A recent study provides insight into how fatigue can develop in people with ME/CFS and possibly related disorders such as Long Covid.
Along with brain fog and acute fatigue, people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) struggle with a severe lack of knowledge about the origins of their symptoms and treatments. By some estimates, this disease affects 2,5 million people in the United States alone. Scientists have failed to identify the underlying biology of this condition.
Researchers have discovered a protein that affects cells' ability to produce energy and is found at extremely high levels in the muscles of ME/CFS patients. The research, published today in the journal Proceedings of the National Academy of Sciences, could lead to the development of new treatments for this condition as well as other diseases such as Long Covid.
Although not involved in the research, Akiko Iwasaki, an immunobiologist at Yale School of Medicine, said the study was "very well done," while expressing concerns that the suspected protein was likely "a piece of the puzzle rather than explaining the entire disease." According to the research, it may be acting as one of many "intermediaries" between the cause of the illness and symptoms such as fatigue.
Initially, Paul Hwang and his colleagues at the National Heart, Lung, and Blood Institute (NHLBI) set out to investigate a 53-year-old woman who had a cancer-promoting mutation in the TP38 gene. This woman (referred to in the study as S1), unlike her brother and father, who inherited this gene, had long-term extreme fatigue despite not being formally diagnosed with ME/CFS.
Muscle tissue samples were examined by Hwang's team for abnormalities in TP53-related metabolic pathways. In this research, a protein known as WASF3 was found in abundance. Scientists discovered a 2011 under-reported study of gene activity in ME/CFS patients that suggested it may also contribute to the disorder. According to Hwang, this protein is known to play a role in the cell's ability to move.
Mitochondria are cellular structures important for energy production, and the mitochondria of ME/CFS and Long Covid patients have been reported to be malfunctioning. NHLBI researchers wondered whether WASF3 interacts with these mitochondria. In fact, scientists have discovered that altering WASF1 levels in cells cultured from S3 and in other human and animal cells can impair mitochondrial function.
High amounts of WASF3 specifically inhibited the ability of mitochondrial proteins to assemble into molecular complexes that facilitate typical energy production.
Next, Hwang's team genetically modified the mice to create more WASF3 than normal. These animals were only able to run on the treadmill half as long as typical mice, as they also suffered from mitochondrial function issues.
The researchers examined muscle samples from 14 ME/CFS patients, along with those from 10 healthy people, to see if the results would apply to people who had been formally diagnosed with the disease. In people with the disease, they discovered higher average levels of WASF3 and lower average levels of related mitochondrial protein complexes.
According to Mady Hornig, a doctor-scientist who studies ME/CFS at Columbia University's Mailman School of Public Health, it's "extremely encouraging" to see this kind of in-depth molecular approach used to treat such a poorly understood disease. Although they have not specifically studied Long Covid, the NHLBI researchers' findings “tackle a very common set of health issues that are so tightly linked to disability in [both] Long Covid and ME/CFS.”
Hornig, who has been a Long Covid patient since 2020, says further research could examine whether WASF3 also has an effect on brain function. According to him, deficiencies in brain energy metabolism may be responsible for cognitive fatigue, which many ME/CFS patients perceive as the most distressing.
It is unclear what causes the high WASF3 levels to begin with. Hwang suggests that stress on the endoplasmic reticulum (ER), a malfunction of the membranes that help the cell fold protein, plays a role. Because viruses can cause ER stress, ME/CFS and related diseases may often develop after infection. (S1 told Hwang that he felt tired after contracting mononucleosis when he was younger).
Hwang's theory has been supported by a series of laboratory experiments: Treating cells of S1 with a drug that inhibits ER stress resulted in decreased WASF3 levels and restoration of mitochondrial function. Individuals with both S1 and ME/CFS displayed biochemical markers of ER stress in their muscles.
On the other hand, WASF3 levels increased when toxins were used to intentionally induce ER stress in cultured cells or animals, according to Hwang.
Pere Puigserver, a cell biologist at Harvard Medical School, thinks more research is needed to fully understand this link. The author contends that determining the sequence of events leading to extinction can be difficult because ER stress can be triggered by mitochondrial malfunction. Because of its multiple cellular functions, WASF3 may also have other effects in ME/CFS patients, he continues.
Hwang acknowledges that there may be more ways to contribute to fatigue in ME/CFS and Long Covid, and individual susceptibility to the disease may vary. With the aim of developing a clinical trial, his lab is currently investigating drugs that can inhibit ER stress or reduce the effects of WASF3 on mitochondria.
Source: A protein that disrupts cells' energy centers may be a culprit in chronic fatigue syndrome | Science | AAAS
📩 16/08/2023 15:23