Are there sex differences in how the body responds to exercise in ME/CFS?


Post-exertional malaise (PEM) –  the worsening of symptoms that follows even minimal physical (and sometimes mental) effort –  is a key feature of ME/CFS, and is included in the symptoms which must be present for a diagnosis of ME/CFS under the NICE guidelines for ME/CFS, alongside fatigue, unrefreshing sleep and cognitive difficulties. PEM is also included in existing case definitions for both ME/CFS (Canadian Consensus Criteria) and CFS (Fukuda criteria).

Research suggests that there are distinct changes in molecules in the body between people with ME/CFS and healthy controls at rest – including differences in the molecules involved in protein production called microRNAs and differences in proteins related to the immune system. However, less is known about whether there are also differences in specific molecules, and how the body produces them, following periods of physical activity when people with ME/CFS experience PEM.

The authors of a study published earlier this year used an exercise test designed to induce PEM, and investigated whether there were differences between people with ME/CFS and healthy controls in the way the body uses information in genes to produce specific proteins (gene expression).

Gene expression is the process that turns the genetic material in the body (deoxyribonucleic acid or DNA) into an observable set of characteristics – from the colour of your eyes, to the way in which your body responds to the environment, such as stress, and other exposures such as infection. Studies that look at changes in gene expression can be used to investigate whether some people are at a higher risk of a disease, or to help explain why a certain group of people are experiencing specific symptoms.

The results of the study showed that there were indeed changes to gene expression four hours after the exercise test in females with ME/CFS, and that the changes related to production of immune system proteins. However, this study did not consider male participants with ME/CFS.

Evidence shows that there are sex differences in ME/CFS; for example, there are three times more females with ME/CFS than males, and there are differences in both how symptoms present and in the course of the disease.

In order to consider potential sex differences in gene expression following physical activity, the same research team conducted another more recent study investigating the effect of the exercise test designed to induce PEM in male participants with ME/CFS, and also considering whether there were sex differences in the response to physical activity.

What did the study do?

The study, carried out in the USA, included 24 female and 11 male participants with ME/CFS, and 21 female and 14 male healthy controls who were of a similar age and body mass index. Participants with ME/CFS were diagnosed using a range of different criteria for ME/CFS (the study specifies “1996 CDC, Fukuda criteria for diagnosing CFS and 2003 Canadian Consensus Criteria for ME/CFS).

The researchers collected information on areas of mental and physical health from all participants. They also took blood samples; before the blood was drawn, participants all ate a standard meal for breakfast, and had 30 minutes of rest in reclining chairs.

Following this, participants underwent an exercise test which was designed to trigger PEM. The test  involved cycling for two minutes at a set resistance (60W), then increasing the resistance every two minutes by a set amount each time (30W), until the participants reached their maximum effort. Blood samples were taken again at the point of maximum effort, and at four hours after.

The blood samples were then used in a series of detailed scientific tests to consider whether immune cells and the expression of genes differed at the different time points – before exercise, at maximum effort, and four hours after maximum effort.

What did the study find?

Overall, there were differences in the response to the exercise test for both male and female participants with ME/CFS, compared with healthy controls. 

Importantly, the results also demonstrated differences in response to the exercise test between male and female participants with ME/CFS. The results were highly complex, and identified changes in expression of many different genes which related to immune signalling pathways.

In summary, compared with measures at rest:

 Male healthy controls had:Males with ME/CFS had:Female healthy controls had: Females with ME/CFS had: 
At peak physical exertion No significant changes in expression of genes Significant changes in expression of 118 genes Significant changes in expression of 102 genesNo significant changes in gene expression
Four hours after peak physical exertionSignificant changes in expression of 1,256 genesSignificant changes in expression of 1040 genesSignificant changes in expression of 831 genesSignificant changes in expression of 1277 genes

What do the findings mean?

This study provides new evidence that there may be a biological sex difference in gene expression of people with ME/CFS in response to an exercise test designed to trigger PEM. It also adds to existing evidence of differences on a molecular level between people with ME/CFS and healthy controls following exercise.

For both male and female participants with ME/CFS, changes in gene expression, both during and following peak physical exertion, related to the immune system – specifically, the part of the immune system that responds to initial infection (the innate immune system). While there was some overlap identified in the immune pathways affected, there were sex differences in the specific genes and cells most involved. The authors suggested that these innate immune system changes could lead to a reduced ability to respond to a physical stress, and therefore contribute to PEM in people with ME/CFS, and that the sex differences in the exact cells affected could explain why the severity of response to exertion has been found to differ between men and women with ME/CFS.

It important to note that the results from this study are limited by the small sample size, and also by the criteria used to diagnose ME/CFS – both the 1996 CDC, Fukuda criteria which is used to diagnose CFS and the 2003 CCC criteria which is used to diagnose ME/CFS were used. These criteria have slightly different symptom requirements for a diagnosis, and it may not be appropriate to combine people diagnosed using the two different methods together in analysis.

In addition, the study only considered the response to physical activity at four hours following maximum exertion. NICE states that PEM “is often delayed in onset by hours or days”, and so more research is needed which considers how the body responds at a molecular level to all types of activity (cognitive, physical, emotional and social) over a longer period of time.

Takeaway messages

  • While distinct changes in molecules of the body have been identified in people with ME/CFS compared with healthy controls at rest, less is known about whether these differences also exist following exercise – during periods of PEM.
  • A study published earlier this year used an exercise test designed to induce PEM, and found that there were changes in the way genes relating to immune function are expressed in females with ME/CFS. However, the study did not consider males with ME/CFS.
  • The researchers conducted another study using similar methods which did consider males with ME/CFS, and looked at biological sex differences in response to the exercise test.
  • The results demonstrated a sex difference in the way genes relating to immune function are expressed in participants with ME/CFS, both at maximum physical exertion and four hours after.
  • These observed changes in gene expression may help explain why people with ME/CFS experience PEM, and also why there are differences in the exact severity of response to exertion experienced between males and females with ME/CFS.
  • This was a small exploratory study, and only looked at PEM four hours after physical activity.
  • More research is needed using larger sample sizes, and considering PEM after different types of activity over a longer period of time.
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