Post by Nadica (She/Her) on Aug 28, 2024 1:57:58 GMT
Could a Widespread Ion Channelopathy be Causing ME/CFS, Long COVID and Gulf War Illness - Published Aug 20, 2024
Listen to the article at the link!
The “transient receptor potential melastatin 3” (better known as TRPM3) saga in chronic fatigue syndrome (ME/CFS) is really something. It’s an example of one group – and only one group – gloaming onto something in ME/CFS and gnawing at it like a dog with a bone.
We’ve seen this kind of single-minded focus before with John Chia and his work with enteroviruses, the Williams-Arriza group, and their focus on the EBV dUTPase protein, and the Barnden group and the brainstem.
Unlike broader areas of ME/CFS research such as metabolomics, cytokines, and exercise physiology these group’s findings have not received as much support from the ME/CFS research field. Each, though, has produced a significant body of research.
No group better illuminates this pattern than Sonja Marshall-Gradisnuk’s work with TRPM3 ion channels at Griffith University in Australia over the past 8 years. (The Griffith group works on other factors in ME/CFS as well.)
Since the publication of the first TRPM3 paper in 2016 (aptly titled “Novel identification and characterization of Transient receptor potential melastatin 3 ion channels…”), the group has published no less than 17 papers on the possibility that disruptions in the TRPM3 (and other TRPM ion channels) are contributing to ME/CFS.
While ion channelopathies were proposed to play a role in ME/CFS as early as 2000, it’s safe to say that TRPM3 channels were on no one’s radar before 2016.
Messed Up Sodium/Calcium Ion Channels?
Ion channels let ions like sodium, potassium, calcium, and chloride pass through the cellular membranes into the cell where they affect all sorts of cellular functions. The TRPM3 ion channels control the flow of sodium and calcium into the cells.
These ions are a big deal. Calcium plays a role in everything from energy production, muscle contraction, neurotransmitters, gene expression, and cell death. Sodium helps maintain the health of the cell membranes and plays a role in electrical signal generation, fluid balance, nutrient transport, and others.
Problems with these small channels have been implicated in a broad range of diseases including migraine, epileptic encephalopathies, chronic pain, low back pain, blood vessel functioning, cerebral palsy, eye diseases, and more. TRPM3 channelopathies can have such a wide reach because they’re found on sensory neurons, on smooth muscles in the blood vessels, brain and spinal cord, skin, pancreas, kidney, ovaries, pituitary gland, and the testes.
Griffith’s TRPM3 Gambit
Griffith’s TRP ME/CFS study was driven by numerous findings of NK cell dysfunction in ME/CFS. Seeking an answer to them, the group looked for ways that calcium signaling – a key factor in NK cell cytotoxicity – might be impaired, and found it. Increased levels of genetic polymorphisms in TRPM3 (and TRPM8) ion channels and acetylcholine receptors in ME/CFS suggested something had gone wrong. From there, the hunt was on.
The next two studies found reduced levels of TRPM3 ion channels on natural killer (down 50%) and B-cells, and an accompanying reduction in intracellular calcium in ME/CFS. Noting that the endogenous opioid system and TRPM3 receptors are involved in pain production, three lab studies found a new reason low-dose naltrexone might work when it does: naltrexone restored the TRPM3 ion channel activity in ME/CFS patients and re-established the appropriate Ca2+ signaling.
An overexpression of TRPM2 channels on NK cells and in TRPM7 ion channels pointed to more possible problems with calcium mobilization in ME/CFS. Recent studies also found dysfunctional TRPM3 ion channels in Gulf War Illness and long COVID.
While most of the Griffith studies have been very small, they have consistently pointed to TRPM3 ion channel dysfunction in ME/CFS and Gulf War Illness and long COVID.
TRPM3 Supersized?
With the recent publication of “Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone”, Wirth and Lohn, perhaps not surprisingly, joined the TRPM3 fray.
In 2016, Wirth and Scheibenbogen proposed intracellular calcium problems driven by problems with a sodium transporter played a core role in the energy production problems in ME/CFS. Since then, in a series of hypothesis papers, Wirth has greatly extended their original ideas. See below.
Wirth and Lohn started their present hypothesis paper on an expansive note, stating that it is “unlikely that ion channel dysfunction (in ME/CFS) is limited to a single organ or cell type…”, and asserting, “An isolated TRPM3 dysfunction in NK cells alone does not satisfactorily explain the pathophysiological role of TRPM3 in ME/CFS.”
