Updated: Oct 6
This was forwarded by a client, related to a CFS Story , i will share more as the days go by, but you will see dots begin to get connected. There appears not to be "one thing" behind CFS, rather many different things that can result in similar bio markers and similar symptomology. And yes, these 'things' can be triggered by some of the same things, viral infections, etc. PEM can be caused by many things, hypoxia/low oxygen being one of them, and that is caused by several things as well....getting to the root cause appears to be the way to get to an effective solution.
What you can see in the links between the articles below is how certain genes are related a bit. HSP90, HIF1A, WASF3.....to hypoxia, adaptosis, mitochondrial respiration and function. HIF1A is one of the genes that will drive hypoxia because it effects many others, such as WASF3. For those of you who have worked with me, you know i look at HIF1A early, and you also know, the herbs that help regulate this gene.
Now, read this published by the NIH:
Protein may be linked to exercise intolerance in ME/CFS
At a Glance
A study suggested that high levels of a protein may reduce energy production in the muscle cells of people with ME/CFS.
Blocking this protein in cells in the lab restored energy production, suggesting a potential new strategy for treating the condition.
Mitochondria, illustrated here, house the complex structures that produce energy molecules for the cell. Kateryna Kon / Shutterstock
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) afflicts more than 2 million people nationwide. People with ME/CFS live with debilitating symptoms including exhaustion, exercise intolerance, cognitive problems, and a worsening of symptoms after even mild exertion (known as post-exertional malaise).
The causes of ME/CFS remain poorly understood, although many people first develop symptoms after a viral infection. This gap in understanding limits both diagnosis and the development of treatments.
A team of NIH researchers led by Drs. Paul Hwang, Avindra Nath, and Brian Walitt have been studying a woman who took days to recover after physical exertion and several of her relatives at the
NIH Clinical Center. Their findings were published on August 22, 2023, in the Proceedings of the National Academy of Sciences.
Tests done while the woman was exercising found a very slow recovery of cellular energy production after exertion. Muscle cells taken from the patient and examined in the lab showed reduced oxygen use. Oxygen is used by mitochondria, the cell compartment that makes energy molecules.
Further laboratory studies led the team to a protein called WASF3. This protein, which was boosted in response to cellular stress, disrupted the cells’ energy production. Blocking WASF3 allowed mitochondria to produce energy at normal levels. The team then showed that extra WASF3 in the cells interfered with formation of the structures that mitochondria use to produce energy.
To better understand the role of WASF3, the team engineered mice to produce excess WASF3. They found that, similar to people with post-exertional malaise, muscles in these mice were slow to recover after exercise. The mice also showed a 50% reduction in their ability to run on a treadmill, even though their muscle strength was comparable to mice without extra WASF3.
To see if WASF3 dysfunction might be involved in ME/CFS, the team compared muscle tissue samples taken from 14 people with ME/CFS to samples from 10 healthy volunteers. They found substantially higher levels of WASF3 in most of the people with ME/CFS.
This dysfunctional increase in WASF3 seemed to be linked to impairment of a cellular signaling pathway called the ER stress pathway. When the team treated human muscle cells with a compound known to increase ER stress, they saw a corresponding harmful increase in WASF3.
The researchers treated cells from the initial study participant with an experimental drug, called salubrinal, known to reduce ER stress. After this treatment, WASF3 levels decreased in the cells, more mitochondrial energy complexes formed, and energy production improved.
“We hope to embark on clinical studies to investigate whether this type of strategy can also work in patients to improve energy levels,” Hwang says.
Mitochondrial dysfunction has been found in some people with Long COVID and other conditions that include fatigue. More research is needed to understand whether targeting ER stress may also be a promising approach for these conditions.
—by Sharon Reynolds
Now read these:
"The WASF3 (WAVE3) gene is an important mediator of cell motility, invasion and metastasis and is expressed at high levels in some advanced stage tumors. In our survey of breast cancer cells, we now demonstrate that exposure to hypoxic conditions increases WASF3 expression levels in MDA231, SKBR3 and MCF7 cells. The WASF3 promoter region contains HIF1A response elements (HRE). ChIP assays demonstrate that HIF1A binds to these HRE elements in the promoter region, and luciferase reporter assays using the WASF3 gene minimal promoter shows that hypoxia results in its upregulation. Phosphorylation of WASF3 is required for its ability to affect invasion and increased phosphoactivation of WASF3 is also seen in cells challenged with hypoxia. These cells also show increased motility in the scratch wound assay. Cells in which WASF3 has been knocked down show no response to hypoxia as expected, implicating the specificity of the hypoxic response to WASF3. Overall, these experiments demonstrate WASF3 is a HIF1A-regulated gene and suggests a mechanism to explain the observation of elevated expression of WASF3 in advanced stage tumors." 
