A new study published in Proceedings of the National Academy of Science sheds some light on the role of a protein that may prevent ME/CFS patients from generating normal amounts of cellular energy.
A Medical Mystery
ME/CFS has no known cause and is not well understood, even by medical professionals. The condition is characterized by extreme fatigue and the inability to recover normally after exertion.
Symptoms can last for years and include neurological concerns such as dizziness, memory problems, and difficulty concentrating. Many sufferers are unable to return to work or perform normal daily activities the way they did before becoming ill.
This medical mystery may be closer to being solved thanks to scientists from the U.S. National Institutes of Health (NIH) and their investigation into the WASF3 protein.
A Plea for Recognition
ME/CFS often arises following a viral infection such as flu or a respiratory virus. It is unknown why some people never fully recover from the initial infection and go on to develop the long-term symptoms of ME/CFS. There is no medical test for ME/CFS.
Doctors can only diagnose ME/CFS by systematically ruling out other possible causes, a process that can sometimes take months or even years.
Adding insult to injury, many doctors have historically misunderstood ME/CFS—even doubting its existence entirely. Routine tests often come back normal, and many sufferers have had their symptoms dismissed by healthcare providers as being “all in their head”.
For decades, physicians prescribed psychotherapy or exercise programs that were inappropriate or actively harmful to their condition.
Advocates have struggled for many years for better recognition of ME/CFS in the international medical community. The U.S. Institute of Medicine finally acknowledged ME/CFS as a physical illness in 2015 and made recommendations to standardize the way it is diagnosed. These criteria were adopted in the U.S., but other countries have been slower to get on board. The UK, for example, did not officially recognize ME/CFS until 2021.
Margaret Parlor, president of the Canadian advocacy group, The National ME/FM Action Network, told us “Society in general, and the health and social service systems in particular, have been reluctant to acknowledge ME. This attitude has tremendous consequences for people who are genuinely energy impaired, and who often do not receive the respect they deserve and the support they need. They may not receive quick and accurate diagnosis and advice which can lead to worse outcomes. Anecdotal and statistical evidence shows that they are dealing frequently with issues like poverty, food insecurity, and social isolation.”
“Kerri”, a British woman living with ME/CFS, explained to Medical News Bulletin that she had to leave university and was bedridden for two years after developing the condition. She shared how her illness is often dismissed as a psychiatric issue, “You see a change in the doctor’s approach as soon as you mention ME. There is a huge bias in the medical community, and we are in a fight against that every time we need to seek treatment.”
This slow adoption of new information by government and medical institutions has had a material effect on the quality of life for ME/CFS patients, and support for research.
The hallmark of ME/CFS is post-exertional malaise. It is normal to feel tired after exercise, but healthy people regain their energy with rest. In contrast, people with ME/CFS experience an extreme and abnormal inability to recover after exercise. You could say they run down their batteries and can’t recharge them.
Dr. Paul Hwang, who led the study, and his team uncovered an important clue as to why people with ME/CFS can’t refill their batteries. They found abnormal amounts of a protein called WASF3 in the mitochondria of patients with ME/CFS.
Known as the “powerhouse of the cell”, mitochondria create energy for every cell in the body by converting oxygen and glucose into a molecule called ATP. When your muscles work, they use ATP as fuel to make each muscle cell contract.
If you can’t make ATP in large quantities and fast, you don’t have enough fuel to operate your muscles, so you feel weak or tired.
Dr. Hwang explains, “When people with ME/CFS exercise, they don’t use up as much oxygen from their blood as normal people. They also make more lactic acid, which is a marker of poor oxygen utilization.” In other words—people with ME/CFS feel exhausted because their cells have trouble generating and using energy effectively.
Researchers in the ME/CFS field have long suspected that something is wrong in the mitochondria of patients with ME/CFS. The findings of Dr. Hwang and his team add strength to this theory and excitingly, point the way for further investigation.
A Role for WASF3 in ME/CFS
Dr. Hwang described the discovery as a prepared accident. Setting out to study the mitochondria of patients with genetic cancer called Li-Fraumeni Syndrome, they found a discrepancy in one patient who also had chronic fatigue.
They detected excess WASF3 in the mitochondria of this patient and felt obligated to investigate further.