They also pointed out how different diseases like ME/CFS may be. While increased TRPM3 activity and calcium levels have been associated with ME/CFS-like symptoms such as cognitive, and musculoskeletal problems, and pain – the TRPM3 problems in ME/CFS involve a “loss of function“; i.e. reduced TRPM3 activity and reduced calcium levels. Until ME/CFS popped up, no diseases had been associated with reduced TRPM3 functioning.
They explained how a disruption of these small but ubiquitous ion channels in the small nerve fibers and the brain could play a large role in ME/CFS. They believe that underactive TRPM3 ion channels may result in reduced CGRP levels, leaving the blood vessels in a vasoconstricted, or tightened-down, state – a key theme in the original hypothesis. Reduced CGRP levels result in sodium overload, increased intracellular calcium levels, and ultimately mitochondrial dysfunction.
Moving onto the small nerve fibers, they write, “it is difficult to believe that a functional defect of TRPM3 as found in natural killer cells… should not be finally involved in the degeneration of the small nerve fibers”, and then proposed that the TRPM3-induced nerve degeneration may contribute to “microcirculatory disturbances, radicular compression, reactive oxygen species, and autoantibodies.”
In the brain, they propose underactive TRPM3 channels may be inhibiting the production of the feel-good chemical GABA. Since GABA inhibits the excitatory neurotransmitter glutamate, reduced GABA activity could result in the hypervigilance and elevated sympathetic nervous system activity (fight/flight) found in ME/CFS.
They noted that the brain overstimulation that’s probably present exerts a double whammy by taking place in a brain that’s already deprived of normal amounts of blood (i.e. energy). That energy mismatch (high energy demand/low energy levels) leads to cognitive problems, brain fog, and hypersensitivities to noise, light, and other sensory inputs.
Because the GABA system also regulates muscle tone and tension, they propose that TRPM3 dysfunction may contribute to skeletal muscle pathophysiology, leading to muscle fatigue and post-exertional malaise (PEM).
Furthermore, the increased blood pressure, heart, and skeletal muscle tone produced by mental stress results in more energy consumption, putting more stress on a broken energy production system, causing more calcium overload, and impairing blood flow to the muscles, leading to skeletal muscle damage and mitochondrial dysfunction. That’s an interesting idea given the muscle pain I often associate with mental exertion.
Overall, they propose that “TRPM3 dysfunction has significant pathophysiological potential, contributing to malperfusion, mitochondrial dysfunction, and small fiber degeneration in ME/CFS”.
They asserted that “investigating TRPM3 dysfunction could be crucial for advancing our understanding of the pathophysiology of these conditions.”
Treatments? TRPM3 Agonists (Enhancers)
The article does not discuss treatments, but some TRPM3-enhancing drugs have been developed, and a recent review called TRPM3 “a new kid on the block in pain treatment?“.
The Pregnenolene Possibility
The best-known source – pregnenolone sulfate (PS) – is a supplement. A precursor to estrogen, progesterone, testosterone, and cortisol, PS is called a “neurosteroid” – a steroid produced in the brain that modulates nervous system excitability. Dr. Myhill calls pregnenolone “the mother and grandmother of all steroid hormones”.
Dr. Teitellbaum reported that he commonly finds dramatically low pregnenolone levels in people with ME/CFS, which he believes are a sign of infection. While he stated that he found pregnenolone can help, he reported that taking it in combination with other supplements can be more effective.
In 2011, he recommended that ME/CFS patients who are not taking statins and have low or low-normal pregnenolone or low cholesterol levels add CoQ10 (200-400 mg a day), pregnenolone (100-200 mg a day), and omega fish oil for three months. If your illness had a flu-like onset, he recommended taking zinc 25 mg a day for 3 months, then 15 mg daily from then on, and possibly adding a statin drug for a couple of months.
Referring to the chronic stress ME/CFS patients’ bodies are under, Dr. Myhill wrote that “pregnenolone may be particularly pertinent in the treatment of chronic fatigue syndrome”. During chronic stress, the “pregnenolone steal” results in more stress hormones being produced at the cost of sex hormones such as testosterone, estrogen, and progesterone. Adding in more pregnenolone helps to rebalance the stress and sex hormones. Myhill uses an Adrenal Stress Profile test to determine if a deficiency of cortisol is present, and if so, uses pregnenolone in 50mg capsules that she suggests absorbing under the tongue.
