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The true nature of an autoimmune disease

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Abstract Here we propose a hypothetical model seeking to map the pathogenesis of a herpesviridae-positive serology subtype of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) as a simultaneous α-ketoglutarate dehydrogenase (α-KGDH) and pyruvate dehydrogenase (PDH) deficiency, with degraded beta-adrenergic signalling cascade and impaired hepatic gluconeogenesis, phasic hyperlactatemia and hyperammonemia - as caused by herpesviridae-mediated antibodies and latent cell burden. For example, “M37GO37” targets dihydrolipoamide succinyltransferase from the α-ketoglutarate dehydrogenase complex (α-KGDC), creating an acute deficiency of α-KGDH, impairing Citric Acid Cycle (CAC) metabolites from succinyl-CoA / Complex V through malate, accumulating α-ketoglutarate (α-KG), reducing adenosine triphosphate (ATP), NAD+ and respiration. “M18GP8”, “M82GP8”, “M37GPl1” antibodies to pyruvate dehydrogenase complex (PDC), plus hypoxia, low physical activity and/or antibodies creating beta-adrenergic dysregulation can each cause a decrease in PDH, Cori Cycle efficiency and insulin resistance. When combined with succinate and argininosuccinate (ASA) deficiency, plus elevated α-KG, nitrogen disposal shunts to nitrogen retention via metabolism to L-glutamate and L-glutamine, triggering glutaminolysis. Sleeping, fasting and respiration decrease lactate and nitrogen retention via metabolic shunting, partially rescuing succinate availability for CAC, urea cycle metabolism via GABA. Each of these α-KGDH, PDH and beta-adrenergic cascade deficiencies are able to cause both of the others, adding additional complexity to diagnosis and treatment. These phases can be accompanied by debilitating symptoms associated with hyperammonemia, GABA deficiency, glutamate-induced excitotoxicity, uremia, hyperlactatemia, adrenergic and cortisol dysregulation, with accompanying hair, skin, GI, collagen, immune, sphingolipid, endocrine, sleep and neurological disorders. This further suggests investigating the herpesvirus family as causal for numerous disorders.
The true nature of an autoimmune
Authors: Joshua Leisk, Aline Noçon ©2021
Key words: Epstein-Barr Virus (EBV), hyperlactatemia, chronic fatigue syndrome, myalgic
encephalomyelitis, fibromyalgia, alpha-ketoglutarate dehydrogenase deficiency, pyruvate
dehydrogenase deficiency, herpesvirus autoimmune spectrum disorder
Here we propose a hypothetical model seeking to map the pathogenesis of a
herpesviridae-positive serology subtype of Chronic Fatigue Syndrome / Myalgic
Encephalomyelitis (CFS/ME) as a simultaneous α-ketoglutarate dehydrogenase
(α-KGDH) and pyruvate dehydrogenase (PDH) deficiency, with degraded
beta-adrenergic signalling cascade and impaired hepatic gluconeogenesis, phasic
hyperlactatemia and hyperammonemia - as caused by herpesviridae-mediated
antibodies and latent cell burden.
For example, “M37GO37” targets dihydrolipoamide succinyltransferase from the
α-ketoglutarate dehydrogenase complex (α-KGDC), creating an acute deficiency of
α-KGDH, impairing Citric Acid Cycle (CAC) metabolites from succinyl-CoA / Complex V
through malate, accumulating α-ketoglutarate (α-KG), reducing adenosine triphosphate
(ATP), NAD+ and respiration.
“M18GP8”, “M82GP8”, “M37GPl1” antibodies to pyruvate dehydrogenase complex
(PDC), plus hypoxia, low physical activity and/or antibodies creating beta-adrenergic
dysregulation can each cause a decrease in PDH, Cori Cycle efficiency and insulin
When combined with succinate and argininosuccinate (ASA) deficiency, plus elevated
α-KG, nitrogen disposal shunts to nitrogen retention via metabolism to L-glutamate and
L-glutamine, triggering glutaminolysis.
Sleeping, fasting and respiration decrease lactate and nitrogen retention via metabolic
shunting, partially rescuing succinate availability for CAC, urea cycle metabolism via
Each of these α-KGDH, PDH and beta-adrenergic cascade deficiencies are able to
cause both of the others, adding additional complexity to diagnosis and treatment.
These phases can be accompanied by debilitating symptoms associated with
hyperammonemia, GABA deficiency, glutamate-induced excitotoxicity, uremia,
hyperlactatemia, adrenergic and cortisol dysregulation, with accompanying hair, skin, GI,
collagen, immune, sphingolipid, endocrine, sleep and neurological disorders.
This further suggests investigating the herpesvirus family as causal for numerous
The purpose of this paper is to stimulate discussion around the nature of the herpesvirus
family, including tick-borne variants such as MHV-68[123][124][125][127][136], their impact on
mitochondrial efficiency, metabolism, and their implied causal relationship for a very
large spectrum of diseases and disorders[95][100]. These disorders relate to the organs /
tissues infected and efficiency of both latent and lytic activity. This paper will primarily
focus on their role in CFS/ME and aim to provoke interest in further research around
applying this model to understanding and treating other diseases which may be directly
caused by the same family of viruses.
CFS/ME is a highly debilitating and poorly understood disorder that is regularly
associated with childhood EBV and less commonly with cytomegalovirus (CMV), human
herpesvirus-6 (HHV-6) and other infections[14]. It is a “bucket term” that broadly
describes a group of symptoms including extreme fatigue and myopathy which lasts for
more than six months[1].
EBV is the fourth member of the human-herpesvirus family, which is known for creating
a plethora of different antigens at different viral stages[109], ‘hijacking’ the host’s adaptive
immune response to replicate and maintain persistence. It has also been demonstrated
to replicate in epithelial cells via transcytosis[110].
Patients commonly report what can be described as cycles of symptoms, with initial
onset reported as a phase of [acute lymphadenopathy and flu-like symptoms], followed
by an overlapping phase of [acute lack of energy for movement, extreme fatigue,
neuralgia, myopathy, nausea, dizziness, neuropathy, increased sweating], with
idiopathic periods of [improved energy production, extreme afternoon exhaustion / post
exercise malaise (PEM), nausea, dizziness, dysautonomia, Raynaud’s Syndrome, liver
pain, gastroparesis, irritable bowel disorder, postural orthostatic tachycardia syndrome
(POTS) and encephalopathy] and confusion, anxiety, depression, restless leg syndrome
(RLS), involuntary muscle spasms, insomnia, endocrine disorders, alopecia, circadian
rhythm shift, edema, eating disorders, tinnitus and/or symptom onset induced by dietary
Here we review current literature and propose a hypothetical model that attempts to map
and describe the aetiology and pathogenesis of a herpesviridae-positive serology
CFS/ME subtype, as a debilitating member of an (author proposed nomenclature)
Herpesvirus Autoimmune Spectrum Disorder (HASD)[95][100], also being a highly treatable
form of viral hepatitis.
HASD CFS/ME displays an array of simultaneous phasic metabolic and mitochondrial
impairments caused by:
1. an induced enzymatic deficiency of α-KGDH[22], initially impairing synthesis of
Complex V in the CAC, creating oxidative stress and unbalancing redox of
Nicotinamide Adenine Dinucleotide (NAD+) with its reduced form, Nicotinamide
Adenine Dinucleotide Hydrogen (NADH)[9][42][44][167][212][213], with
2. an induced enzymatic deficiency of PDH, initially impairing lactic acid clearance,
fatty acid synthesis, and
3. an induced dysregulation of beta2-adrenergic pathways leading to enzymatic
deficiency of activating monophosphate-activated protein kinase (AMPK),
dysregulating hepatic gluconeogenesis, along with many other pathway
alterations discussed further on.
In Japan, while studying primary biliary cirrhosis (PBC), Matsui et al., 1993[16] and
Fukushima et al., 1995[3] previously isolated and described a number of EBV-produced
mitochondrial antibodies, including “M37GO37”, which targets dihydrolipoamide
succinyltransferase (EC, an E2 component of α-KGDC[3[8][22] - completely
inhibiting production of α-KGDH in uninfected and presumably infected cells, which
already exhibit similar metabolic features[44].
Three additional antibodies “M18GP8”, “M82GP8”, “M37GPl1” target the PDC, causing
moderate impairment of pyruvate dehydrogenase[16].
Kojima et al. 1999[73] also reported an Epstein-Barr virus infection resembling
autoimmune hepatitis with lactate dehydrogenase (LDH) and alkaline phosphatase
(ALP) abnormalities.
