A Study on the Role of WASF3 in ME/CFS

Understanding ME/CFS

A recent study published in the Proceedings of the National Academy of Sciences has examined a protein that could hinder patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) from producing adequate cellular energy. ME/CFS remains a medical enigma with no identified cause, even among healthcare professionals. The condition is characterized by profound fatigue and an inability to recover normally after exertion. Symptoms may persist for years and often include neurological issues such as dizziness, memory challenges, and concentration difficulties, leading many affected individuals to struggle with returning to work or managing daily activities.

A Call for Acknowledgment

ME/CFS frequently develops after a viral infection, such as influenza or a respiratory virus. The reason some individuals fail to fully recover and experience prolonged symptoms remains unclear. Currently, there is no definitive medical test for ME/CFS, and diagnosis relies on the exclusion of other potential causes, a process that can take extensive time. Historically, many healthcare providers have misunderstood ME/CFS, questioning its validity. Routine tests typically yield normal results, and patients often find their symptoms dismissed as psychosomatic.

For decades, inappropriate treatments, such as psychotherapy and exercise programs, have been prescribed, sometimes exacerbating the condition. Advocacy for better recognition of ME/CFS has been ongoing. In 2015, the U.S. Institute of Medicine recognized ME/CFS as a physical illness and recommended standardized diagnostic criteria, which have been adopted in the U.S. but lag in other regions. For instance, the UK only officially recognized ME/CFS in 2021.

Voices of Patients

Margaret Parlor, president of the Canadian advocacy group The National ME/FM Action Network, remarked, “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.” Kerri, a British woman with ME/CFS, shared her experience with Medical News Bulletin, highlighting the bias she encounters in healthcare settings. “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.”

New Insights into ME/CFS

Post-Exertional Malaise

A defining characteristic of ME/CFS is post-exertional malaise. While it is typical for healthy individuals to feel fatigued after exercise, they usually recover with rest. Conversely, those with ME/CFS experience an extreme inability to recuperate. Dr. Paul Hwang, who led the study, identified abnormal levels of the WASF3 protein in the mitochondria of patients with ME/CFS. Mitochondria, known as the cell’s “powerhouse,” generate energy by converting oxygen and glucose into ATP, the fuel for muscle contraction. Insufficient ATP production results in weakness and fatigue.

Dr. Hwang explained, “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.” This indicates that individuals with ME/CFS struggle with energy generation and utilization at the cellular level.

Discovering WASF3’s Role

Dr. Hwang’s team made a serendipitous discovery while studying the mitochondria of patients with Li-Fraumeni Syndrome, a genetic cancer predisposition. They found elevated WASF3 levels in one patient’s mitochondria and subsequently compared the muscle cells of this patient with those of a healthy sibling. The results revealed abnormal WASF3 levels in the ME/CFS patient, correlating with slower recovery from exercise.

Further experiments involved genetically modified mice that overproduced WASF3. These mice demonstrated reduced endurance on a treadmill compared to their healthy counterparts. When tissue samples from ME/CFS patients were analyzed, researchers found significantly higher WASF3 levels compared to those from healthy individuals, establishing a potential link between elevated WASF3 and ME/CFS symptoms.

The Impact of Cellular Stress

Interestingly, WASF3 levels were found to be influenced by cellular stress. Emerging research highlights the association between cellular stress and mitochondrial dysfunction in various chronic conditions, including rheumatoid arthritis and cardiovascular disease. Scientists suspect that certain viral infections, including COVID-19, may contribute to mitochondrial damage, which could relate to ME/CFS and other fatigue-related disorders.

Future Directions for Research

Next Steps in WASF3 Research

Although this research is in its initial stages, the findings open avenues for further investigation. Dr. Hwang notes that the study included only 14 patients, indicating that elevated WASF3 levels may not account for fatigue in all individuals with ME/CFS. Future research will focus on the correlation between WASF3 levels and fatigue severity.

Dr. Hwang stated, “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.”

Looking Ahead

Margaret Parlor expressed cautious optimism about the implications of the study, emphasizing that the findings lend credibility to the understanding that ME/CFS symptoms have a biological basis. She also highlighted the need for increased national focus and funding for ongoing research. A 2020 NIH study revealed that the disease burden of ME/CFS is double that of HIV/AIDS and more than half that of breast cancer, indicating a significant disparity in research funding.

For patients like Kerri, the pursuit of research, medical acknowledgment, and effective treatment options is urgent. “It would be amazing if we could have some small steps towards change. Studies like this need more exposure and international recognition,” she concluded.

References

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