Dr. Ronald Hoffman of “Intelligent Medicine” reports that PS is an endocannabinoid, akin to CBD (cannabidiol), and like CBD, can help with pain, mood, and improve memory. He states that PS was briefly used as an anti-inflammatory in the fifties, but its poor bioavailability led to it being abandoned. Worried about its effects on DHEA and other hormones, he used it in small amounts in his patients until two studies using 500 mg/day found that it helped with low back pain and depression. He wrote that PS is now being studied in multiple sclerosis to dampen neuroinflammation.
Still, given its potential effects on hormones, he recommends that it be taken under the supervision of a health practitioner and that baseline blood levels of pregnenolone and its metabolites be assessed over time. His Bottom Line is:
“Pregnenolone’s wide range of benefits, its relative freedom from side effects, the reassuring fact that it’s one of the body’s most prevalent natural hormones, and its ubiquity as an over-the-counter supplement warrant its investigation for a wide range of ailments for which there exist few safe and effective options”.
Drugs
A TRPM3-enhancing drug called nifedipine is used mostly to relax blood vessels and allow more blood flows in, and treat esophageal spasms. It appears to be a cousin to nimodipine which can be helpful in ME/CFS.
Nimodipine For Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia
Perhaps the most potent TRPM3 enhancer – a drug called CIM0216 – is available only for research purposes. On a longer timeframe, there’s the drug Wirth and company are attempting to bring to market to treat ME/CFS.
ME/CFS Muscle Study Results in Drug Company Startup
Conclusion
Time will tell if Marshall-Gradisnuk, and Wirth and Lohn, are correct that dysfunctional TRPM3 ion channels are contributing to, or even causing, ME/CFS and similar diseases. The evidence for TRPM3 dysfunction in ME/CFS – quite a few positive small studies – is broad but shallow and bigger studies are needed. Still, it is good to see two different groups – the Griffith group with its focus on immune cells, and the Wirth and Lohn with their focus on blood vessel functioning and energy production – mesh.
While eyes may glaze over at the advent of yet another new hypothesis, each one opens a new window and a new way of looking at these diseases. I remember thinking at one time that the field was stagnant and searching for new ideas. No more. With more eyes than ever taking a gander at these diseases, more and more creative ideas are emerging.
Listen to the article at the link!
The “transient receptor potential melastatin 3” (better known as TRPM3) saga in chronic fatigue syndrome (ME/CFS) is really something. It’s an example of one group – and only one group – gloaming onto something in ME/CFS and gnawing at it like a dog with a bone.
We’ve seen this kind of single-minded focus before with John Chia and his work with enteroviruses, the Williams-Arriza group, and their focus on the EBV dUTPase protein, and the Barnden group and the brainstem.
Unlike broader areas of ME/CFS research such as metabolomics, cytokines, and exercise physiology these group’s findings have not received as much support from the ME/CFS research field. Each, though, has produced a significant body of research.
No group better illuminates this pattern than Sonja Marshall-Gradisnuk’s work with TRPM3 ion channels at Griffith University in Australia over the past 8 years. (The Griffith group works on other factors in ME/CFS as well.)
Since the publication of the first TRPM3 paper in 2016 (aptly titled “Novel identification and characterization of Transient receptor potential melastatin 3 ion channels…”), the group has published no less than 17 papers on the possibility that disruptions in the TRPM3 (and other TRPM ion channels) are contributing to ME/CFS.
While ion channelopathies were proposed to play a role in ME/CFS as early as 2000, it’s safe to say that TRPM3 channels were on no one’s radar before 2016.
Messed Up Sodium/Calcium Ion Channels?
Ion channels let ions like sodium, potassium, calcium, and chloride pass through the cellular membranes into the cell where they affect all sorts of cellular functions. The TRPM3 ion channels control the flow of sodium and calcium into the cells.
These ions are a big deal. Calcium plays a role in everything from energy production, muscle contraction, neurotransmitters, gene expression, and cell death. Sodium helps maintain the health of the cell membranes and plays a role in electrical signal generation, fluid balance, nutrient transport, and others.
Problems with these small channels have been implicated in a broad range of diseases including migraine, epileptic encephalopathies, chronic pain, low back pain, blood vessel functioning, cerebral palsy, eye diseases, and more. TRPM3 channelopathies can have such a wide reach because they’re found on sensory neurons, on smooth muscles in the blood vessels, brain and spinal cord, skin, pancreas, kidney, ovaries, pituitary gland, and the testes.