Mitochondrial antibodies with similar targets have also been identified in PBC by a
number of other US-based studies[26][27][28][30], however those authors had not yet
attributed a causal link to any specific viral infection, possibly due to the language and
technological barriers around information sharing which existed during this decade.
It was initially considered that many of the observed metabolomic datasets in recent
studies[5][76][78][108] featured elevation of serum α-KG, known as Complex IV, produced by
oxidative decarboxylation of isocitrate via isocitrate dehydrogenase[8[11]].
Although α-KG can be also synthesised endogenously from glutamate via glutamate
dehydrogenase (GDH)[19] and/or from galacturonic acid by the microorganism
Agrobacterium tumefaciens[6], we did not consider these two sources to be a sufficient
explanation for the elevated serum α-KG in CFS/ME patients, when simultaneously
accompanied by an acute cellular energy crisis and other symptoms[1][2][77][156][167][180].
Based on reported urea cycle abnormalities, we hypothesised that elevated α-KG could
also be derived from a defect in the production of Complex V in the CAC, where
[Succinyl-CoA + NADH + H+ + CO2] is normally produced from oxidative
decarboxylation of [α-KG + NAD+ + CoA-SH] by [α-KGDH, thiamine pyrophosphate,
lipoic acid, Mg++, transsuccinytase][8][11][42][47].
This defect would cause an accumulation of α-KG produced in Complex IV of the
CAC[8][11][44] and an increased use of Branched-Chain Amino Acids (BCAAs)[10], as
observed in CFS/ME by Missailidis et al., 2020[9]. Each impaired CAC cycle, caused by
eg. glycolytic energy usage for muscle activation and brain function, would continue to
accumulate one additional unit of α-KG / Complex IV. Elevated α-KG is also associated
with degraded ATP Synthase, reducing ATP production and mTOR[39][56].
α-KGDH is a critical enzyme in regulating efficiency of the CAC and is highly sensitive to
oxidative stress, while paradoxically being a source of it - in the presence of reactive
oxygen species (ROS), such as hydrogen peroxide (H2O2) and 4-hydroxy-2-nonenal
(HNE), α-KGDH can be completely inhibited, acutely regulating energy production[167].
With α-KGDH deficiency, elevated α-KG / Complex IV can be metabolised to
L-glutamate and L-glutamine[4][21] thereby increasing nitrogen retention[20], while impairing
normal metabolism and renal excretion as urea through the UC[4][21][39]. This is relative to
high levels of α-KG[22], with low levels of succinate->[...]->argininosuccinate (ASA)[107][131]
and driven by CAC activity or glutaminolysis[216].
We considered that a Complex V production defect, via HHV-induced α-KGDH
deficiency was the highest probability vector for simultaneously explaining many of the
key CFS/ME features[10][14][24][42][44].
Some CFS/ME features, such as high lactate:pyruvate ratio and downstream cascading
effects, including lactic acidosis, insulin resistance, dysautonomia and glutaminolysis
were as yet explained[44][76]. We considered that this lactate:pyruvate ratio appeared likely
related to PDC/PDH abnormalities.
With similar characteristics to some cancers, α-KGDH deficiency causes depletion of
succinate and fumarate, thereby inducing hypoxia, insulin resistance, decreasing AMPK,
decreasing collagen production, bone density via a cascade of deficiencies downstream
from prolyl hydroxylases [P4H->hydroxyproline->[collagen]->prolidase->proline<->P5C]
and promoting carcinogenesis via disrupting epigenetic regulation via hypoxia-inducible
transcription factors (HIF)[60][78]. HIF affects hundreds of genes, including those
contributing to the Warburg effect, as well as DNA methylation and histone methylation.
Notably, it also affects expression of PDH[59][126][174].
However, while α-KGDH deficiency and/or “M18GP8”, “M82GP8”, “M37GPl1” antibodies
to PDC[16] would cause a direct deficiency of PDH[66][67], this seemed like a fairly simplistic
answer and we considered that other factors or alternative scenarios, involving different
antibodies, could create the same deficiencies.
Nilsson et al., 2020 performed related research and were unable to find antibodies to
PDC in 160 out of 161 CFS/ME patients. They were further unable to detect
antimitochondrial antibodies (AMA) in a spot-check of 29 random samples from the
CFS/ME cohort, however they did not specify if they also tested any PBC control
samples for AMA. Interestingly, the two methods they used for detecting antibodies to
PDC yielded different results on the same samples, suggesting the testing
methodologies are unreliable[128].
Relative to rescuing CAC efficiency from α-KGDH deficiency, Complex V / Succinyl CoA
can also be created from methylmalonyl CoA by the enzyme methylmalonyl-CoA
mutase, through the utilisation of deoxyadenosylcobalamin[79]. This may negatively
impact serum B12 levels and reduce PDH, which is needed to produce acetyl-CoA,
required as an irreversible, rate-limiting intermediate in the pathway to malonyl-CoA.
This reaction is also involved in the catabolism of some BCAAs and odd-chain fatty
GABA is another pathway to partially rescue Complex V / Succinyl CoA, via
succinate.The metabolism and depletion of GABA to partially restore succinate levels
and CAC efficiency can cause hypoxia and decreased PDH[70], sleeping disorders[50][51],
ulcerative colitis[158] and anxiety disorders[49][53].
During α-KGDH deficiency and/or when under oxidative stress, a further pathway to
rescue succinate has been shown to exist by decarboxylation of α-KG, pyruvate and
The ratio of NAD+:NADH determines the direction and rate of critical enzymatic
reactions involved in mitochondrial activity. Relative to α-KGDH and PDH impairments,
NAD+:NADH redox balance could be impaired, depleting NAD+ and pooling NADH,
causing further impairment to many enzymatic reactions, impacting mitochondrial
Lactate is largely produced in muscle cells and is generally thought to be transported by
blood into the liver, where it is normally metabolised into glucose via the Cori Cycle and
transported back to the cells for reuse. Recent studies have shown that lactate can also
be used as a preferential source of energy and trigger for cell proliferation. Lactate can
also be shared between cells[7][61][77].
Lack of physical activity and/or carnitine both decrease PDH and lead to lactate
increase. Hepatic function, with a particular focus on lactate metabolism and
gluconeogenesis, is a key factor in maintaining systemic glucose:lactate homeostasis[68].
Even in the absence of viral antibodies, the forced sedentary lifestyle imposed on
CFS/ME patients could acutely contribute to ongoing symptoms of hyperlactatemia, with
or without lactic acidosis, as determined by transient urea cycle efficiency[191][237][238][239].
Another CFS/ME feature is hypoxia, which induces insulin insensitivity and
beta-adrenergic dysregulation[132] via increased G protein coupled receptor type 2
(GRK2). ß2-adrenergic signalling cascade dysregulation leads to impaired fatty acid
oxidation[55][71]. This cascade has implications for further impairing the immune response
to viral infections and downregulation of natural killer (NK) cell production[147] and altering
glutamate metabolism[23][37].
However, antibodies for ß2-adrenergic receptors, muscarinic acetylcholine receptors,
gamma-opioid receptors, dopamine receptors, serotonin and serotonin receptors have
also been discovered in a subset of CFS/ME patients, for whom removal /
immunoadsorption of IgG provided significant, yet temporary benefits. These antibodies
would also be able to cause the previously described CFS/ME pathway alterations, by
inducing the same three pivotal looping cascades of defects - α-KGDH deficiency,
PDH deficiency and impaired β2-adrenergic cascade. In addition, each identified
antibody target may benefit from additional consideration and therapeutic intervention
while these antibodies are present in the serum[35][37][62][128][129][130][132][147][165].
These three pivotal cascades of defects, including further disturbances to calcium
channels, described later[105][106], can cause increased insulin resistance, decreased
cyclic adenosine monophosphate (cAMP)[186], decreased adenosine
monophosphate-activated protein kinase (AMPK)[245], decreasing the Cori Cycle
efficiency and leading to hyperlactatemia or lactic acidosis[61][71]. cAMP pathway defects
can also disrupt normal cardiac function by dysregulating protein kinase A (PKA)[187][188].
The Cori Cycle defects result in post-exercise malaise (systemic inflammation, acute
hepatitis, neuropathy, myopathy, encephalopathy, psychosis)[64], gut microbiome
dysbiosis[155], increased digestive activity[154], depression, increased cancer risk and
pyramidal symptoms[43][44][45][52][63][72].
