Any Light gene expression study is big news. If you’re not up on the Lights’, two of their past studies showed astonishing changes in gene expression after exercise in chronic fatigue syndrome. They have a third bigger study in the works plus a Lyrica ME/CFS gene expression study (and probably a few others..)
In this study the Light’s examined gene expression levels in chronic fatigue syndrome and post-prostate cancer fatigue. ME/CFS patients needed an exercise challenge to light up the charts in their past two studies but no exercise challenge was used in this study. That suggested this study might not find much and, indeed, fewer genes popped up than before, but that mean they didn’t find much; on the contrary..
Fatigue in Cancer and Chronic Fatigue Syndrome (ME/CFS)
Many disorders can cause fatigue but the physiological causes of fatigue are not clear. Fatigue is worse in ME/CFS than post-cancer fatigue, and the gender balance is decidedly different (mostly women in ME/CFS), but cancer researchers point to many of the same suspects as do ME/CFS researchers; pro-inflammatory cytokines, anemia, HPA axis, serotonin neurotransmitter issues, muscle and ATP metabolism.
This suggests it’s possible that different triggering factors (cancer/ cancer treatment; infection in many people with ME/CFS) spark similar responses at the molecular level. If that’s true then finding drugs to reduce fatigue just got a whole lot easier.
These two disorders are quite different, however. While many symptoms are similar (fatigue, reduced exercise ability, poor sleep, muscle weakness, cognitive problems) some significant differences exist, including the all-important post-exertional malaise, widespread muscle and joint pain and orthostatic intolerance found in chronic fatigue syndrome.
In this study the Lights and Dr. Bateman measured the expression of 46 genes from adrenergic (sympathetic nervous system), immune, metabolite detecting, mitochondrial/energy and transcription factor pathways in 30 fatigued prostrate cancer patients, 39 ME/CFS patients and 22 healthy controls. Many of these genes were the same ones the Lights used in prior ME/CFS studies.
While the post-prostrate cancer fatigue (PCF) patients were more fatigued than the healthy controls, the ME/CFS patients were significantly more fatigued than the post-cancer patients. A similar percentage of ME/CFS (51%) and PCF patients (43%) had evidence of mild to moderate depression and similar percentages of people with ME/CFS and PCF reported sleep problems (90/92%).
The remarkably different patterns in gene expression found suggested fatigue was being produced in very different ways in these two disorders. In fact, of all the genes that were expressed differently in either PCF or ME/CFS from the healthy controls, not one was expressed differently in the same direction in the two disorders. In order words if a gene was over-expressed in PCF, it was under-expressed in ME/CFS.
Eight of of the 46 genes in PCF patients differed from both the ME/CFS patients and the healthy controls. Only two genes in the chronic fatigue syndrome patients differed from both the PCF patients and the healthy controls. The low number of differentially expressed genes in the ME/CFS patients highlighted the need for an exercise challenge in this disorder
Mitochondrial and Inflammation Genes Pop
A gene that had been implicated in a past ME/CFS study by another investigator popped up. The decreased expression of HSPA2 in two studies by independent groups suggested something, indeed, is awry in the mitochondrial pathways of people with ME/CFS. The Light’s suggested the down regulation of this gene could be reflect a problem in producing energy or be the result of fatigue and subsequent inactivity.
After not showing abnormal expression of any of the genes that were highlighted in past exercise studies, ME/CFS patients showed abnormally high expression of a gene the Lights had never tested before (P2RX7). This gene, which regulates pain levels, particularly in inflammation associated pain, was significantly down-regulated in PCF.
Genes That Make Your Symptom Worse
Next, the Lights determined which genes appeared to contribute most to fatigue and pain. These were genes that were most highly active in the worst off patients (and less expressed in those with lesser degrees of pain and fatigue).
None of the genes mentioned above appeared to make a difference in the amount of fatigue and pain either group experienced; instead genes with normal expression at the group level were implicated. (The expression of these genes varied markedly within the ME/CFS group but they did not appear to be elevated or reduced compared to the other groups.)
We’ve seen this pattern – genes or cytokines at normal levels that appear to be having abnormal effects - in Dr. Broderick’s work with Dr. Klimas. Their gene expression networks suggest a genes place in a network is more important than its level of expression (relative to other disorders). It appears that some genes take on extraordinary importance in dysregulated networks. They don’t need to be unusually active to affect the body; they simply need to be present. These genes or cytokines that are missed in most studies.
A Common Fatigue Producing Pathway Shows Up…
Thus far the two groups have looked very different, but when symptoms were taken into account; i.e when they determined which genes were most highly associated with fatigue and pain, similarities emerged.
Fatigue severity in ME/CFS was best predicted by lower expression of a gene called DBI and higher expression of a gene called TNF. The fact that fatigue severity in PCF was associated with lower expression of DBI and higher levels p P2RY1, suggests DBI may be a key player in producing fatigue, in general.
