WASF3 – disrupting cellular energy production in ME/CFS

Malfunctioning mitochondria have long been thought to play a role in ME/CFS but working out exactly what is wrong is taking time.

You may hear mitochondria called “the powerhouse of the cell.” Mitochondria are an energy factory. The job of mitochondria is to process oxygen and convert substances from the foods you eat into energy. Mitochondria exist in nearly every cell in the human body. Mitochondria produce 90% of the energy our bodies need to function. [Cleveland]

US researchers have now discovered unusually high levels of a protein called WASF3 in a woman with ME/CFS.  They tested it in cultured cells and mice and found the protein could disrupt mitochondrial function. They then compared healthy people with people with ME/CFS and found all people with ME/CFS had high protein levels.

Other experts warn this might only be part of the answer but the group is now looking at drugs that could reduce WASF3’s effects on mitochondria, with an eye toward designing a clinical study.

WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome by Ping-yuan Wang, Jin Ma, Young-Chae Kim and Paul M Hwang in PNAS Vol. 120, No. 34, Aug 2023 [doi.org/10.25444/nhlbi.23681013]

Significance: 

Chronic fatigue is a debilitating symptom that affects many individuals, but its mechanism remains poorly understood. This study shows that endoplamic reticulum (ER) stress–induced WASF3 protein localizes to mitochondria and disrupts respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise endurance.

Alleviating ER stress decreases WASF3 and restores mitochondrial function, indicating that WASF3 can impair skeletal muscle bioenergetics and may be targetable for treating fatigue symptoms.

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging.

A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies.

We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress.

Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue.

Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation.

In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.

Independent: A woman who survived breast cancer twice may have inadvertently furthered long Covid research

Read the story of how Amanda Twinam’s search for answers to her low energy inspired Dr Paul Hwang to study how the protein called WASF3 was plugging up her energy production process. Dr Hwang is now focused on curing ME/CFS, and his team plan to trial a new drug.

Science.org: A protein that disrupts cells’ energy centers may be a culprit in chronic fatigue syndrome

Psychiatrist: A Protein That Zaps Cellular Energy May Underlie Chronic Fatigue

Initial findings from the DecodeME questionnaire data published

The Study team report:

We’ve analysed questionnaire answers from the first 17,000 DecodeME participants and the results have been published by NIHR Open Research – read the paper HERE.

We are still recruiting participants and will continue to collect information as more join the study – take part HERE.

Main findings from our analysis:

Being female, older and ill for longer increase the chance of greater severity

Our findings support the assumption that ME/CFS is significantly more common in females as 83.5% of participants reported their sex assigned at birth as female. Furthermore, our data suggests that females are more likely to experience severe symptoms. This likelihood further increases with age and if they have had the condition for more than 10 years.

Additionally, a higher percentage of female participants reported other co-occurring health conditions.

Two-thirds (66.7 per cent) of women, and slightly more than half (52.7 per cent) of men, reported at least one active co-occurring condition. Similarly, 39.2 per cent of women and 28.6 per cent of men reported at least one inactive co-occurring condition.

The most common active co-occurring condition was irritable bowel syndrome (41.3 per cent), with clinical depression (32.4 per cent), fibromyalgia (29.5 per cent), anaemia (14.1 per cent) and hypothyroidism (12.8 per cent) also featuring prominently.

Women also reported, on average, more symptoms than men – 42 compared with 36.

The most common of these symptoms were brain fog – a term commonly used to describe the cognitive impairment experienced by participants – unrefreshing sleep, and muscle pain.

Experts say that gaining a better understanding of how ME/CFS affects people is the first step to developing effective treatment options.

To further improve our understanding, we are still recruiting participants whose questionnaire answers will help us understand even more about ME/CFS. Many of these participants will also be invited to provide a DNA sample to contribute to the DNA portion of the study, which aims to identify the biological causes of the illness.

Take part HERE.

Do you know someone with ME/CFS? Spread the word and help them take part in the world’s largest ME/CFS study. Go to our ways to share page to find out how.

See also:

Trial By Error video: Professor Chris Ponting Discusses on DecodeME’s First Results

Open Access Government: ME/CFS study reveals chronic fatigue syndrome affects women more than men

Guardian: ME/CFS Women with ME tend to have more symptoms than men, study suggests

Independent: Women with ME tend to have more symptoms than men, study suggests 

Sky News: Women ‘suffer more from ME’, according to largest ever study into the disease

The viral origin of ME/CFS

Experienced US researcher Prof Maureen Hanson explores the evidence for the viral connection to ME/CFS and finds no proof that multiple infections lead to ME/CFS. She sees enteroviruses as the most likely culprit and although long COVID and ME/CFS overlap more data is needed to determine if they are identical.

Excerpts from her article:

Can any infection lead to ME/CFS?