The described altered state of metabolism with hypoxia and hyperlactatemia also
remodels mitochondrial energy production towards glutaminolysis[25][45][65][216] which can
bypass currently degraded steps of the CAC (succinyl-CoA, succinate, fumarate,
malate), via transamination at oxaloacetate, while increasing metabolites of ammonia
and producing further lactate[76][77].
A “partial recovery” state, or reversal of described impairments, could be expected
intra-daily - during sleep[69] and resting periods, when energy production demands are
reduced and less than the maximum capability provided by the impaired beta-oxidation
cascade, thus sparing available succinate for CAC and UC metabolism needs. During
this “recovery state”, NAD+ biosynthesis and recovery via increased NAMPT normally
occurs as well[212][213]. Fasting and metabolic ketosis can also induce this “partial
recovery” state, by allowing additional mitochondrial efficiency via ketogenesis as an
alternate energy source and increased relative efficiency of hepatic gluconeogenesis.
Additional events may occur when (diurnal) GABA levels spike[51], which could be
depleted and metabolised to succinate[48][70], partially healing CAC and UC efficiency.
[Figure 1 - Pathway Diagram]
(High resolution included with supporting files)
This may also adversely affect sleep schedules[50][51][69], contribute to a number of anxiety
disorders[53][182] and eating disorders[181].
During sleep, elevated lactate levels and/or lactic acidosis could decline, reducing or
ameliorating lactatemia-related symptoms. However, with some relationship to ammonia
and nitrogen balance, if lactate levels decline and serum pH increases sufficiently during
eg. a typical 8 hour sleep cycle, mitochondrial energy production could revert from
glutaminolysis to impaired glycolytic metabolism or fatty acid oxidation.
In this state, mitochondrial efficiency could now be proportional to GABA->succinate[70]
and/or B12/methylmalonyl CoA->succinyl-CoA availability[79] and while impaired by
α-KGDH deficiency, cause a proportional “low energy state”, until enough impaired
mitochondrial activity, with insufficient PDH, again causes lactate to increase and serum
pH to decrease. This lactate elevation may retrigger glutaminolysis[7][65], allowing for a
small phase of increased mitochondrial efficiency, until lactate levels again reach a
debilitating level or acute lactic acidosis, or merely hyperlactatemia, as pH balance is
somewhat compensated for by the increased ammonia also created by the process.
Further, if UC efficiency is unable to match ammonia synthesis rates, generated by
glycolysis, glutaminolysis and/or α-KGDH deficiency, both minor and extended phases of
L-glutamate induced excitotoxicity[12][19], hyperammonemia, uremia[13] and symptoms
resembling multiple sclerosis[12][23][74] may be observed, following physical activity.
The stages described above can be expected to cyclically repeat[14][54][166] over days or
weeks. Relative to both renal clearance and hepatic function, some of these phasic
symptoms may overlap or be observed simultaneously.
PDH or acetyl-CoA abnormalities described earlier can also reduce conversion of
intracellular fatty acids into ceramides, perhaps favouring the use of sphingolipids in
ceramide synthesis, which are needed for other purposes[184].
The resulting decrease in sphingolipids[98], including sphingosine-1-phosphate and
sphingomyelin, are associated with muscle contraction dysfunction, mechanical pain
response, ion channel dysregulation, liver abnormalities, cognitive dysfunction, bipolar
disorder, anxiety, myelin formation abnormalities, schizophrenia (including dissociation,
derealization, delusions, and paranoia), mast cell dysregulation (further causing
histamine and serotonergic issues) and irritable bowel
PDH->acetyl-CoA deficiency is also a rate limiter in sterol production pathways, which
when combined with hypoxia and insulin resistance, has implications for a potential
cascade of endocrine alterations, sleep dysregulation issues, including circadian rhythm
alterations via cortisol[84] (and previously mentioned GABA [50][51]).
The endocrine alterations may also cause hirsutism, alopecia, ovarian follicle
disturbances, fibroids, endometriosis via compensatory upregulation of adrenal cortex
pathway hormone production, including 5-alpha reductase (5-AR) and
dihydrotestosterone (DHT) in response to dysregulated cortisol[85][185]. This effect would
be enhanced by mast cell dysregulation and gut / skin barrier degradation, with follicle
thinning/loss from the cortisol dysregulation and acute collagen synthesis impairments
downstream from α-KGDH deficiency, as previously
This could be further impacted and sustained by a compensatory rebound effect of
hypothalamic–pituitary–gonadal (HPG)-axis suppression by DHT dominance, which
could be observable via pathology markers as “in range”, yet low luteinising hormone
(LH) and oestradiol (OE2) insufficiency (eg. in males - LH < 2.8IU/L, OE2 <70 pmol/L),
indicating hypothalamic feedback and gonadotropin hormone-releasing hormone
(GnRH) regulation is being governed by elevated 5-AR metabolites - allopregnanolone
or DHT[86][87].
These combined alterations would have further implications for hepatic function,
including lipid accumulation / non-alcoholic liver disease (NAFLD) and lactate
metabolism via gluconeogenesis[91][153].
At this time, it’s not at all clear which pathogens express the antigens associated with
each antibody. Early indications would suggest that EBV, MHV-68, CMV, HHV-6, HHV-7
would have the highest probability of being causal in CFS/ME, however this area has not
been adequately explored and it’s likely other common pathogens may have
successfully evolved through the use of similar vectors[157].
The model as described is extensible and may allow other pathogens or known
antibodies to be tested against it to predict pathophysiology.
For example:
A plausible pathophysiology for HHV-seronegative CFS/ME, based on a Clostridium
infection, which has been reportedly found in 22% of CFS/ME patients by Dr.
Jacob Teitelbaum.
[Figure 2 - Flowchart for HASD CFS/ME Model]
(High resolution included with supporting files)
Applying the HASD model, C.diff-secreted GDH, increasing serum GDH, further elevates
α-KG, thus degrading Complex V. This degradation of Complex V, as previously
described, is capable of causing inhibition of α-KGDH, leading to the entire looping
cascade of CFS/ME metabolic alterations. These symptoms are related to the
C.diff-secreted GDH, when combined with organ-specific elevated expression of GDH.
Notably, these organs are focused on synthesis tasks (eg. liver, gonads, etc)[39][56][214][217].
This further suggests that CFS/ME induced by c.diff infection, without a HHV
seropositive co-infection, could be treated by eg. Metformin and epigallocatechin gallate
(EGCG), which is found in green tea and acutely inhibits GDH (and therefore being
specifically contraindicated in HASD CFS/ME.)[38][215][217].
[This example has been annotated in blue on “Figure 2.”
This model also allows for speculation around the existence of eg. HHV-mediated or
other heterophile antibodies to GDH, as a further trigger for inducing CFS/ME.
Research into creating a comprehensive map of antigens / antibody targets for each
pathogen is sorely needed.
In previous years, latent cells have been traditionally thought of posing an insignificant
long-term health risk, however research has shown that these cells are programmed to
prefer glycolysis and glutaminolysis, further creating a lactate, hypoxia and ammonia
burden which can also trigger lytic reactivation and latent cell proliferation[7][44][65][216].
In addition to the well-known lytic replication phase, these cells have now been
demonstrated to replicate via transcytosis, having further implications for a number of
In key ways, many herpesviridae-infected cells share common metabolic features with
senescent cells and cancer cells featuring the “Warburg” or “Reverse Warburg” effect -
hypoxia, lactate, elevated aerobic glycolysis and a preference for glutaminolysis, via
enhanced expression of KGA, GLS1, GLUD1, GLUD2 proteins[44][140][173][216].
Mirroring the behaviour of senescent cells and various cancer cells, these infected cells
are able to influence the behaviour of neighbouring cells and recruit them[110]. Various
suspected herpesviridae-related diseases and disorders show symptoms with strong
relevance to the location of these infected latent cells and their burden on neighbouring
cells and tissues[95][100][134[183].
It’s possible that hypoxic complications from SARS-CoV-2 infections / COVID-19 are
able to reactivate a latent EBV (or other HHV) infection, causing mononucleosis, chronic
fatigue, hair loss, headaches, dyspnea and other symptoms associated with “Long
COVID” syndrome[177][178].
As the herpesviridae-infected cells behave like senescent and various cancer cells, this
suggests they are also susceptible to the same treatment methods already being
explored, for example - selectively disabling glycolysis, glutaminolysis or
phosphodiesterase 4 (PDE4)[98][143][176][180][189][190].