"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.
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."
"Inactivation of HSP90 and HSP70 leads to loss of invasion in a variety of cancer cell types, presumably as a result of destabilization of, as yet, undefined clients of these molecular chaperones that influence this phenotype. The WASF3 gene has been shown to be up-regulated in high-grade tumors and its downregulation leads to loss of invasion and metastasis. WASF3 phosphorylation by ABL kinase is essential for its ability to regulate invasion. Mass spectroscopy analysis now shows that HSP90 is present in the WASF3 immunocomplex from prostate cancer cells. Inactivation of HSP90 in these and other cell types does not affect WASF3 stability but prevents its phosphoactivation as a result of destabilization of ABL. HSP70 was also found in the WASF3 immunocomplex and inactivation of HSP70 results in destabilization of WASF3 through proteasome degradation. Knockdown ofWASF3, HSP90, and HSP70 individually, all lead to loss of invasion but as knockdown of WASF3 in the presence of robust expression of HSP90/70 has the same effect, it seems that the influence these chaperone proteins have on invasion is mediated, at least in part, by their control over the critical invasion promoting capacity of the WASF3 protein. Overexpression of HSP70 in WASF3 null cells does not enhance invasion. These observations suggest that targeting HSP90/70 may have efficacy in reducing cancer cell invasion."
"The study focused on a woman (S1) who experienced severe long-term fatigue. Measuring her muscles for phosphocreatine regeneration after exercise revealed a significant delay in mitochondrial ATP synthesis capacity. This discovery was followed up with a cell assay which found increased phospho-activation of an enzyme in a signaling pathway (MPAK).
In a large database meta-analysis, MPAK was previously associated with chronic fatigue syndrome. In that meta-data study, the gene WASF3, which produces a protein that can activate increased phospho-activation, was highlighted as a good candidate for further investigation.
The researchers tested S1's muscle tissue and revealed elevated levels of WASF3, indicating that her condition and the mechanism behind it were related to a larger pathology of chronic fatigue syndrome seen in other research.
Taking the investigation further, a genetically engineered mouse model with elevated WASF3 levels showed mice exhibiting mitochondrial dysfunction and reduced treadmill performance.
Turning once again to the scientific tool of reading previous research, the team found WASF3 reported to be regulated by BiP (GRP78), an endoplasmic reticulum (ER) chaperone for protein quality control whose defective response can cause ER stress and metabolic disorders. With an understanding of interactions between the ER and mitochondria for muscle function, the current team reasoned that ER stress may regulate WASF3 in muscle cells.
To test the link between ER stress and WASF3, researchers treated human myoblasts with ER stress inducers and observed increased WASF3 protein. The level of WASF3 was inversely correlated with that of MTCO1, the last enzyme in the mitochondrial electron transport chain, which drives oxidative phosphorylation.
This disruption leads to reduced mitochondrial oxygen consumption, providing a molecular explanation for symptoms like exercise intolerance and post-exertional malaise in patients with chronic fatigue.
Muscle samples from ME/CFS patients also displayed higher WASF3 levels and lower levels of associated mitochondrial protein complexes."
First published: 14 May 2012. https://doi.org/10.1002/ijc.27631
 WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic ncephalomyelitis/chronic fatigue syndrome. Ping-yuan Wang, Jin Ma, Young-Chae Kim https://orcid.org/0000-0002-5130-4413, , and Paul M. Hwang https://orcid.org/0000-0002-5976-7834 firstname.lastname@example.orgAuthors Info & Affiliations. Edited by Se-Jin Lee, University of Connecticut School of Medicine, Farmington, CT; received February 17, 2023; accepted June 27, 2023. August 14, 2023. 120 (34) e2302738120. https://doi.org/10.1073/pnas.2302738120
 HSP90 and HSP70 Proteins Are Essential for Stabilization and Activation of WASF3 Metastasis-promoting Protein*□S Received for publication, December 18, 2011, and in revised form, February 1, 2012 Published, JBC Papers in Press, February 7, 2012, DOI 10.1074/jbc.M111.335000 Yong Teng, Lambert Ngoka, Yun Mei, Leslieann Lesoon, and John K. Cowell1 From the Georgia Health Sciences University Cancer Center, Augusta, Georgia 30912
 Following chronic fatigue mechanisms to the source: WASF3 and mitochondrial respiration by Justin Jackson , Medical Xpress. AUGUST 17, 2023