Griffith’s TRPM3 Gambit
Griffith’s TRP ME/CFS study was driven by numerous findings of NK cell dysfunction in ME/CFS. Seeking an answer to them, the group looked for ways that calcium signaling – a key factor in NK cell cytotoxicity – might be impaired, and found it. Increased levels of genetic polymorphisms in TRPM3 (and TRPM8) ion channels and acetylcholine receptors in ME/CFS suggested something had gone wrong. From there, the hunt was on.
The next two studies found reduced levels of TRPM3 ion channels on natural killer (down 50%) and B-cells, and an accompanying reduction in intracellular calcium in ME/CFS. Noting that the endogenous opioid system and TRPM3 receptors are involved in pain production, three lab studies found a new reason low-dose naltrexone might work when it does: naltrexone restored the TRPM3 ion channel activity in ME/CFS patients and re-established the appropriate Ca2+ signaling.
An overexpression of TRPM2 channels on NK cells and in TRPM7 ion channels pointed to more possible problems with calcium mobilization in ME/CFS. Recent studies also found dysfunctional TRPM3 ion channels in Gulf War Illness and long COVID.
While most of the Griffith studies have been very small, they have consistently pointed to TRPM3 ion channel dysfunction in ME/CFS and Gulf War Illness and long COVID.
TRPM3 Supersized?
With the recent publication of “Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone”, Wirth and Lohn, perhaps not surprisingly, joined the TRPM3 fray.
In 2016, Wirth and Scheibenbogen proposed intracellular calcium problems driven by problems with a sodium transporter played a core role in the energy production problems in ME/CFS. Since then, in a series of hypothesis papers, Wirth has greatly extended their original ideas. See below.
Wirth and Lohn started their present hypothesis paper on an expansive note, stating that it is “unlikely that ion channel dysfunction (in ME/CFS) is limited to a single organ or cell type…”, and asserting, “An isolated TRPM3 dysfunction in NK cells alone does not satisfactorily explain the pathophysiological role of TRPM3 in ME/CFS.”
They also pointed out how different diseases like ME/CFS may be. While increased TRPM3 activity and calcium levels have been associated with ME/CFS-like symptoms such as cognitive, and musculoskeletal problems, and pain – the TRPM3 problems in ME/CFS involve a “loss of function“; i.e. reduced TRPM3 activity and reduced calcium levels. Until ME/CFS popped up, no diseases had been associated with reduced TRPM3 functioning.
They explained how a disruption of these small but ubiquitous ion channels in the small nerve fibers and the brain could play a large role in ME/CFS. They believe that underactive TRPM3 ion channels may result in reduced CGRP levels, leaving the blood vessels in a vasoconstricted, or tightened-down, state – a key theme in the original hypothesis. Reduced CGRP levels result in sodium overload, increased intracellular calcium levels, and ultimately mitochondrial dysfunction.
Moving onto the small nerve fibers, they write, “it is difficult to believe that a functional defect of TRPM3 as found in natural killer cells… should not be finally involved in the degeneration of the small nerve fibers”, and then proposed that the TRPM3-induced nerve degeneration may contribute to “microcirculatory disturbances, radicular compression, reactive oxygen species, and autoantibodies.”
In the brain, they propose underactive TRPM3 channels may be inhibiting the production of the feel-good chemical GABA. Since GABA inhibits the excitatory neurotransmitter glutamate, reduced GABA activity could result in the hypervigilance and elevated sympathetic nervous system activity (fight/flight) found in ME/CFS.
They noted that the brain overstimulation that’s probably present exerts a double whammy by taking place in a brain that’s already deprived of normal amounts of blood (i.e. energy). That energy mismatch (high energy demand/low energy levels) leads to cognitive problems, brain fog, and hypersensitivities to noise, light, and other sensory inputs.
Because the GABA system also regulates muscle tone and tension, they propose that TRPM3 dysfunction may contribute to skeletal muscle pathophysiology, leading to muscle fatigue and post-exertional malaise (PEM).
Furthermore, the increased blood pressure, heart, and skeletal muscle tone produced by mental stress results in more energy consumption, putting more stress on a broken energy production system, causing more calcium overload, and impairing blood flow to the muscles, leading to skeletal muscle damage and mitochondrial dysfunction. That’s an interesting idea given the muscle pain I often associate with mental exertion.