This further suggests that induced necrosis of these cells could also be explored by
causing selective mitochondrial starvation, by perhaps creating a sustained
simultaneous state of [high lactate + low serum glucose + selective glycogen depletion +
glutamine depletion]
, eg. performing a “water fast” for 3 or more days and exercising,
while inhibiting both PDH kinase and GDH/GLS[38][98][140][175].
Implications and considerations for diagnostics and
management of the HASD CFS/ME model hypothesis
This HASD CFS/ME hypothesis model describes a complex array of disorders, which
suggest a number of challenges and a combination of therapeutic targets. We will further
review therapeutic options that may be appropriate for management and prevention or
remission of symptoms, based on this model.
As the model includes both a lytic and latent herpesviridae infection as the root cause,
these are logically the most desirable therapeutic targets for achieving long-term
remission, however symptomatic relief can also be provided and may further enhance
the patient’s immune response.
As with any infection, managing patient awareness around expected symptoms
associated with a sustained period of a heightened immune response could be advisable
- rashes, lymphadenopathy, fevers / chills would all be expected, especially in the early
stages of treatment.
The patient would be expected to go through various stages of recovery, from being
bed-ridden, through periods of afternoon fatigue and headaches, to periods of minor
limitations and then symptomatic relief, in a non-linear manner and relative to consistent
levels of appropriate physical activity.
Remission would come from a full arrest of lytic phase replication, combined with a
sufficient reduction of latent hepatic cell burden, allowing normal hepatic and other
metabolism, without interruption by neighbouring infected cell metabolism.
A key understanding of the proposed HASD CFS/ME model is that treatment MUST
include a comprehensive therapeutic intervention for each of the primary targets
1. HHV Latent and Lytic Infection
2. α-KGDH Deficiency Cascade (including CAC, NAD+ depletion, nitrogen disposal)
3. PDH Deficiency Cascade (PDH/PDHK, carnitine pathways, NAD+)
4. ß2-Adrenergic Cascade (β2-AR->cAMP->AMPK-> Hepatic Gluconeogenesis)
5. Muscarinic Acetylcholine Receptor Homeostasis
A failure to treat each of these targets simultaneously will likely result in a short-term
improvement, followed by a delayed and intense, avoidable cascade of CFS/ME
Any treatment should also include therapeutic interventions to address the
secondary antibody targets, being mainly neurotransmitters and their receptors.
Confirming a positive CFS/ME diagnosis has traditionally been problematic, as serology
markers can be inconclusive or altered by heterophile antibodies and viral behaviour,
where coinfections exist.
In the absence of a industry-standardised panel for assessing HHV infections and further
identifying antibodies present, a thorough approach to diagnostics would include
serology markers for the known family, with quantitative results. Simplified results
displaying “positive” or “negative” are not sufficient for a meaningful interpretation, as the
titres are critical tools in assessing infection status:
HSV-1 IgG, IgM
HSV-2 IgG, IgM
EBV Early Antigen (EA),
EBV Viral Capsid Antigen (VCA) IgG, IgM
EBV Nuclear Antigen (EBNA) IgG
HHV-6 IgG, IgM
HHV-7 IgG, IgM
Clinical Notes for EBV:
Interpreting serology for EBV has many complications. Due to the different stages of
infection and antigens expressed, EBV positive serology is normally interpreted via
multiple markers:
EBV EBNA IgG “positive” indicates a long-established latent infection and level of
burden. A “negative” results with any other EBV marker as “positive” indicates a recent
EBV EA anything other than “negative” indicates a recently active lytic infection,
regardless of other markers. In the presence of EBNA+, can indicate a chronic /
reactivating infection.
EBV VCA IgG “high” positive indicates an active or recent infection and severity | “low”
positive, in the absence of EBV EA or EBV VCA IgM indicates immunity.
EBV VCA IgM “high” positive indicates an active infection | “low” positive may indicate
the presence of a chronic coinfection, such as CMV, or HHV-6.
Heterophile antibodies can be a useful marker for diagnostics.
PCR tests - these are exceptionally useful for detecting and quantifying a lytic phase at
the time of the test
. Given the difficulties sometimes involved with patients being able to
travel on the day of a scheduled blood draw, owing to debilitating symptoms, PCR tests
can be an unreliable tool for initial screening, unlike lagging data provided by
immunoglobulin counts.
Faecal tests - testing for the presence of C.diff and other infections that may require
further treatment or interfere with HASD CFS/ME treatments.
Liver Function Tests (LFT) - the standard metabolic markers for inferring liver function
are not expected to be helpful in assessing impairments described in this model.
Some other early diagnostics ‘clues’ towards an undiagnosed chronic HHV infection may
also include:
1. Haematology markers showing a historical pattern of subclinical or low levels of
lymphocytes, without any obvious signs of infection.
2. T / B cell profiles on flow cytometry testing may also look unfavourable, with reference to
low CD4:CD8, as seen in HIV infections.
3. Blood urea levels may show a pattern of unusually low or high readings, unrelated to the
patient’s recall of dietary protein intake.
4. History of fussy eating disorder, low BMI and/or GI intolerances.
5. History of anxiety, depression, bipolar disorder or schizophrenia.
6. History of obsessive / compulsive behavioural disorders, including unusual levels of
dietary supplement usage.
7. Alopecia or other endocrine-related disorders.
8. History of connective tissue disorders or cysts.
9. History of nasal infection.
10. A positive “succinic acid challenge” (see “α-KGDH Deficiency Interventions / Succinate”)
where the patient chooses to consume up to 4 doses of succinic acid at 25mg per dose,
20 minutes apart, while monitoring for any physiological response, including a ‘surge of
energy’, ‘a sustained adrenaline spike’, or in other HASD patients, expected delayed
inflammation of infected tissues.
There have been previous attempts to create a robust vaccine for EBV, however one
extremely promising piece of work was published in 2018.
van Zyl DG, Tsai M-H, Shumilov A, Schneidt V, Poirey R, Schlehe B et al., created
“Immunogenic particles with a broad antigenic spectrum stimulate cytolytic T cells and
offer increased protection against EBV infection ex vivo
and in mice”[121].
This research will hopefully provide a scalable, long-term solution. We wish the authors
the very best of luck in this endeavour and will continue to watch their work with interest.
Despite promising early indications for CFS/ME and despite demonstrating efficacy for
preventing similar EBV-infections following organ transplants, the monoclonal antibody
“rituximab” failed to show efficacy for CFS/ME in a phase 3 double-blind trial[29], where
the treatment was periodic b-cell depletion, with 2 infusions of rituximab, 500 mg/m2 of
body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose
of 500 mg at 3, 6, 9, and 12 months.
It is possible this was an off-target treatment, related to high specificity against an
expressed protein and the variance amongst EBV mutations / strains, often presenting
different protein targets for monoclonal antibody therapies, including
However, we would suggest that, unlike in posttransplant lymphoproliferative disease
(PT-LPD), the extensive latent hepatic infection and burden to surrounding cells in
CFS/ME patients is not being treated by periodic b-cell depletion therapy alone. This is
an incomplete approach. Lytic reactivation of latent cells could also be expected and
therefore any EBV-mediated antibodies created would persist for months in between
periodic treatments, allowing acute symptoms to continue.
Tenofovir is a nucleotide reverse transcriptase inhibitor that shows strong efficacy
against EBV lytic replication[119] and a number of other problematic viruses, including
Human Immunovirus (HIV) and Hepatitis B (HBV). Tenofovir is commonly used even
during pregnancy and appears to be a fairly low-risk treatment.
Significant side effects reported include high blood lactate and an enlarged liver, which
has been previously attributed to drug-induced disease modifications for HBV[120],
however in retrospect, could also fit the expectations described in this paper for hepatic
infection by EBV or other HHV, where Tenofovir was used without simultaneous dosing
of a PDH kinase (PDHK) inhibitor. Long term use is associated with nephrotoxicity and
Recent advances in understanding HHV / EBV replication has identified that an existing
drug, “Spironolactone” (aldactone), can cause degradation of xeroderma pigmentosum
group B-complementing protein (XPB), in both B lymphocytes and epithelial cells,
inhibiting EBV SM-dependent late lytic gene transcription[17].
