Dissecting fatigue

Uncovering the many dimensions of fatigue

It’s that familiar story where you’ve executed the first 21km of the race flawlessly and on the 25th kilometer you are still going strong and on target, and then that sensation creeps up, initially just as a minor hindrance in some muscle but before you even realize it, it is right there, front and center. The legs that were in effortless rhythm now seems to have a lost a bit of the snap, your exertion to maintain the pace appears to have increased somewhat and that confident feeling you had a few kilometers back? Premature?

Yes, I am talking about fatigue, a concept that requires no introduction for a distance runner. Everyone has experienced fatigue in one form or another and recognizes that preparing for it and handling it well is critical for both training and racing.

Despite the universality of the experience - you know exactly what a fellow runner means when they were too fatigued to do a workout - try defining it and you’ll soon realize that there is no simple definition that encompasses all forms of it.

Science of Fatigue

Here, we’ll explore the science of fatigue in the context of endurance performance: the causes, physiological characteristics and the subjective manifestations. In particular, we’ll take a closer look at the difference between peripheral and central fatigue and learn that these are not cut-and-dry distinctions as they may seem. In the process, we’ll discover the fascinating interactions between muscles, neuronal signaling, brain regulation, the role of environmental and physiological factors

For starters, the way we feel fatigue during a run is closely tied to — and probably caused by — changes happening in our muscles and nervous system, along with shifts in how our whole body is functioning. That includes everything from enzyme activity and cellular responses to how much blood your heart's pumping out with each beat — all drifting away from their usual, steady rhythm.

Not all fatigue is created equal

Imagine your workout for the morning is 10 repetitions of 400m at a pace significantly faster than your 5k race pace. You’ve completed 6 repetitions and nailed the pace so far but the rest interval of 90 seconds feels increasingly short. Yet you have been recovering quickly enough to maintain the same intensity and continue to do so. You proceed to have a perfectly executed workout.

Now consider the day following a long weekend run of 32kms, one where you ran the last 7km at target marathon pace. Your muscles are sore and when you start the short recovery run, everything seems to be hurting, your heart rate is all over the place and it seems like a small miracle that you ran as fast you did the previous day. In both cases, you are fatigued, except 90s was enough to recover sufficiently in the first scenario and 24 hours in the second was not only not enough, but seems to have made it worse.

Short vs Long term fatigue

The reason for the different course of recovery is that the first is an example of short term fatigue which happens because the energy required for the high-intensity activity leads to accumulation of metabolic byproducts in the muscles that limit its ability to function efficiently. These include hydrogen ions generated from the anaerobic metabolism that creates an acidic environment, reactive oxygen species and inorganic phosphate that causes metabolic stress. Once these are cleared -ie, the blood carries them away and are neutralized - the recovery is nearly complete and you are able to run the next lap at the same intensity.

However, in the case of the long run, the prolonged fatigue has its origins in structural muscle damage that is caused by overworked muscles. The muscle fibers in those cases need repair and restoration and indeed the body’s process of repairing and healing it is precisely what causes some of that soreness. The response involves inflammatory responses - driven by cytokines - extending to the next day that makes the muscles so unwilling to push hard.

However, this is not to be understood as a case of either or. As anyone who got carried away and went all-out in the final 400m rep would know, you often pay the price for the recklessness in the subsequent workouts. Even if the workout was performed in a controlled way, recovery isn’t all of 90 seconds in the first example: you can feel both muscular and even whole body fatigue well after the workout. Likewise the long run is not devoid of lactate/hydrogen ions causing metabolic stress. In reality, there is a combination of short term and long term fatigue components operating for most activities but we can still talk about predominant type of fatigue and the principal factor that limits performance.

Fatigue at a peripheral vs central level

Duration of recovery isn’t the only axis of variation for fatigue; we’ve long recognized the difference between peripheral and central fatigue.