There is actually no proof that multiple different pathogens can cause ME/CFS. Yet, this hypothesis persists largely due to the overinterpretation of data from at least 2 studies. The limited evidence depends on how ME/CFS is defined.

Why is the enterovirus family the most likely culprit in ME/CFS?

History offers persuasive evidence to suspect the enterovirus (EV) family of causing ME/CFS. Both circumstantial and direct evidence exists to support such a conclusion.

What is the relationship between human herpesviruses (HHVs) and ME/CFS?

A striking number of ME/CFS patients mention an acute infection with EBV or some other human herpesvirus (HHV) as the start of their illness. Whether this is true or not is not known. If someone has a long course of mononucleosis, an additional virus that may or may not cause symptoms might be necessary for induction of ME/CFS.

Infections with HHVs are common and lifelong. Healthy people maintain viruses such as EBV in a latent state.

Reactivation of dormant HHVs as a result of onset of ME/CFS may have sometimes been mistaken for a new infection, resulting in patients believing that an HHV induced their chronic illness.

Should the post-SARS-CoV-2 infection syndromes be called “ME/CFS”?

… while it would be correct to say that someone has post-COVID illness with symptoms diagnostic of ME/CFS, referring to a post-COVID syndrome as actual ME/CFS will confuse the scientific literature and cloud clinical trials.

Recently, a study of 9,764 individuals experiencing symptoms following acute COVID-19 resulted in classification of the cases into 4 subgroups and the identification of 12 core symptoms among 44 that were considered. Unfortunately, one of the key ME/CFS symptoms—unrefreshing sleep—was not evaluated. The 12 core symptoms include ones that are not identified as core symptoms in any of the ME/CFS diagnostic criteria.

Nevertheless, the intriguing overlap in symptoms between some forms of post-COVID illness and ME/CFS suggests that disruptions in the same pathways may be occurring in both diseases, but to conclude the 2 syndromes are identical without more data, especially at the molecular level, is currently unwarranted.

Conclusion

Ignoring the abundant evidence for EV involvement in ME/CFS has slowed research into the possible dire but hidden consequences of EV infections, including persistence in virus reservoirs. Prior to the SARS-CoV-2 pandemic, the ability of RNA viruses to persist in tissues for long periods was largely ignored.

Further, recognizing that EVs are prime candidates for causing ME/CFS suggests how critical it is to pursue a relevant inquiry into this diverse virus family. Do hidden reservoirs harbor these viruses? Have they induced autoimmunity through molecular mimicry? Is it past or current infection that has resulted in the many findings of immune dysfunction in ME/CFS?

Read the full paper:

The viral origin of myalgic encephalomyelitis/chronic fatigue syndrome, by Maureen R Hanson in PLoS Pathog 19(8): e1011523. [doi.org/10.1371/journal.ppat.1011523]

Medical express: Chronic fatigue syndrome may have a post-viral infection origin

Home-based testing protocol to measure physiological responses to everyday activities in ME

Physios for ME and an exercise specialist have trialled a safe method of measuring the effect of everyday activities on people with ME/CFS.

CPET exercise testing in the lab has, in the past, shown abnormal reactions to exercise, but now a portable metabolic assessment system and a physiological stress monitor has shown people with ME/CFS also react abnormally to normal everyday activities such as:

• Lying for 5 min
• Sitting for 5 min
• Standing for up to 5 min
• Typical bathroom activities (e.g. washing, grooming, toileting) for up to 5 min
• Walking downstairs
• Typical kitchen activities (e.g. preparing breakfast, hot drinks) for up to 5 min
• Walking upstairs
• A formal cognitive activity (serial sevens test [31]) and other standardised mental arithmetic problems were performed while sitting for up to 5 min.

“All participants demonstrated some physiological abnormalities during testing, which supports preliminary success to further develop this home-based assessment approach.

However, there was no single activity that all participants could complete that caused roughly similar abnormal response(s) in all participants. Thus, future work to produce a standardised testing protocol that yields broadly informative findings on ME pathophysiology is likely to require additional study with larger samples.

Perhaps surprisingly, the activity that caused most participants to exceed their anaerobic threshold was the cognitive task, which all but one participant was able to complete.”

All participants were positive about the testing process and would recommend it to others. 11 showed signs of undiagnosed Orthostatic Intolerance, and the evidence of over doing it (i.e. exceeding anaerobic thresholds) suggested who might benefit from heart rate monitoring  as part of an energy management strategy.

Home-based testing protocol to measure physiological responses to everyday activities in ME: a feasibility study, by Nicola Clague-Baker, Sarah Tyson, Karen Leslie, Helen Dawes, Michelle Bull & Natalie Hilliard in Fatigue: Biomedicine, Health & Behavior (2023) [DOI: 10.1080/21641846.2023.2245584]

Research abstract

Background and objectives
Individuals with Myalgic Encephalomyelitis (ME) have shown altered physiological responses during maximum cardiopulmonary exercise testing. However, maximal testing is not representative of the everyday activities reported to cause or increase symptoms in ME, and is not accessible for those with severe or very severe illness. The aim of this study was to assess the feasibility and acceptability of a home-based testing protocol to measure physiological responses in ME to everyday activity.