At lower doses, spironolactone has existing clinical uses as a potassium sparing diuretic
and at higher doses as an anti-androgen, providing some additional considerations if
used as a treatment for EBV infections[40][41]. At 100mg/day, 30% of males developed
symptoms of gynecomastia[113]. However, even at 200-400mg/day, male participants who
experienced anti-androgenic symptoms, such as gynecomastia[114], over 4-13 months
had complete reversal of these effects upon cessation of dosing[112]. A mild aromatase
(CYP19) inhibitor to rebalance the oestradiol to DHT ratio could be considered in
unusual cases - as HASD CFS/ME patients would be expected to already exhibit high
DHT and low oestradiol, owing to chronic cortisol elevation[115].
This discovery prompted an encouraging pilot study of patients with positive serology for
EBV (n=21)
, by Campo et al, 2020[18], with 5 out of 16 participants who tolerated
25mg/day of spironolactone and multivitamins showing full remission of CFS/ME and the
remaining participants showed a reduction of CFS/ME symptoms at the time of the
report. The duration of the study was not reported. We noted no mention of patient
hydration or electrolyte management was included, which may have contributed to some
of the participant intolerance / dropouts, if not an omission in reporting. Considering
spironolactone’s 1.4 hour (and metabolites’ 13.8 - 16.5 hour half-life)[110], the dosing
schedule used may not have been optimal in maintaining the serum levels needed for
antiviral efficacy and twice daily dosing of 25mg could be considered.
While spironolactone shows some early signs of strong efficacy at safely modulating
EBV and other HHV lytic infections, relative to the lifespan of b-lymphocytes and serum
antibodies, it’s reasonable to expect it would take months to reach a state of viral lytic
phase remission. Unlike the targeted b-cell depletion of rituximab, this treatment or
tenofovir allows the immune system to simply recover and remodel around maintaining a
robust, persistent response to EBV lytic events or reactivation.
After an expected 2 month “initial recovery” phase, as indicated by an unremarkable T /
B cell profile on flow cytometry testing, an extended “maintenance dose” of
spironolactone could be continued, while using lytic phase reactivating compounds, such
as histone deacetylase (HDAC) inhibitors[179] or compounds such as cordycepin[116][117]
and/or thymoquinone[118] (which appears to have additional effects against latent cells),
until full remission is achieved. Patients should be cautioned that additional attention to
their symptoms management protocol may be required to address increased levels of
We would caution this complementary approach could be ill-advised during the initial
treatment phase, as increasing an already elevated lytic activity may exceed
spironolactone’s dose efficacy and the capabilities of a still-recovering immune system.
Metabolic Shunting
As already described in previous studies for senescent cells, lymphomas and other
cancers, altering the metabolic parameters for infected cells, by eg. PDE4 inhibition
and/or PDHK inhibition and/or anaplerosis and/or GLS1 inhibition is sufficient to impact
cell proliferation and cause tumor shrinkage. The author’s opinion is that administration
of the therapeutic interventions described in “Symptoms Management” may have
selective, positive effects on infected cell viability and may also extend to targeting other
cells exhibiting the same metabolic features[98][140][143][144][147][149][150][151][175][176][179][180][189][190].
The symptoms described in the HASD model are considered to be highly debilitating and
sometimes life-threatening, requiring an increased level of patient awareness around
expectations, timeline and management.
Due to the nature of the infection, the impact of HASD CFS/ME impairments would relate
to both lytic phase activity and separate latent cell location, burden and activity. In this
CFS/ME model, the primary burden revolves around hepatic impairments with other
organs, such as the brain, as secondary targets.
HASD CFS/ME should be considered as a chronic form of viral hepatitis and the
methods reviewed in this section could also be suitable for early stage intervention of
HHV infections, including mononucleosis.
The mitochondrial and metabolic impairments described previously suggest some key
targets for therapeutic intervention. The additional challenges for CFS/ME patients
involve the existing adaptations or long-term compensations around mitochondrial and
metabolism alterations, including lactic acid cycle efficiency, glutaminolysis and receptor
homeostasis, including GABA, dopamine, beta-adrenergic, muscarinic and others.
As previously stipulated, all primary targets described herein must be addressed
simultaneously to form a therapeutic intervention in this model.
It has been previously described that entering and exiting a ketogenic diet induces
temporary metabolic and mitochondrial impairments, while enzymatic adaptations inside
the cells and microbiome alterations are enacted. We would postulate that in HASD
CFS/ME, rehabilitation from adaptations to chronically altered hepatic metabolism would
be expected to have a similar, albeit longer transitional period with reduced efficiencies,
including expression of PDH and PDK[191][192][193][194].
The ratio of Acetyl-CoA to CoA acts as a rate limiter for critical enzymatic reactions
involved in pyruvate and carnitine metabolism pathways. These would have acute
effects for altering efficacy of therapeutic interventions and/or inducing preventable
symptoms. Caution is advised around co-administration of any medications or
supplements which further alter these ratios[159][160]161].
Based on the awareness of HHV-mediated antibodies and pathway alterations that
affect acetylcholine (ACh) receptor expression and homeostasis, the use of
anticholinergics would be expected to create cognitive and muscle activation
impairments in HASD CFS/ME patients[62][103][128].
Aspirin has a direct interaction with α-KGDH and α-KG binding. It has been
demonstrated to increase permeability of the mitochondrial inner membrane, as
demonstrated by acute intramitochondrial release of NAD(P)+[145][146]. This indicates
aspirin / acetylsalicylate / salicylate could add additional complications to HASD.
Berberine is an over-the-counter (OTC) dietary supplement with similar properties to
Metformin that has been trialled as a successful therapeutic intervention in the
management of type-2 diabetes, with further benefits suggested for metabolic disorders
and related gut microbiome dysbiosis[219][220][222] and IgE based food allergies[223].
Berberine has been shown to have antidepressant effects by antagonising dopamine
receptors, also suppressing innate and adaptive immune responses in experimental
models of colitis[221]. It has also been shown to positively affect liver cancer cells by
suppressing glutamine uptake via SLC1A5[224], suggesting benefits against latent HHV
Unfortunately, due to the mechanisms of action beyond activating AMPK that affect
hepatic gluconeogenesis, berberine is contraindicated in HASD CFS/ME[246][247].
Epigallocatechin Gallate (EGCG) is found in green tea and acutely inhibits GDH,
affecting the metabolism of α-KG to glutamate and vice-versa. While this may provide
significant benefits for inhibiting latent cell proliferation in HHV or excess ammonia /
glutamate production from elevated α-KG in HASD CFS/ME, the effects of drinking
green tea and/or consuming extracts of green tea could create acute, temporary hepatic
impairments for HASD CFS/ME patients which could persist for days[38].
Metformin is a commonly prescribed drug for managing type-2 diabetes, with similar
properties to Berberine. Intolerances to Metformin have been reported, complicit to
expected glucose:lactate alterations in the GI tract and related gut microbiome
Benefits against neurodegenerative diseases have been reported, as well as a reduction
in all-cause mortality for type-2 diabetics with cancers[226][227][228].
Unfortunately, due to the mechanisms of action beyond activating AMPK that affect
hepatic gluconeogenesis, metformin is contraindicated in HASD CFS/ME[246][247].
α-KGDH Deficiency Interventions
Resolving α-KGDH deficiency in the HASD CFS/ME model would allow for acute
improvements to mitochondrial efficiency and amelioration of the downstream cascade
of impairments. Resolving this deficiency via anaplerosis at succinate may also positively
alter immune response and infected cell viability, particularly when combined with the
“PDH Deficiency Interventions’ described.
Succinate (succinic acid / amber acid / butanedioic acid)
has shown high efficacy at
reversing key menopausal symptoms in two randomised, double-blind,
placebo-controlled clinical trials[143][144]. In the first trial, the daily dose used was
10.54-11.4 mg/kg. The second trial used approximately half that dose, or 400mg/day.
The resulting commercialised product, Amberen, is available for these purposes. It has
shown benefits for specific types of cancer cell lines.
Succinic acid is available as both a dietary supplement and food additive (E363) in many
countries. In the HASD model, exogenous succinate provides a direct way of healing the
CAC, via anaplerosis, at the point where an α-KGDH deficiency creates the cascade of
impairments, leaving only a redox depletion of NAD+ to resolve exogenously and an
elevation of α-KG to be metabolised to an increased glutamate and glutamine load,
before being further excreted as urea.
Relative to patient activity levels, sufficient attention to hydration and urination sufficiency
would be necessary. Increasing GDH may possibly provide some benefits for increasing
a-KG metabolism (see: "β2-Adrenergic Cascade / Corydalis Ternata.")