Peripheral fatigue, by definition, identifies the physiological and biochemical changes to the muscles and their properties at a local level as distinct from the more “command and control” central fatigue - modifications that are driven by brain and the central nervous system (CNS) more broadly. To most athletes, this makes intuitive sense: we know that muscles being exerted over a long period of time develop certain attributes of fatigue (lactate/hydrogen ions buildup we mentioned earlier) and at the same time, there are other aspects such as perception of effort changing over the course of a race that likely have their origins in the brain.

Unraveling the Science Behind Central and Peripheral Fatigue

The difference between peripheral and central fatigue is not one of vague conjecture. There is a credible scientific theory based on our understanding of force production, muscle damage, nervous system function etc. There have been multiple studies that together have helped us develop a more comprehensive understanding of fatigue.

Scientists for example test how much the athletes can contract their muscles after a long workout. Or examine the response of the same muscle to an induced electrical stimulus. We have robust findings on how optimal fueling and hydration can significantly delay the onset of fatigue. We also have evidence from both science and the experience of trained athletes regarding the impact of external temperature on the time to fatigue.

Nonetheless, the more we examine the evidence related to central and peripheral fatigue, the more it seems that they are intertwined and influence each other rather than operating as separate and independent contributors to declining performance. This should not come as a surprise when one considers the simple fact that the central nervous system (CNS) processes and responds to, the signals from various sensory receptors in the body and it is only natural to assume that peripheral changes would be influencing the central processing and decision making.

Classic attributes

However, let’s first consider the typical attributes of peripheral and central fatigue. Peripheral fatigue represents the changes at the muscular level from high demand that has been placed on it. This includes structural damage to muscle fibers itself, the inflammatory response to the original damage in terms of cytokines and reactive oxygen species (ROS), alterations to the metabolic milieu characterized by increase in hydrogen ions¹, inorganic phosphate and ROS contributing to metabolic stress, reduced muscle ATP and muscle glycogen stores. What all these factors have in common is their contribution to inherently reduce the ability of the muscle to contract. In other words, when your brains sends the signals to contract, the amount of force (and power) generated would be lower if the muscles are in a fatigued state. At the level of each muscle unit or fiber, the time taken to contract and relax are also increased during peripheral fatigue.

Peripheral fatigue also impacts muscle contraction by directly interfering at the neuromuscular level. The signal for muscle contraction from the brain reaches the muscle fibers through a process known as excitation-contraction coupling. This is the mechanism by which the message is delivered from the motor neuron to the muscle cell. Further, this leads to release of calcium ions in the muscle cell that is critical in initiating the contraction. In the presence of peripheral fatigue, this calcium release is disrupted, reducing muscle contraction and hence force generated. Turns out glycogen depletion is one of the reasons why calcium release disruption happens.

To summarize, one can think of peripheral fatigue as impacting the ability of the muscle to contract upon the reception of the signal to do so.

In contrast, central fatigue causes reduction in the strength of the signal from the CNS to the muscle . When you experience central fatigue, although you want to maintain the same pace the brain delivers a weaker signal to drive the muscle. We know this from experiments in a laboratory setting where we determine for athletes in a fatigued state, the maximum voluntary contraction (MVC) of a muscle group - something like a 1 rep maximum of leg extension - to the magnitude of response generated by an external electrical stimulus to the muscle. If MVC is lower than that obtained through extraneous stimulation, that’s evidence that the central drive “isn’t fully driving the muscle”.

Presynaptic inhibition

Central fatigue also manifests through another intriguing mechanism at the spinal chord. Neurons arriving from the brain (called upper motor neurons) relay the messages to the neurons that ultimately drive the muscles (lower motor neurons) at an important junction (synapse) that is located in the spinal chord. Here the signal strength can be diminished by something called presynaptic inhibition. So even though your brain may send a strong signal to contract your muscles, presynaptic inhibition will weaken that signal before it reaches the muscle. The fascinating aspect to this process is that the inhibitory effect at the synapse is modulated by signals of fatigue from the muscles.

