Energy and exercise.

The physiology of fatigue

The level of the brain

Fatigue is probably best understood as a tool the brain uses in its energy budgetting.

It is very important the brain does not run out of resources, so fatigue tends to kick in whenever there is a possibility of this on the horizon.

This means that fatigue is based on expectations and contextual information, like other symptoms, it is an experience generated by our predictive brain. 

Some of this contextual information is coming from other systems in the body.

For example, we feel fatigued when we have an infection or inflammation. The immune system signals to the brain we need to conserve energy, we might need to fight off a pathogen, or recuperate and heal.

The brainstem

The autonomic nervous system communicates at the level of the brainstem and has a central role in the signalling of fatigue and energy regulation.

This is a complicated picture (a small amount of stress can increase energy in the short term–physiological relaxation can actually make you feel exhausted), but chronic physiological stress means there is a lower threshold to trigger symptoms.

The autonomic nervous system is also regulating blood-flow throughout the body, including to muscle tissue. 

Muscle tissue

For obvious reasons, scientists looking for a footprint of fatigue, have been drawn to skeletal muscle.

When looking at muscle in fatigue, you might see less blood/oxygen flow to muscles (perfusion), and a less healthy milieu around the cells.

Immune cells may be activated in this milieu and play a role in maintaining the sleep-like protective state of the muscle cells.

Skeletal muscle cells

The muscle cells themselves can show changes as fatigue becomes chronic.

For example, the ion pumps that are important for maintaining the contractibility of the cells slow down.

This means that some ions, importantly sodium and calcium (Ca2+), build up inside cells.

This build up of ions can effect the strength of contractions of the muscle.

Mitochondria

Mitochondria are small organelles that live in all our cells. They originate from bacteria, but have been a fundamental part of the physiology of eukaryote cells for over a billion years.

Mitochondria’s primary role is  to produce the unit of energy called ATP, which feuls many processes in the cell, including running the ion pumps.

For this mitochondria require oxygen, that trickles down to them from the air we breath, via the circulatory system (perfusion), and energy from the food we eat.

Another function of mitrochondria is to act as a calcium buffer. When calcium builds up in the muscle cells, in the beginning the mitochodria soak it up.

However after a certain level, calcium becomes mildly toxic to the mitochondria, it slows down their production of ATP.

ATP is needed to pump the ion channels, which slow down even more: a dysfunctional loop is established.

The whole picture

When you take the whole picture into account, the evidence suggests that in severe and long term fatigue, dysfunctional loops are established at multiple levels (see figure).

New dysfunctional steady states are set up and it becomes impossible to distinguish which loop started first, and which are knock-on effects of dysfunction in other parts of the system.

However, the whole system is effected by movement.

This is why gentle movement, stretching, dancing, walking, or swimming, done within your body’s limits, is essential to waking up your muscles.

Let’s take a moment to address a few common misconceptions about PEM:

1: PEM is only experienced in Myalgic Encephalitis (ME)

You might come across the idea that post-exercise crashes are exclusively tied to ME.

While it’s true that people with ME experience PEM, it’s important to remember that this symptom isn’t limited to just one condition.

In fact, PEM can occur across a wide range of conditions and syndromes.

We hope this brings some reassurance: experiencing PEM does not automatically mean you have ME. It’s a symptom that can be seen in different contexts, and it’s not always indicative of a severe chronic health issue.

2: Exercise is harmful if you have PEM

You will often read on the internet that exercise can be harmful, and make symptoms worse. It is important to hold this frightening thought in balance.

While there have been examples where exercise therapies were not well-implemented and pushed people too hard, it’s important to recognize that a paced and gentle approach to movement is necessary to rebuild health.

The key is to work within your body’s limits and gradually build up tolerance, without pushing too far too fast.

You can read our advice on pacing in our Guide to Recovery Planning Skills

3: You can’t trust the research?

You might come across claims that research on graded exercise therapy (GET) is unreliable or that it’s been tainted by fraud. Such claims can understandably be concerning.

In our reading of the literature, multiple trials show that GET has a positive impact for most people with fatigue, and we encourage you to explore our references.