In the herpesviridae seropositive CFS/ME model, succinate would rapidly restore
mitochondrial efficiency, however caution should be noted around using this “suddenly
available” energy without also simultaneously treating the PDH deficiency and
β2-adrenergic cascade impairments
, otherwise lactate will accumulate with physical
activity, leading to preventable myopathy, hepatitis, encephalopathy and general
inflammation. Relative to individual circumstances, painful symptoms from
hyperlactatemia could take hours or many days to resolve, also leading to latent cell
proliferation and lytic reactivation, in extreme circumstances.
Based on available clinical trial data and further addressing expectations around
CFS/ME dysfunctional beta-adrenergic signalling and dysautonomia, a suggested initial
assessment dose schedule of approximately 0.25mg/kg, repeated every 20 minutes and
up to 100mg, or until sustained “mild adrenergic overstimulation” is experienced.
A repeat dose of slightly less than the sum of the combined dosing to reach “mild
adrenergic overstimulation” could then be used as a therapeutic dose, every 3-4 hours,
with expectations of increasing this dose over 1-2 weeks, until no adrenergic
dysregulation is experienced by the patient at any dose, indicating metabolic adaptations
have been completed. This dose will need to be maintained until all related antibodies
have cleared and hepatic latent cell burden is resolved. Additional dosing may be
required, relative to significant increases in physical activity.
In HASD CFS/ME, before succinate treatment has restored normal metabolism, an
excess dose of succinate could be expected to cause temporary effects such as mild
dizziness and/or elevated heart rate, due to previous compensatory metabolic
adaptations, an effect which could be potentially useful as a blunt diagnostics tool.
During early treatment for HASD patients (with or without CFS/ME), acutely increased
immune response as indicated by skin rashes and inflammation in tissues with latent
cells would be expected.
GABA (+ Arginine)
GABA and arginine (NOT α-ketoglutarate form)
are both available as dietary
supplements in many countries and could help provide an exogenous route to help
restore GABA levels and receptor homeostasis[49], particularly during initial treatment.
These supplements also provide a backup path to synthesising succinate, should
physical activity levels exceed available intracellular succinate, ultimately caused by an
insufficient succinate dosing schedule. An excess dose of GABA may cause a temporary
flushing / skin tingling effect, or a mild sedative effect.
Based on the HASD CFS/ME model expectations for diurnal elevation of
α-KG->Glutamate, a speculative dose range could be 2 x 500mg - 750mg, taken in the
afternoon / evening, only if excess glutamate is observed. A fast-acting β-adrenergic
agonist could also assist with glutamate scavenging[37]. (see: "β2-Adrenergic Cascade /
β2-Adrenergic Agonists (short-acting)")
Arginine is required to assist transport of GABA across the blood-brain barrier[141]. Based
on published metabolomics data and HASD CFS/ME model expectations, if the patient is
already treating α-KGDH deficiency via anaplerosis at succinate, serum arginine may
already be sufficiently elevated. As indicated by “Plasma Amino Acids” pathology, a
suggested dose range is 250-500mg, taken in the afternoon / evening.
B12 / Methylcobalamin
Active + inactive serum B12 sufficiency should be assessed and resolved via diet and/or
therapeutic intervention, as B12 could be easily depleted during any metabolism to
Alpha-Lipoic Acid
(see entry under “PDH Deficiency Interventions / Alpha-Lipoic Acid (ALA)”)
Indications could include:
Absence of energy, where dietary sufficiency and dosing of succinate and β2-adrenergic
cascade therapeutic interventions are optimal.
NAD+, or precursors Nicotinamide Riboside (NR), Nicotinamide Mononucleotide (NMN)
and/or Niacin (Nicotinic Acid / Vitamin B3) would be a required cofactor in treating
α-KGDH deficiency via anaplerosis and the dosing schedule would relate to physical
activity levels. At this time, NMN has been suggested as providing a superior method of
maintaining NAD+ pools over a longer duration[67][212][213][218].
Based on the HASD CFS/ME model, a suggested dosing of NMN would be 125-250mg,
3 times per day and also before any sustained exercise periods.
PDH Deficiency Interventions
Resolving PDH deficiency will prevent unwanted lactate generation during energy
production. PDH kinase inhibition and/or PDH promotion, along with appropriate
progressive increases to daily activity will further increase PDH levels via metabolic
Excess lactate generated from an “inappropriate” amount of physical activity, relative to
PDH levels, would be first noticed as intense, burning muscle pains which linger. This
could be largely prevented, in future, by administration of a suitable PDH promoter or
PDHK inhibitor, such as ones described herein.
Burning muscle pain would be followed initially by delayed upper-right abdominal pain
(liver), headache swelling and general inflammation, if hepatic gluconeogenesis is
simultaneously impaired. (See also
: “β2-Adrenergic Cascade”
NB. The upper-right abdominal pain should be considered as a “critical state”, which
needs immediate remediation via a fast-acting beta2-adrenergic agonist to prevent lactic
acidosis and hyperammonemia symptoms - following any upper right abdominal pain, it
would be expected that headaches, neck inflammation, hot or swollen distal extremities
will be experienced.
Remarkably, a rapid intervention is already commonplace and is dosed via an inhaler,
for another autoimmune disease - asthma. (see: "β2-Adrenergic Cascade /
β2-Adrenergic Agonists (short-acting)")
A further psychological challenge, from a patient education perspective, is that
increasing PDH and improving liver metabolism function, to further progress their
recovery will require a lengthy adaptation time and appropriate levels of basic exercise,
such as walking. Exercise can induce excess lactate and cause systemic pains, in
absence of appropriate treatments. “Learning the limits”, then progressively and
appropriately challenging those limits each day / week / month is a necessary activity to
increase their lactate metabolism efficiency.
Using a ‘step-counter’ may be a useful tool in objectively tracking progress.
Dichloroacetate (DCA)
Dichloroacetate has been demonstrated as a highly effective PDHK inhibitor in clinical
trials for cancers and has been successfully used for congenital lactic acidosis since the
Common side effects reported include peripheral neuropathy, delusions, cognitive
impairment, mood swings and gastrointestinal upset, at doses of 6.25-12.5mg/kg, twice
per day. It has been reported that patients with GSTZ1 polymorphisms metabolise DCA
twice as fast and therefore require twice the standard dose for cancer treatments,
however it was mentioned that PDHK inhibition was still achieved[96][97][148]. This also
suggests a lower dose of DCA may be effective for HASD CFS/ME, with a more
side-effect friendly profile.
It has been suggested from case reports that mitigations for these side effects can be
achieved by use of vitamin B1 (as benfotiamine / thiamine), alpha lipoic acid, L-carnitine
and a proton pump, such as pantoprazole[68][133][148][150]. The anaplerotic healing of CAC
efficiency / proton pumps as provided by succinate would further suggest additional use
of pantoprazole could be unnecessary.
Resveratrol has been shown to be a potent PDHK inhibitor and tumor suppressor, with a
mild side-effect profile. It has also demonstrated some ability to increase expression of
proteins required to form Complexes I-V, suggesting therapeutic benefit for some
inherited mitochondrial diseases. High doses have been known to cause diarrhea and
Based on available pharmacokinetics data, dosing at 500-750mg, three times a day with
meals would yield a suitable steady-state for PDK inhibition, providing gastrointestinal
upsets or neuropathy are not experienced[142][152].
(Not to be confused with Acetyl-L-Carnitine.)
L-Carnitine deficiency in mitochondrial myopathy disorders is a well-known cause for
reduced PDH and lactate clearance issues[160]. L-Carnitine and acetyl-CoA is reversibly
converted to acetyl-carnitine by carnitine acetyltransferase (CAT)[159]. The ratio of CoA to
acetyl-CoA limits PDH kinase.
Care should be taken, as the acetylated form “Acetyl-L-Carnitine” would induce the
opposite effect
Common dosing schedules for L-Carnitine range from 7-15mg/kg/day.
Alpha-Lipoic Acid (ALA)
(Not to be confused with flaxseed derivatives / linolenic acid or linoleic acid.)
ALA is available in multiple forms - of the two enantiomers, (R)-(+)-lipoic acid (RLA) and
(S)-(-)-lipoic acid (SLA), RLA is suggested as superior. It’s also available as a mixture,
(R/S)-lipoic acid (R/S-LA). ALA is noted for being a PDH promoter, tumor metastasis
suppressor and also protects α-KGDH from oxidative stress[36][150][162][171].
Case reports and pharmacokinetic data would suggest an optimal dose range in HASD
CFS/E is 250-400mg, 3 times per day and before sustained exercise.