Methods
Researchers attended participants’ homes to collect data and provide equipment for independent testing. Adults with ME who met the International Consensus Criteria wore a portable metabolic assessment system and a physiological stress monitor. Blood pressure, heart rate, oxygen saturation and lactic acid were assessed during a range of everyday positions and activities in their own homes.

Results
Online recruitment yielded 70 volunteers in 24 h. 17 eligible individuals reflecting a range of illness severities were enrolled. All participants found the procedures acceptable with 12 (70%) subjects completing every listed activity. Apparent physiological abnormalities were identified in all participants.

Conclusion
Physiological measurement during everyday activities was feasible for our participants who represented a range of ME severities. Activities must be adapted for different levels of severity to avoid significant symptom exacerbation. Further research is needed to develop home-based assessment protocols to advance the biobehavioral understanding of ME.

Severe ME clinical training for health professionals

For Severe ME Awareness Day, Learna / StudyPRN are providing all healthcare professionals with free educational content via their ‘Question of the Day’ Campaign to challenge and improve clinical knowledge, understanding and patient management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Clinicians are invited to complete the course to receive a 0.5 Hour CPD Certificate.”

Take part here

Author Dr Nina Muirhead says:

“To mark Severe ME Awareness 2023, this is a short case based series to improve knowledge and increase awareness.

Our case is presented over 5 days and covers four years in the life of a 28 year old man, Rishi.

Questions are designed to engage learners with some of the greatest challenges associated with very severe ME/CFS, including diagnosis and investigations, home visits, managing severe malnutrition and navigating hospital admission as well as recognising the impact of severe and very severe ME/CFS on the quality of life of patients and their families.”

Struck down by ME and vaccinations – Uplifted by poetry and card-making

A lover of the outdoors, and a literature and languages graduate, Ffion’s ME deteriorated after a COVID vaccination.

Her life was already restricted, though she had found a release through writing poetry (often humorous) and making cards, and was occasionally able to enjoy short walks in nature. The vaccination changed that. Now, she says:

Must lie down, darkened room, eye-mask on, in silence, 5-7 hours a day. 

Generally spend, daily, 15-17 hours lying in/on bed.

When upright for c. 1hr in house, very limited – able to:

• make 1-2 cards a day, on a good day
• type a couple of emails
• write and upload a poem
• listen to a little Audible (unable to read book etc. since 2010 and unable to hold face-to-face or phone conversation for more than a couple of minutes…. Oh, the irony…. and me a literature and languages graduate….)
• watch c. 20-30 mins of “easy” TV in evening – nothing fast-paced, active, bright/flashy etc and no more French films for me, nor sub-titled ones, etc. etc.

To sum up

When able to do so very little
It’s a struggle …
To fill in an endless day …

“Activity” must be
Meticulously measured …

Added?

No, divided ….

Then …

Taken away …

Ffion’s husband manages her poetry blog. Each poem is accompanied by a carefully chosen image and she has noted the important role he plays in her life and creativity.

Thank you to the good man in my life

Lying, quietly, in comfy bed …
Room bathed in monochromatic light …

Gradually, the world awakens …
Advancing daylight vanquishes night.

And then appears …. The Good Man …
His presence a balm to my burnt-out brain …

“How was your night?”, he gently asks …
And day – if not Life – begins again …

Ffion marks Severe ME Day 2023 with: A life in a day

Read more poems by Ffion: ffionoriginalpoems

See Ffion’s cards on Facebook: Ffion.cards.1

Caring for people with ME/CFS who are bedbound

Emerge Australia has put together a guide to help you care for a loved one who is severely impacted by ME/CFS and has become bedbound

People who are mostly or entirely bedbound by ME/CFS may need support with:

ME/CFS leaves some people so unwell that they are not able to manage any activities of daily living without help.

They are often extremely sensitive to light, sound and touch, and need total care.

They may not be able to speak or may only be able to speak in short bursts.

While some of the information in the guide is tailored for people living in Australia it also covers the range of symptoms and disabilities and the need to work with healthcare professionals and look out for changes to the bedbound person’s condition.

Also included are practical tips for helping with activities of daily living:

• bathing
• toileting
• tooth brushing
• dressing
• eating and drinking
• moving and better positioning to protect the person from pressure ulcers, contractures, skin and joint irritation, and poor alignment
• mobility and transfers to protect both the carer and person with ME/CFS from injury due to lifting and turning
• setting up the room to protect the person from unnecessary physical, cognitive or emotional exertion
• Support and socialising

Read the 8 page guide online

Download the pdf