The researchers compared the muscle cells of the patient with ME/CFS to the muscle cells of a sibling (brother or sister) who did not have the disease. They found abnormal amounts of WASF3 in the muscle cells of the patient with ME/CFS, but not in the healthy sibling. When tested, the muscle cells with abnormal amounts of WASF3 did not recover as quickly from exercise, leading the researchers to wonder if surplus WASF3 was causing exercise intolerance in the patients with ME/CFS.
The team tested this intriguing hypothesis on mice genetically modified to overproduce the WASF3 protein. The mice that overproduced WASF3 were able to run half as long on a treadmill compared to normal, wild-type mice.
The group then compared several muscle tissue samples from patients with ME/CFS to healthy volunteers. They found significantly higher WASF3 levels in the samples from people with ME/CFS.
Together, these findings suggest a connection between too much WASF3 and ME/CFS symptoms.
An intriguing aspect of this finding was that WASF3 protein levels were driven by cellular stress.
Scientists are now discovering links between cellular stress and mitochondrial damage in many chronic conditions e.g. rheumatoid arthritis and cardiovascular disease. Researchers believe that by exposure to certain viruses, including COVID-19 can cause mitochondrial dysfunction.
The authors hope their research will provide insights, not only into ME/CFS, but into other disorders associated with fatigue such as rheumatic arthritis and long COVID.
What’s next for WASF3?
This work is in its early stages, it will be some time before clinical tests can be developed for WASF3. In the meantime, the NIH researchers hope other research groups will validate their work- confirming their results and gathering more test subjects.
Dr Hwang acknowledges that this study involves a sample size of only 14 patients. WASF3 levels in muscle tissue may explain fatigue in only some ME/CFS patients. The next stage of this research will be testing how closely extra WASF3 correlates to abnormal fatigue.
He tells us, “We do not believe that WASF3 is the cause of ME/CFS, but rather is one of the factors mediating energy deficiency in muscle. We need to see if we can target WASF3 in ME/CFS patients and fix the bioenergetic defect that we have described.”
He continues, “Having identified WASF3 in the mitochondria, we are now very interested in studying its role in ME/CFS. In our lab we are working on finding the best that we can, realizing that treatment is a priority.”
Looking to the Future
Margaret Parlor of the National ME/FM Action Network was cautiously optimistic about the study. She stated that the results add credibility to the growing understanding that the symptoms of ME/CFS have a biological foundation. However, she points out, that there is a need for increased national attention and funding for ongoing research.
A 2020 study of disease funding by the U.S. National Institutes of Health (NIH) found the disease burden of ME/CFS is double that of HIV/AIDS and over half that of breast cancer. To be proportionate with the disease burden, the study found that funding for ME/CFS research would need to increase roughly 14-fold.
Further research, credibility with medical professionals, and meaningful treatment options cannot come soon enough for people like “Kerri”, “It would be amazing if we could have some small steps towards change. Studies like this need more exposure and international recognition. We need to turn the tide of public and medical perception of the illness.”
To find out more about WASF3 check out our interview with Dr Paul Hwang. Want to get to grips with the science behind the story? Join us at MNB:Journal Club for a translation of the original research article.
Centers for Disease Control and Prevention (2023). Myalgic encephalomyelitis/chronic fatigue syndrome. Accessed September 7, 2023, https://www.cdc.gov/me-cfs/about/index.html.
Komaroff (2019). Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome. JAMA. 322 (6):499–500. doi:10.1001/jama.2019.8312
Lim, E. J., Ahn, Y. C., Jang, E. S., Lee, S. W., Lee, S. H., & Son, C. G. (2020). Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Journal of translational medicine, 18(1), 100. https://doi.org/10.1186/s12967-020-02269-0
Mirin, A. A., Dimmock, M. E. & Jason, L. A. (2020). Research update: The relation between ME/CFS disease burden and research funding in the USA. Work. 66(2), 277—282. https://doi.org/10.3233/WOR-203173
Wang, P., Ma, J., Kim, Y., Son, A., Syed, A., Liu, C., Mori, M., Huffstutler, R., Stolinski, J., Talagala, S., Kang, J., Walitt, B., Nath, A., & Hwang, P. (2023). WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proceedings of the National Academy of Sciences of the United States of America, 120 (34). https://doi.org/10.1073/pnas.2302738120
Zhang, C., Syed, T.W., Liu, R. and Yu, J. (2017) Role of endoplasmic reticulum stress, autophagy, and inflammation in cardiovascular disease. Frontiers of Cardiovascular Medicine, 4(29) doi: 10.3389/fcvm.2017.00029