Exercise plays a crucial role in favourable metabolic adaptations to PDH and PDHK
expression. Studies have shown 1 week of aerobic exercise is insufficient for these
adaptations, whereas 8 weeks of consistently exercising conferred beneficial results[191].
Hyperlactatemia Crisis Intervention
Indications could include:
Onset of upper right abdomen pain (liver), followed by neuralgia, systemic inflammation
and/or hot, swollen hands and feet.
B2-Adrenergic Agonists
ß2-adrenergic agonists provide rapid intervention and prevention to hyperlactatemia.
Therapeutic options are readily available via inhalers, as short-acting interventions for
the treatment of asthma. (see: “β2-Adrenergic Cascade / β2-Adrenergic Agonists
Sodium Bicarbonate
Sodium bicarbonate is routinely used in the treatment of lactic and metabolic acidosis,
however in the HASD CFS/ME model, would likely provide little benefit, as the pH levels
may be already balanced by concomitant ammonia production[75].
β2-Adrenergic Cascade
Indications could include:
“Insensitivity to β-oxidation” - “feeling cold” / no energy on waking or fasting.
“Hyperlactatemia” - swelling, inflammation, liver pain, headache / encephalopathy.
β2-Adrenergic Agonists (short-acting)
For autoimmune diseases, such as asthma, there are a number of short-acting
beta-adrenergic agonists available for rapid and convenient dosing, in the form of
inhalers, with effects that typically last 4-6 hours[229]. These are sometimes supplied as
prescription or OTC in different countries.
Commonly used β2-Adrenergic Agonists include Salbutamol (albuterol), levalbuterol and
adrenaline. They provide metered doses at typically 100-200 mcg and are used 3-5
times a day, or as needed.
Common side-effects can include over-stimulation, agitation, panic, tachycardia.
In HASD CFS/ME, dosing would likely approximate schedules for asthma.
Therapeutic intervention targeting, or combined with, cAMP and/or AMPK may be
β2-Adrenergic Agonists (long-acting)
Complementary to short-acting β2-adrenergic agonists, long-acting β2-adrenergic
agonists provide extended period of agonism. Commonly prescribed examples are
salmeterol, formoterol, with metered doses[230].
Common side-effects can include over-stimulation, agitation, panic, tachycardia.
In HASD CFS/ME, dosing would likely approximate schedules for asthma.
Therapeutic intervention targeting, or combined with, cAMP and/or AMPK may be
Forskolin, an extract of coleus forskohlii, is a highly potent cAMP promoter and
has been demonstrated to significantly enhance nerve regeneration and
positively alter immune responses related to asthma and chronic obstructive
pulmonary disorder. Important to the HASD CFS/ME model, downstream of
cAMP, forskolin increases hepatic gluconeogenesis and mitochondrial biogenesis
via PGC-1α[233]. Forskolin’s effects are significantly improved when combined with
a PDE4 inhibitor[231][232][234]. Forskolin also increases CYP3A activity, which may
be a consideration for some drug-drug interactions[235].
Commonly used doses range from 2.5 - 60mg of the active extract, up to 3 times
per day, with positive effects on body composition[236].
In the HASD CFS/ME model, a suggested dose could be 5-15mg of the active
extract, 3 times per day.
Exercise plays a significant role in positively altering fatty acid oxidation efficiency via
beta-adrenergic signalling. An appropriate, consistent, daily exercise routine is a critical
requirement for metabolic recovery from the impairments induced by CFS/ME and may
take many months[237][238].
Transport protein CD36 appears to also be a critical player in these adaptations and
could be worthy of further exploration[239].
The challenge in HASD CFS / ME is self-identifying the appropriate amount of exercise
and progressively increasing it. Excessive activity would induce ammonia and glutamate
burden, relative to UC efficiency. Afternoon naps may be initially required. Without
appropriate symptomatic management, it would also induce hyperlactatemia and other
H1 Antagonists
Ketotifen is a H1 antagonist and mast cell stabilizer that has been demonstrated
to upregulate expression of β2-adrenergic receptors and be an effective drug in
treating asthma. Ketotifen is available both as OTC ocular drops and as tablets,
for treating allergic reactions[240][241][242][243].
In HASD CFS/ME, ketotifen could be useful as a means of resensitising
β2-adrenergic receptors following dysregulation by antibodies, metabolic
impairments or excessive use of β2-adrenergic agonists.
Common side effects include drowsiness, at higher doses. An evening dosing
schedule could be considered.
Corydalis Ternata
Benzylisoquinoline alkaloids and other compounds from corydalis ternata, such as
berberine, coptisine and protopine have been demonstrated to antagonise H1 receptors
(increasing β2 receptor expression), plus increase GDH and AMPK activity[202][203][204].
While protopine may be beneficial for altering Cori Cycle and α-KG metabolism
efficiency, it exhibits mild anticholinergic effects, which may prove problematic as a
therapeutic intervention in HASD CFS/ME[209].
Muscarinic Acetylcholine Receptors
Indications could include:
1. Muscle spasms / cramping.
2. Myopathy other than post-exercise lactate.
In the general adult population and relative to gender, the recommended daily choline
intake is approximately 400-550mg / day with a reported tolerable upper limit of >3.5g /
day. Frequent anecdotal reports indicate excessive intake of choline has been
associated with depressive effects, in a subset of the population. Dietary choline comes
mostly from organ meats, eggs, and soy lecithin[153].
In the HASD CFS/ME model, daily choline intake should be relative to activity levels,
with the minimum intake increased to 750mg and consumed across 3-4 servings per day
to maintain optimal systemic levels against metabolic half-life and expected 3-5 hour
digestion + absorption delays[62][210].
Choline from dietary supplements like choline bitartrate may be useful in maintaining
sufficiency. Attention should be given to any digestion and pharmacokinetic data of any
supplement to maintain systemic sufficiency.
Endocrine Disruption - Resolving Adrenal Cortex Dominance
Human Chorionic Gonadotropin (hCG)
It is expected that the described HASD therapy over 6-8 weeks would restore normal
endocrine function via amelioration of the impairment cascade, as observable by a
remission of symptoms relating to endocrine disruption, including those resembling PFS
and remission of tissue and follicle abnormalities such alopecia, PCOS or endometriosis.
This would be quantified in male patients by testing 24 hour urine cortisol, DHT,
Adrenocorticotropic Hormone (ACTH), Dehydroepiandrosterone (DHEAS), LH, FSH,
Testosterone (T), Sex-Hormone Binding Globulin (SHBG), Free T, OE2, Thyroid
Stimulating Hormone (TSH) and Prolactin (PRL).
In males, if 24 hour urine cortisol, serum DHEAS and DHT are in mid-normal / normal
range, yet LH and OE2 have not concomitantly increased to normal ‘mid-range’ values
(LH > 4-7IU/L, OE2 > 90-120pmol/l), a therapeutic endocrine “challenge” could be
performed, via a 4 week intervention of parenteral injections of the LH analogue, hCG, to
restore oestrogen dominance over other HPG feedback inputs - overriding
allopregnanolone and DHT[68].
Extrapolation from older “min/max” peer-reviewed literature correlates with more recently
published anecdotal case report data[201] suggesting that a single 150IU dose of hCG
provides a serum LH analogue with a Cmax of approximately 1IU/L and a Tmax of 8 hours.
Further, a 500IU dose of hCG provides a serum LH analogue with a Cmax of
approximately 3IU/L and a Tmax of 36 hours[195][196][197][198][199][200].
Therefore, in males, a suggested therapeutic serum hCG Cmax target for each of the 4
weeks could be:
Week 1 - 6IU/L (as 1000IU, once, eg. on day 1)
Weeks 2,3 - 3IU/L (as 500IU hCG, every 3.5 days, eg. on days 7, 10.5, 14, 17.5)
Week 4 - 1.5IU/L (as 250IU, every 2 days, eg. days 21, 23, 25, 27)
Mildly elevated oestradiol (130-150pmol/L) during week 1 is expected and desired. Minor
and temporary symptoms, such as nipple sensitivity and alterations to libido may be
noticed during week 1 and 2. Retest serum markers at 3 weeks following cessation of
Neurotransmitter Homeostasis
Normalisation of Glutamate, Glutamine and GABA
Cabrera-Pastor et al., 2019 reported on the effects of increasing cyclic guanosine
monophosphate (cGMP) to reverse a plethora of neurotransmitter imbalances caused by
“hyperammonemia, hepatic encephalopathy or Alzheimer's disease”[49].