Dynamic interplay

Presynaptic inhibition in fact naturally leads us towards understanding the interaction between the two modes of fatigue. The mechanism there involves the fatigue originating in the muscle (and hence, peripheral) causing the spinal chord to diminish the drive from the brain to contract the muscle (a manifestation of central fatigue). The peripheral and central fatigue are interlinked and working in tandem!

Indeed the more one considers central and peripheral fatigue as independent components, the more the picture seems fractured and incomplete. It would seem almost naive to imagine that they are independent despite the fact that they often operate in different ways . We have seen for example that central fatigue is understood as impacting neuronal transmission and signal strength. That description does not quite tell us why this is happening and what are the causes of it. Likewise we’ve seen that peripheral fatigue diminishes the muscle contractile properties and causes localized muscle damage but there are sensory receptors in the muscle sending this information back to the brain.

Feedback loop

The communication and feedback between the brain and peripheral muscle tissues suggests that central regulation is influenced, in part, by the condition of the skeletal muscles. If the muscle fibers show relatively little damage or oxidative stress, central drive is maintained at a steady level. However, if signs of fatigue are detected—such as an acidic environment or glycogen depletion—the brain initiates a protective response by reducing central drive. This response serves to prevent further deterioration of the underlying cause of peripheral fatigue.

While this feedback loop is a critical part of how fatigue develops and evolves, it cannot explain everything. We know for example that environmental conditions such as temperature and humidity affects race performance and can advance or delay fatigue in the athlete. The reason for this has to do - at least partially - with how these factors influence the rise in core temperature. Now elevated core temperature can impact muscle function but that’s only a small part of the story. It can reduce enzymatic activity and metabolic efficiency throughout the body besides accelerating loss of plasma volume from dehydration which in turn increases the heart rate. Thus there is an independent central component here that contributes to the overall fatigue even though markers of peripheral fatigue are also elevated in adverse environmental conditions.

Psychological Dimension

Despite extensive discussion of the physiological aspects of fatigue, anyone who has run a race is familiar with its psychological elements of performance. Every endurance runner understands the impact of motivation, expectation, mood, and stressors on both training and racing. For example, pain perception tends to decrease when motivation is high. There’s the added edge that only race day seems to bring out. A determined runner can often defy the odds, persisting despite adverse conditions. There is little doubt that psychological factors influence central regulation—and, consequently, the characteristics and perception of fatigue.

Another challenge to any simplistic understanding of fatigue is the “kick” at the end of a race: however tired a runner may be and whatever the degree of slowdown in pace since the start of the race, there is very often a reserve available a few hundred meters from the finish line. That rules out peripheral fatigue as an absolute speed limiter: clearly there are still fast-twitch fibers available for the last-ditch effort. What about central fatigue? At the very least, it seems to be partially determined by the expectations of how long the activity will continue and the need to conserve resources for the same.

Summary

Fatigue is a complicated phenomena having multiple dimensions to it. Not all fatigue is created equal and so are the methods to delay and recovery from them.

Of all the categorization, the conception of central and peripheral fatigue represents an important distinction in how fatigue manifests. Although they differ from each other in terms of the physiological and biochemical processes that characterize them, there is significant interdependence between them too: information about the condition of the muscles is carried to the brain which in turn responds and tunes the signals accordingly.

In the next part, we’ll explore the strategies to delay the onset, minimze its impact and recover from it. Ultimately, fatigue is a natural response to the loading; how we choose to adapt and deal with it is the key.

1. Low pH reduces the number of high-force cross bridges in fast fibers, and the force per cross bridge in both fast and slow fibers. The former is thought to involve a direct inhibition of the forward rate constant for transition to the strong cross-bridge state. In contrast, inorganic phosphate (Pi) is thought to reduce P0 by accelerating the reversal of this step. Both H+ and Pi decrease myofibrillar Ca2+ sensitivity. This effect is particularly important as the amplitude of the Ca2+ transient falls with fatigue.

https://doi.org/10.1152/japplphysiol.01200.2007