What are the different types of fatigue?
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When we exercise, we often experience a temporary (and reversible) reduction in strength, which is called “fatigue.” Importantly, it is the loss in strength (the ability to voluntarily produce muscle force) that is the definition of fatigue, and not any accompanying feelings that we might have.
Most of the time, we don’t stop to think about how this reduction in strength occurs. Yet, it is useful to think about fatigue by looking at the sequence of events by which we produce muscle force, and then consider the ways in which fatiguing mechanisms can impair each of these events.
What events are involved in force production?
Once we decide to produce a muscular contraction, the motor cortex generates an electrical signal that it sends to the agonist (working) muscle. This signal then travels down the spinal cord and the efferent nerves to the neuromuscular junction of the muscle.
At the neuromuscular junction, the signal stimulates action potentials to travel along the cell membrane of activated muscle fibers. These action potentials travel until they reach transverse tubules (T tubules) that run down from the cell membrane and into the muscle fibers itself. Within the T tubules are voltage sensors that sit adjacent to sarcoplasmic reticulum calcium ion release channels at structures known as “triadic junctions.” When the voltage sensor detects the presence of action potentials, it interacts with the sarcoplasmic reticulum calcium ion release channels, and stimulates them to release calcium ions into the cytoplasm of the muscle fiber. In this way, the muscle fiber converts an electrical signal into a chemical signal.
Once calcium ions are released by the sarcoplasmic reticulum calcium ion release channels, they are detected by a protein known as troponin, which is located on actin myofibrils, and this allows another a protein known as tropomyosin to move and thereby reveal myosin binding sites on actin. Consequently, nearby myosin heads bind to actin, causing a crossbridge cycle. The formation of actin-myosin crossbridges is what generates muscle fiber tension, and in this way muscle force is produced.
To understand fatigue during exercise, it helps to see that if any of these steps are impaired, then muscle force is reduced. Let’s look at each step in turn.
#1. CNS fatigue — motor cortex
Once we decide to produce a muscular contraction, the motor cortex generates an electrical signal that it sends to the agonist (working) muscle. In broad terms, the size of this signal is what determines the degree of motor unit recruitment when it reaches the muscle. Larger signals lead to higher levels of motor unit recruitment. Since the degree of motor unit recruitment determines the number of activated muscle fibers, it has a big impact on the amount of muscle force that is produced.
We regulate the size of this signal (and therefore the degree of motor unit recruitment) by controlling the amount of effort we employ in producing a movement. When we use a high effort, this results in a large signal (and therefore a high degree of motor unit recruitment). Consequently, our perception of effort and the level of motor unit recruitment in a contraction are usually closely related, even when fatiguing mechanisms are occurring at other points in the sequence of events that lead to crossbridge formation.
However, it does seem to be possible to alter the size of this signal relative to the perceived effort (as is often observed when experiencing mental fatigue). If the size of the signal can be reduced for a given level of perceived effort, then this would lead to a reduction in the level of motor unit recruitment that is possible, because even maximum effort would no longer cause a big enough signal to trigger maximum motor unit recruitment. This in turn would reduce muscle force, by reducing the number of activated muscle fibers.
Indeed, towards the end of various types of exercise, our ability to achieve a maximal level of motor unit recruitment is reduced, and we can measure this as a decrease in voluntary activation. The reduction in voluntary activation can and does occur at the level of the motor cortex, and we can call this a “supraspinal” form of central nervous system (CNS) fatigue.
Like mental fatigue, afferent feedback from muscles that is caused either by metabolite accumulation or an inflammatory response could alter the size of this signal relative to the perceived effort. We can perhaps imagine this as these uncomfortable sensations requiring a proportion of our available effort to overcome. Thus, we reduce the effort that is available for creating a signal that causes motor unit recruitment.
Indeed, CNS fatigue during aerobic exercise is highest when exercise duration is long (which is when the inflammatory response is high), while CNS fatigue during strength training exercise is highest when metabolites and fatiguing sensations are high, as when training closer to failure or using lighter loads.
#2. CNS fatigue — spinal cord
Once the motor cortex has generated an electrical signal, it travels down the spinal cord and the efferent nerves to the neuromuscular junction of the muscle. We might imagine that the magnitude of the electrical signal is always unchanged by its passage through the spinal cord, but this is not actually the case.
In fact, it does seem that the size of the signal that comes out the bottom of the spinal cord can sometimes be smaller than the size of the signal that goes into the top, and this causes a reduction in voluntary activation that we can call a “spinal” form of CNS fatigue. While a great deal of research has been devoted to exploring this curious phenomenon, we still don’t really know how and why it happens. It seems that after a large number of repeated muscular contractions, the transmitted signal from the spinal cord starts to be reduced, relative to the signal that is actually sent by the motor cortex.
#3. Peripheral fatigue — muscle fiber membrane
Any fatiguing mechanism that acts on our ability to produce an electrical signal that causes motor unit recruitment at points in the sequence of events up to the neuromuscular junction is called “CNS fatigue” but any fatiguing mechanism that acts on our ability to produce force inside muscle fibers is called “peripheral fatigue.”
