin. Increases in GLUT4 protein content are associated with increases in glucose transport into muscle fibers. In line with this, researchers have reported reduced insulin-dependent glucose uptake into muscles after eccentric training workouts. This indicates that eccentric training workouts reduce the rate at which muscle glycogen is replenished by reducing the ability of muscle fibers to take in glucose. This is important, because it explains why consuming more carbohydrate after an eccentric training workout does not accelerate the replenishment of muscle glycogen. Clearly, the problem is not the availability of glucose. The problem is getting the glucose into the muscle fibers.
Importantly, recent research has shown that oxidative stress can block the transport of glucose across the muscle cell membrane. Indeed, when researchers assessed changes in glucose metabolism at the same time as changes in oxidative stress after muscle- damaging, eccentric exercise in rodents, they found significant reductions in insulin-dependent glucose uptake (but not in insulin-independent glucose uptake), and significant reductions in in GLUT4 plasma membrane content, as well as non-significant reductions in muscle glycogen. In tandem with these changes, they reported increases in oxidative stress markers, as well as increases in the activity of oxidative stress within the insulin signaling pathway. These findings indicate that the reactive oxygen species (ROS) produced during muscle-damaging exercise also act to impair the insulin-induced transport of glucose into muscle fibers. Therefore, eccentric training workouts are able to delay the recovery of muscle glycogen by preventing muscle fibers from taking up glucose, even in the presence of both insulin and glucose. This again helps to explain why consuming more carbohydrate after an eccentric training workout does not accelerate the replenishment of muscle glycogen.
What does this mean in practice?
In practice, it seems that muscle-damaging strength training workouts (or eccentric training workouts) reduce the rate at which muscle glycogen can be replenished, likely due to the effects of oxidative stress, which results from the muscle damage caused by calcium ion-related processes. Importantly, the consumption of more carbohydrates cannot increase the rate of muscle glycogen replenishment after muscle-damaging workouts, because the problem is caused by the inability of muscle fibers to take up glucose, not by the lack of available glucose.
A low level of muscle glycogen resulting from muscle-damaging exercise may have negative effects on the ability to perform sustained anaerobic exercise in the post-workout recovery period, since this type of exercise relies heavily on the availability of muscle glycogen. This could therefore be relevant for certain types of athletes (such as soccer players) who perform eccentric training regularly in the form of Nordic curls for improving sprinting performance and for reducing hamstrings strain injury risk, but who also need to be able to perform high-intensity aerobic and anaerobic running exercise during practice and match play.
What is the takeaway?
Low muscle glycogen does not cause fatigue by making the muscle run out of fuel. It causes fatigue by provoking excitation-contraction coupling failure, which can last for days after a workout. Thus, the fatigue caused by reaching low muscle glycogen levels is not immediately removed by replacing the lost muscle glycogen through carbohydrate consumption. This suggests that strength training workouts should not be performed either in a state of glycogen depletion or to the point of glycogen depletion, because this will cause the sustained fatigue to last longer afterwards.
Additionally, muscle-damaging workouts can reduce the rate at which muscle glycogen is replenished after exercise, by preventing glucose from entering muscle fibers. This means that eccentric training workouts (such as Nordic hamstring curls) have the potential to interfere with sustained, high-intensity endurance running performance (such as soccer match play) unless great care is taken to [A] ensure that the workout is not done in a glycogen-depleted state, and to [B] minimize the amount of muscle damage that is caused by the eccentric training workout (perhaps by using relatively low volumes).
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