As explained in a paper, published in the Journal of Translation Medicine, muscle-related symptoms – including “exertional muscle pain, very early fatiguability, muscle twitching and cramps, tremor, heaviness – even to the point of a complete inability to perform movements – as well as severely delayed recovery following even minimal physical activity” are common in ME/CFS, and closely linked to post exertional malaise (PEM), which is known as the cardinal feature of the disease.
While research teams have tried to attribute these muscle symptoms in ME/CFS to a single biological mechanism, attempts to date have been unsuccessful. Rather, studies have indicated that overlapping groups of symptoms, including, autonomic dysfunction, flu-like symptoms, cognitive impairment, sleep disturbances, and respiratory complaints, may link to multiple interacting processes within the body, such as:
- Persistent or intermittent activation of the immune system.
- Dysregulation of the autonomic nervous system.
- Endothelial dysfunction: Dysfunction of the thin layer of cells that line blood vessels in the body.
- Abnormalities in cellular metabolism; how cells produce and use energy.
The researchers go on to note that observations in the research findings to date point to ME/CFS being a ‘multisystem disorder in which impaired vascular and metabolic regulation may contribute substantially to muscle function and exercise intolerance’, adding that biological sex, and the effect of sex hormones, lead to further layers of complexity – something which has been observed previously.
To further explore how other systems in the body could be linked to muscle function, the researchers looked at how muscle problems relate to other symptom groups, and explored whether these relationships vary by sex, by an age-based approximation of menopausal status, and by illness duration.
What did the researchers do?
This study is number 5 of 7 in a wider programme of work:
- Study 1 found that ME/CFS symptoms may form groups, or clusters, over the course of the illness.
- Study 2 found further evidence that ME/CFS symptoms occur in clusters.
- Study 3 examined differences between men and women in brain, sensory and automatic body-function symptoms.
- Study 4 found that immune and gut symptoms may group differently in men and women, and may also vary with menopausal status.
- Study 5, the current study, examines how muscle symptoms fit into the wider pattern of ME/CFS symptoms and whether this differs by sex or menopausal status.
- Study 6 will examine how symptom patterns change with illness duration and whether sex or sex hormones may affect these changes.
- Study 7 aims to show that ME/CFS symptoms are connected through a changing network of biological systems, rather than being separate problems.
All studies use (or plan to use) information from people with “physician-diagnosed ME/CFS” who were enrolled in the APAV-ME/CFS registry.
In study 4, the researchers explained that, in the registry, “it can be assumed that the diagnosis was primarily based on the Canadian Consensus Criteria or the International Consensus Criteria, given that these diagnostic methods are widely used in Germany.”
Study 5 included 736 participants (599 women and 137 men), and used several statistical methods to look at:
- Which of 14 ME/CFS symptoms were linked to muscle problems and how often symptoms appeared together.
- Whether several symptoms might be connected by an underlying pattern, which they called a “latent physiological symptom-dysregulation factor”. In simple terms, this means a possible shared problem with how the body regulates itself.
What did the study find?
Findings from this exploratory study were complex, but results indicated that:
- People reporting breathing problems were about two and a half times as likely to report muscle problems.
- Flu-like symptoms and difficulties regulating body temperature were each associated with roughly twice the likelihood of muscle problems.
- In a smaller model focused on physiological symptoms, cardiovascular symptoms were also associated with muscle problems.
Importantly, these results are statistical associations between reported symptom groups; they do not mean that one symptom causes another.
The underlying associations were strongest between muscle problems and breathing difficulties, cardiovascular symptoms, and temperature-regulation problems. More moderate links were found with visual disturbances and flu-like symptoms. The analysis suggested that these symptoms may be linked by a shared problem with how the body regulates itself.
What did the subgroup analyses show?
When the sample was divided by sex, different symptom associations reached statistical significance in women and men. However, the overall statistical test did not establish that the pattern of associations truly differed by sex. One individual finding suggested that the link between breathing symptoms and muscle problems may differ between women and men, but this needs confirmation. The authors therefore present the subgroup patterns as descriptive and exploratory rather than firm evidence of sex-specific forms of ME/CFS.
The menopausal-status analysis also requires particular caution. Participants were grouped using age as a proxy for menopausal status rather than using each person’s confirmed reproductive or hormonal status. Such groups may suggest questions for future research, but they cannot demonstrate that menopause or hormones explain any observed difference.
Limitations
As acknowledged by the research team, there were several limitations of this study, including:
- The data were collected at a single point in time. The study therefore provides only a snapshot of participants’ symptoms, rather than showing how their illness changes over time. It also cannot establish which came first—for example, whether muscle symptoms influence other symptoms or whether other symptoms influence muscle symptoms.
- In this study, menopausal status was defined using age groups; those under 50 were classed as pre-menopausal, and those over 50 years as post-menopausal. Not only do these age-defined groups miss out peri-menopausal women, but they cannot determine menopausal stage, provide information on hormone concentrations, use of hormonal medication, or individual reproductive history.
- Dividing the sample into smaller sex, age-proxy and illness-duration groups reduces statistical precision. Testing many possible relationships also increases the chance that apparently important findings arise by chance.
- A relationship being statistically significant in one subgroup but not another does not itself prove that the subgroups differ. The overall sex-interaction test – a test that looks at whether the shape of an association differs between males and females – was not significant, and it is possible that the differences are due to differences in sample sizes.
- Participants in this study came from one ME/CFS registry and may not represent everyone with ME/CFS, including people who are undiagnosed, too unwell to enrol, treated in different health systems, or from under-represented demographic groups.
Conclusion
This study provides preliminary evidence that muscle problems may be integrated into a wider pattern of physiological symptoms in ME/CFS, particularly symptoms involving breathing, circulation, temperature regulation, and flu-like symptoms. The main value of the study is in generating ideas for future research, not in proving a cause or defining distinct sex- or menopause-related subtypes. Replication in more diverse samples, direct measurement of menopausal and hormonal status, longitudinal follow-up, and objective physiological data will be needed before the proposed “symptom-dysregulation factor” can have clinical implications.