At the neuromuscular junction, the electrical signal from the CNS stimulates action potentials that travel along the cell membrane of activated muscle fibers. The first point at which peripheral fatigue can occur is therefore the transmission of the electrical signal along the surface of the muscle fiber cell membrane (this is a major problem for research methods that use surface electromyography (EMG) to assess CNS fatigue instead of using voluntary activation, as EMG measures the electrical signal of the muscle cell membrane and can therefore be affected by this type of peripheral fatigue).
Several studies have found that the maximum size of the action potentials that can travel along the cell membrane of activated muscle fibers can be reduced by fatiguing exercise. This is referred to as a “loss of sarcolemmal excitability” because the sarcolemma is another name for the muscle cell membrane. Losses of sarcolemmal excitability reduce muscle fiber force because the action potentials that reach the T tubules will be decreased even when the signal arriving at the neuromuscular junction is not altered.
Losses of sarcolemmal excitability could occur through at least two different mechanisms. Firstly, they could occur by the generation of reactive oxygen species, since these inhibit the sodium-potassium pump that maintains cell membrane excitability. Indeed, studies that have found beneficial effects of antioxidants on fatigue have also found smaller impairments in sodium-potassium pump activity during exercise. Secondly, they could happen due to damage being experienced by the muscle cell membrane from the production of phospholipases, which are triggered when calcium ions are released into the cytoplasm due to excitation-contraction coupling, but are not successfully taken back up into the sarcoplasmic reticulum afterwards. This is a fairly common occurrence, especially in the fast twitch muscle fibers, which do not have a lot of mitochondria to deal with loose calcium ions during fatiguing exercise.
Interestingly, the existence of these two mechanisms means that losses of sarcolemmal excitability could be either quickly reversed (because metabolite accumulation is quickly reversed) or slow to reverse (because damage to the cell membrane is slow to reverse), depending on which mechanism is dominant during exercise (metabolite accumulation or calcium overload).
#4. Peripheral fatigue — excitation-contraction coupling
Action potentials traveling along the muscle cell membrane eventually reach T tubules that run down from the cell membrane and into the center of the muscle fiber itself. Within the T tubules are voltage sensors that sit adjacent to sarcoplasmic reticulum calcium ion release channels at triadic junctions. When the voltage sensor detects the presence of action potentials, it interacts with the sarcoplasmic reticulum calcium ion release channels, and stimulates them to release calcium ions into the cytoplasm of the muscle fiber. In this way, the muscle fiber converts an electrical signal into a chemical signal.
If the voltage sensor cannot interact properly with the sarcoplasmic reticulum calcium ion release channels, then the signal that reaches the triadic junction will be irrelevant, since no calcium ions will be released into the muscle fiber. When this happens, it is called “excitation-contraction coupling failure” and it can be measured by recording involuntary muscle force in response to electrical stimulation at low (20Hz) and high (100Hz) frequencies. When excitation-contraction coupling failure is present, force is usually reduced to a much greater extent at low than at high frequencies, and a change in the ratio low-to-high frequency force is called “low frequency fatigue.” Therefore, low-frequency fatigue is used to test for the presence of excitation-contraction coupling failure.
Excitation-contraction coupling failure may occur through at least two totally different mechanisms. Firstly, it might occur due to metabolic changes, such as the accumulation of phosphate ions, which could bind with calcium ions in the sarcoplasmic reticulum and thereby reduce their availability. Secondly, it could occur due to disruptions to minor proteins in the triadic junctions, which hold the structure in place. Such disruptions likely occur due to the actions of proteases such as calpains, which are triggered when calcium ions are released into the cytoplasm, but are not successfully taken back up into the sarcoplasmic reticulum afterwards.
Interestingly, the existence of these two mechanisms means that losses of excitation-contraction coupling failure could be either quickly reversed (because metabolite accumulation is quickly reversed) or slow to reverse (because damage to the minor proteins of the triadic junctions is slow to reverse), depending on which mechanism is dominant during exercise (metabolite accumulation or calcium overload).
#5. Peripheral fatigue —myofibrillar sensitivity
Once calcium ions are released by the sarcoplasmic reticulum calcium ion release channels, they are detected by a protein known as troponin, which is located on actin myofibrils, and this allows another a protein known as tropomyosin to move and thereby reveal myosin binding sites on actin. Yet, if troponin fails to detect the presence of calcium ions, then nothing happens. When this occurs, it is called a “loss of myofibrillar calcium ion sensitivity.”
Precisely how a loss of myofibrillar calcium ion sensitivity occurs is very unclear, and several mechanisms have been suggested, including metabolite (hydrogen ion and phosphate) accumulation and the generation of reactive oxygen species. Out of all the mechanisms of fatigue inside the muscle, it is the most opaque.