The diazepam binding inhibitor (DBI) - better known as the ‘GABA receptor module’ – has the ability to regulate energy production, modulate mood, and affect adrenal steroid production (testosterone, corticosterone). A GABA/glutamate imbalance has been proposed in ME/CFS/FM. (By reducing glutamate levels, Lyrica may be restoring the GABA/Glutatmate balance in the central nervous system in fibromyalgia.)
- Dig Deeper: Glutamate – One More Piece in the Chronic Fatigue Syndrome (ME/CFS) Puzzle? The Neuroinflammatory Series
The fact that DBI popped up in a 2008 ME/CFS study examining 1,467 stress-response genes is gravy. That study put DBI into the ’regulators of energy metabolism’ category (and called it acyl-coenzyme A (acyl-CoA) binding protein.)
TNF – an unpregulated gene, tumor necrosis factor has been associated with fatigue severity in some ME/CFS studies and not in others. A key pro-inflammatory cytokine, TNF is associated with the kind of immune response (innate) most often associated with ME/CFS.
Oxygen Delivery and Blood Vessel Problems
Another gene that fits smack dab in the middle of some major ME/CFS hypotheses – VIPR2 – was under-expressed in ME/CFS patients. The fact that it was down-regulated in the post-prostrate-cancer fatigue patients, as well, suggested it might be able to spark a fatigue response in other disorders.
This gene’s regulation of hypoxia (low oxygen levels) and vasodilation (blood vessel size) in, get this, the central nervous system (and the periphery) is intriguing given the low cerebral blood flows, the low VO2 max and workload in the repeat exercise studies, the findings suggesting oxygen is not being used by the mitochondria and the high rates of migraine found in ME/CFS.
Interestingly, this gene also popped up in another ME/CFS study but it was over-expressed (instead of being under-expressed).
Exercise Needed to Highlight Abnormal Gene Expression in Chronic Fatigue Syndrome (ME/CFS)
This reinforces our prior interpretation that dysregulated fatigue pathways in CFS are more clearly revealed after exercise than at rest. The Study Authors
This study highlighted how important it is to challenge people with ME/CFS with exercise. Many of the 46 genes in this study were abnormally expressed in prior ME/CFS studies that incorporated exercise challenges but only two were highlighted in this study.
The fact that many more genes were abnormally expressed in PCF – a much less severe condition – may indirectly validate the key role post-exertional malaise plays in ME/CFS. People with ME/CFS have been speaking about the hit exertion brings them from the day this illness burst on the scene. The term post-exertional malaise was coined by the ME/CFS community. “Crash’ and ‘relapse’ are used frequently.
Post-cancer patients coined their own term for the brain-fog they experience (chemo-fog) but they haven’t coined a term for PEM.
Fatigue to ME/CFS may be somewhat akin to snow for Eskimo’s; a term with many different permutations. One study highlighted 5 different types of fatigue present in ME/CFS that are not present in the population at large.
We don’t know what results a PCF gene expression study with an exercise challenge would bring, but it’s clear that substantial gene expression differences exist when PCF patients are at rest, and, at least for these genes, that’s not true for ME/CFS.
Maximizing Research Opportunities
Research funds are hard to come by, but the Lights’ in Utah, Dr. Klimas in Miami and Dr. Baraniuk in Georgetown are getting ME/CFS research done by using ME/CFS patients as control groups in studies funded for other disorders. This study, for instance, was funded by the Huntsman Cancer Institute and the NIH.
It’s hard to know what the treatment implications of these findings are. Finding a common molecular pathway for fatigue would be a huge, huge finding that would undoubtedly interest drug companies.Hopefully fatigue researchers will start probing for DB1 in other disorders.
The study also provides other potential targets for fatigue and pain relief in ME/CFS. Gene expression findings, however, need to be validated by studies which indicate that the protein the gene codes is actually increased in the body. These findings also need to be validated in other studies.
Changes in group gene expression results suggested the fatigue in post-prostrate cancer and ME/CFS patients is being produced in very different ways, but taking symptom severity into account revealed a potential common pathway involving energy metabolism, GABA/glutamate and the HPA axis. Finding a common fatigue pathway would be a huge boon for drug companies seeking to develop drugs to relieve fatigue.
Two genes involved in mitochondrial energy production and inflammation that were highlighted in the ME/CFS group could at some point provide targets for interventions.
The few genes highlighted in the ME/CFS group contrasted in the large numbers of dysregulated genes in the Lights past exercise studies suggested exercise challenges are needed to fully explore gene expression differences in chronic fatigue syndrome. The fact that this is so in ME/CFS but may not be happening in PCF – a much less severe condition – suggests post-exertional malaise may indeed be a unique feature of chronic fatigue syndrome.