Overall, they propose that “TRPM3 dysfunction has significant pathophysiological potential, contributing to malperfusion, mitochondrial dysfunction, and small fiber degeneration in ME/CFS”.
They asserted that “investigating TRPM3 dysfunction could be crucial for advancing our understanding of the pathophysiology of these conditions.”
Treatments? TRPM3 Agonists (Enhancers)
The article does not discuss treatments, but some TRPM3-enhancing drugs have been developed, and a recent review called TRPM3 “a new kid on the block in pain treatment?“.
The Pregnenolene Possibility
The best-known source – pregnenolone sulfate (PS) – is a supplement. A precursor to estrogen, progesterone, testosterone, and cortisol, PS is called a “neurosteroid” – a steroid produced in the brain that modulates nervous system excitability. Dr. Myhill calls pregnenolone “the mother and grandmother of all steroid hormones”.
Dr. Teitellbaum reported that he commonly finds dramatically low pregnenolone levels in people with ME/CFS, which he believes are a sign of infection. While he stated that he found pregnenolone can help, he reported that taking it in combination with other supplements can be more effective.
In 2011, he recommended that ME/CFS patients who are not taking statins and have low or low-normal pregnenolone or low cholesterol levels add CoQ10 (200-400 mg a day), pregnenolone (100-200 mg a day), and omega fish oil for three months. If your illness had a flu-like onset, he recommended taking zinc 25 mg a day for 3 months, then 15 mg daily from then on, and possibly adding a statin drug for a couple of months.
Referring to the chronic stress ME/CFS patients’ bodies are under, Dr. Myhill wrote that “pregnenolone may be particularly pertinent in the treatment of chronic fatigue syndrome”. During chronic stress, the “pregnenolone steal” results in more stress hormones being produced at the cost of sex hormones such as testosterone, estrogen, and progesterone. Adding in more pregnenolone helps to rebalance the stress and sex hormones. Myhill uses an Adrenal Stress Profile test to determine if a deficiency of cortisol is present, and if so, uses pregnenolone in 50mg capsules that she suggests absorbing under the tongue.
Dr. Ronald Hoffman of “Intelligent Medicine” reports that PS is an endocannabinoid, akin to CBD (cannabidiol), and like CBD, can help with pain, mood, and improve memory. He states that PS was briefly used as an anti-inflammatory in the fifties, but its poor bioavailability led to it being abandoned. Worried about its effects on DHEA and other hormones, he used it in small amounts in his patients until two studies using 500 mg/day found that it helped with low back pain and depression. He wrote that PS is now being studied in multiple sclerosis to dampen neuroinflammation.
Still, given its potential effects on hormones, he recommends that it be taken under the supervision of a health practitioner and that baseline blood levels of pregnenolone and its metabolites be assessed over time. His Bottom Line is:
“Pregnenolone’s wide range of benefits, its relative freedom from side effects, the reassuring fact that it’s one of the body’s most prevalent natural hormones, and its ubiquity as an over-the-counter supplement warrant its investigation for a wide range of ailments for which there exist few safe and effective options”.
Drugs
A TRPM3-enhancing drug called nifedipine is used mostly to relax blood vessels and allow more blood flows in, and treat esophageal spasms. It appears to be a cousin to nimodipine which can be helpful in ME/CFS.
Nimodipine For Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia
Perhaps the most potent TRPM3 enhancer – a drug called CIM0216 – is available only for research purposes. On a longer timeframe, there’s the drug Wirth and company are attempting to bring to market to treat ME/CFS.
ME/CFS Muscle Study Results in Drug Company Startup
Conclusion
Time will tell if Marshall-Gradisnuk, and Wirth and Lohn, are correct that dysfunctional TRPM3 ion channels are contributing to, or even causing, ME/CFS and similar diseases. The evidence for TRPM3 dysfunction in ME/CFS – quite a few positive small studies – is broad but shallow and bigger studies are needed. Still, it is good to see two different groups – the Griffith group with its focus on immune cells, and the Wirth and Lohn with their focus on blood vessel functioning and energy production – mesh.
While eyes may glaze over at the advent of yet another new hypothesis, each one opens a new window and a new way of looking at these diseases. I remember thinking at one time that the field was stagnant and searching for new ideas. No more. With more eyes than ever taking a gander at these diseases, more and more creative ideas are emerging.