#6. Peripheral fatigue — the crossbridge cycle
Once tropomyosin moves and reveals myosin binding sites on actin, nearby myosin heads bind to actin, causing a crossbridge cycle. The formation of actin-myosin crossbridges is what generates muscle fiber tension (many times a second), and in this way muscle force is produced. If myosin cannot bind to actin or if the crossbridge cycle is disrupted in any way, then muscle fiber force will be reduced. Also, if force-bearing structures (myofibrils and the cytoskeleton) are damaged, then crossbridge cycles that do occur may not be able to transmit force effectively out of the muscle fiber and to the tendon.
A key element of the crossbridge cycle is that it requires energy in the form of ATP. The reaction using this ATP creates phosphates, and is reversible. Thus, an accumulation of phosphates inhibits the crossbridge cycle by stopping the flow of energy into it. Metabolite accumulation occurs quickly during very fatiguing exercise, and so an impairment of crossbridge forces in this way is likely to be one of the first things to occur.
When (fast twitch) muscle fibers are lengthened, they tend to display disruptions to their sarcomeres afterwards, which has been interpreted either as damage (the popping sarcomere hypothesis) or as myofibrillar remodeling. To the extent that this is damage that impairs muscle fiber force, it could arise for two reasons: (1) mechanical tension, and (2) calcium ion-induced release of proteases. Traditionally, it was assumed that mechanical tension was the way in which eccentric contractions caused damage, but it is now becoming clear that eccentric contractions likely bring about calcium overload by opening stretch-activated ion channels, which adds far more calcium into the cytoplasm than can be taken back up by the sarcoplasmic reticulum and the mitochondria.
Thus, we can see that myofibrillar force can be impaired either by the accumulation of metabolites, which affects the crossbridge cycle, or by the accumulation of calcium ions, which causes damage to myofilaments.
Interestingly, the existence of two categories of mechanism that affect the force produced by myofilaments means that losses of myofibrillar force can be either quickly reversed (because metabolite accumulation is quickly reversed) or slow to reverse (because damage to the myofilaments is slow to reverse), depending on which mechanism is dominant during exercise (metabolite accumulation or calcium overload).
Why does this matter?
CNS and peripheral types of fatigue
When fatiguing mechanisms occur in the brain or spinal cord, they cause CNS fatigue, and when they occur inside the muscle, they cause peripheral fatigue. Importantly, when CNS fatigue is triggered, the size principle is respected. This means that the first motor units to be affected by CNS fatigue are the highest-threshold motor units. These motor units control the most responsive, highly-adaptable, fast twitch muscle fibers, which are the ones that grow after strength training. Owing to the size principle, these motor units are affected regardless of which muscle fibers are working during the exercise bout. Thus, when aerobic exercise causes CNS fatigue, it actually affects muscle fibers that are not actually working. Similarly, when we stimulate CNS fatigue with light loads during strength training, we can risk reaching “muscular failure” without actually training the muscle fibers of some of the highest-threshold motor units.
In contrast, peripheral fatigue only affects the working muscle fibers. Thus, when peripheral fatigue predominates and CNS fatigue is minimized, the muscle fibers of the highest-threshold motor units are trained most effectively.
Peripheral types of fatigue
Fatiguing mechanisms inside the muscle during exercise can involve both metabolite accumulation (which is quick to occur, but also quick to reverse) and calcium ion overload (which is slow to occur and to reverse). Importantly, the proportion of each depends on the exercise. This has a large impact on the time that the muscle then takes to recover from the workout.
In concentric and isometric contractions involving at least moderate forces, metabolite accumulation predominates. In contrast, in eccentric contractions, there is little metabolite accumulation, because metabolic efficiency is so much higher. Thus, fatiguing mechanisms involving calcium ion overload tend to predominate during and after eccentric contractions, and this is reflected in the slower rate of fatigue and recovery in eccentric contractions (albeit noting that the amount of calcium ion overload is also exacerbated by the actions of stretch-activated ion channels).
What is the takeaway?
When we exercise, we often experience a temporary (and reversible) reduction in strength, which is called “fatigue.” Fatiguing mechanisms can occur at many points in the sequence of events by which we produce muscle force (from the brain to the actin-myosin crossbridges inside muscle fibers).
When fatiguing mechanisms occur in the brain or spinal cord, they cause CNS fatigue, and when they occur inside the muscle, they cause peripheral fatigue. Some forms of exercise (such as those of longer duration or which involve more fatiguing sensations) cause proportionally more CNS fatigue, while other forms of exercise cause less. When CNS fatigue is triggered, muscles still abide by the size principle. The first motor units to be affected by CNS fatigue are the highest-threshold ones, which control the most responsive, highly-adaptable, fast twitch muscle fibers. Peripheral fatigue only affects the working muscle fibers. Thus, CNS fatigue has a much more negative effect on our ability to stimulate hypertrophy than peripheral fatigue.
Likewise, fatiguing mechanisms inside the muscle during exercise can involve both metabolite accumulation (which is quick to occur, but also quick to reverse) and calcium ion overload (which is slow to occur and to reverse), and the proportion of each depends on the exercise. This has a large impact on the time that the muscle then takes to recover from the workout, and explains why eccentric contractions take so much longer to recover from than concentric and isometric contractions.
If you enjoyed this article, you will like my second book (see on Amazon).