Their work indicated therapeutic uses for:
1. Phosphodiesterase 5 (PDE5) inhibitors, such as tadalafil, sildenafil, zaprinast, to
reduce metabolism of cGMP. These could be incompatible in HASD CFS/ME due
to decreased gluconeogenesis[249].
2. GABA modulating neurosteroids, such as pregnenolone, allopregnanolone -
which are also increased by endogenous LH levels or hCG therapy.
3. GABA-A receptors antagonists (bicuculline).
4. Inhibitors of cyclooxygenase, such as ibuprofen, for reducing neuroinflammation.
Polygala Tenuifolia
Research has shown that Polygala can exert agonistic effects on β-adrenergic,
α-adrenergic, D & D dopamine and 5-HT(2A) receptors[205][206]. This may prove
beneficial against impairments caused by HASD CFS/ME antibodies for these or related
Taurine has been demonstrated to reduce production of catecholamines in hypertensive
patients, which may be relevant to some HASD CFS/ME patients[244].
Tyrosine is a key intermediate in catecholamine synthesis pathways. It has also been
identified as a target for heterophile antibodies in CFS/ME[128]. Exogenous tyrosine exerts
pressure on catecholamine production and may be beneficial in restoring impaired
neurotransmitter homeostasis[207][208].
Further Research is Needed for Potentially Related Diseases
This paper is intended to allow a better understanding of herpesviridae, which can be used and
extended by all. This model outlines key pathways only and more research is needed.
If this model is validated and proven robust through clinical trials, then the HASD signature of
mitochondrial and metabolic disturbances described in this paper suggests significant research
is needed into exploring a large number of diseases and disorders that display a related profile
of metabolic alterations and impairments.
Based on the evidence presented in this paper, it is the authors’ opinion that many common
diseases and disorders are simply the same ubiquitous herpesviridae infection(s), presenting
different symptoms based on the location and burden of the latent cells and any level of lytic
We hope to see further research in attempting to apply this model to -
Multiple Sclerosis[74][94][138], Parkinson’s Disease[94][260][261], Alzheimer’s Disease[94][183][15], ALS[94][266],
bipolar disorder[63][105], schizophrenia[101][102][103][105][248], anxiety disorders[256], depression[128][257],
narcolepsy[128], sleeping disorders[49][50][51], eating disorders[49], fibromyalgia[43], fibrosis[267],
rheumatoid arthritis[44][138][264], psoriatic arthritis[44][264], polycystic ovary syndrome[185],
endometriosis[96], mast cell activation syndrome (MCAS)[99][243], eczema and other skin
disorders[44][253][254][255], alopecia[92][185], hirsutism[252], colitis[44][258], irritable bowel
disorder[44][65][154][155][262], coeliac disease[259], gut microbiome disorders with elevated butyrate[154],
Raynaud’s Syndrome[265], Ehlers Danlos Syndrome[250][251], Addison’s Disease[268], Hashimoto’s
Disease[269], Lupus / SLE[138][265], myasthenia gravis[270], primary biliary cirrhosis[3][16][26][27][30],
NAFLD[54][107][168], Type-1[271] diabetes, Leigh Disease[45][135], Reye Syndrome[45][273], Fumarase
Deficiency Syndrome[249], mitochondrial diseases where genomic sequencing is negative,
lymphomas[33][44][72][179][189][190], multiple myeloma[44][148], food allergies[272], lactic acidosis[45],
congenital lactic acidosis[45][263], Sudden Infant Death Syndrome (SIDS)[45][172][263],
colic[45][154][155][263], cancers featuring the “Warburg” or “Reverse Warburg” effect[44], “Long COVID”
syndrome[177][178], as well as dislipidemia, insulin resistance, hypogonadism, Post Finasteride
Syndrome and Post-SSRI sexual dysfunction.
With special thanks to J Carlson and S Asnani.
Data Availability Statement
All materials used have been cited. Images were created in Draw.IO and source files to extend
this model are available upon request to the corresponding author.
Author Contributions
JL conceived the design and authored the manuscript. AN reviewed methodology, provided
oversight and guidance, expert lab experience, analysis skills, audited / validated citations and
edited the manuscript. All authors critically reviewed the final manuscript.
This work was unfunded and conducted out of human interest.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or
financial relationships that could be construed as a potential conflict of interest. Authors have
joint-filed a patent relating to the formulation of a treatment protocol.
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... We recently shared our novel understanding of a rather complicated disease model by submitting a few articles for peer-review and journal publication purposes [1] [2] . This model appears to accurately describe the pathophysiology of a very large number of diseases and disorders in a way that allows them to be treated and potentially cured [1] [2] . ...
... We recently shared our novel understanding of a rather complicated disease model by submitting a few articles for peer-review and journal publication purposes [1] [2] . This model appears to accurately describe the pathophysiology of a very large number of diseases and disorders in a way that allows them to be treated and potentially cured [1] [2] . Largescale testing has not yet been performed. ...
... There have been some early challenges in communicating our understanding of this model, as the language used was unfortunately as complicated as the disease model itself [1] [2] . ...
Full-text available
Here we describe the root cause of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis, the growing list of related diseases in the proposed spectrum, related cancers, senescent cells, their previously described mitochondrial / metabolic disturbances and their related pattern of metabolite depletions and compensations as being virally-induced by upregulated expression of protein levels for “GLS1 - KGA, GAC” and “GLUD1”, “GLUD2”. We further describe some practical solutions to this problem, in plain language. [PLEASE NOTE: This is a "special edition", intended for a wider audience and hyperbole contained here may not be present in the final version.] {Errata, second paragraph on Page 9 of 39 should read: First, if α-KG levels are low - converting glutamate into α-KG (while importantly making ammonia and NADH) - this was incorrectly written as NAD+}
... In "The true nature of an autoimmune disease" we hypothesised a complex, extensible model of impaired mitochondrial and metabolic disorders in human herpesvirus (HHV) seropositive CFS/ME as part of a Herpesvirus Autoimmune Spectrum Disorder (HASD) [1] . ...
... The HASD CFS/ME model is primarily based around metabolic impairments caused by alterations to metabolic behaviour in HHV-infected latent hepatic cells, with further complications associated with any lytic activity [1] . ...
... Aspartate, or aspartic acid is a key metabolite for many enzymatic reactions, including those in transamination of α-KG to oxaloacetate [1] [60] . ...
Full-text available
Abstract In cells, where mitochondria are utilising glutaminolysis and transamination - whether caused by normal function or when specifically altered by eg. virally induced overexpression of KGA, GLS1, GLUD1 and/or GLUD2 - key enzymatic reactions for energy production are reversed during the transamination of aspartate=>oxaloacetate and α-KG=>glutamate + ammonia, consuming additional pyridoxal 5-phosphate (P5P). Excessive glutaminolysis and transamination increases nitrogen / urea burden, while consuming aspartate, before further consuming acetate and butyrate for increased α-KG=>[..]=>glutamine disposal via the phenylacetylglutamine (PAGN) pathway to urine. Further, this elevates lactate and affects neighbouring cell metabolism via the lactate shuttle. Depletion of acetate could lead to many impaired reactions involving acetyl-CoA, with implications to beta-oxidation pathways, mitochondrial function, pyruvate:lactate balance and any pathways that require an acetyl donor, such as choline=>acetylcholine and carnitine=>acetyl-L-carnitine. Depletion of acetate would cause further dysregulation to the urea cycle (UC), creating an elevation of glutamate, acting as a rate limiting factor for glutaminolysis and further causing impairment of mitochondrial Nicotinamide Adenine Dinucleotide (NAD+):NADH redox, favouring NADH. Aspartate depletion also dysregulates production of reactive oxygen species (ROS), sex hormones, thyroid hormones, alpha-melanocyte-stimulating hormone, GABA and dopamine release. Depletion of butyrate dysregulates immune and mitochondrial apoptotic regulation via Nuclear Factor Kappa B (NF-κB) signalling. It further impacts nitrogen metabolism. The depletion of NAD+ acts as a rate limiting factor for many enzymatic reactions, including glutamate dehydrogenase (GDH), further impairing glutamate<=>α-KG metabolism. We further describe a role for acetate, aspartate, butyrate, P5P and Vitamin B5 in a therapeutic intervention against the HASD model for CFS/ME.
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L-lactate has energetic and signaling properties and its availability is modulated by activity-dependent stimuli, which also regulate adult hippocampal neurogenesis. Studying the effects of L-lactate on neural precursor cells (NPCs) in vitro, we found that L-lactate is pro-proliferative and that this effect is dependent on the active lactate transport by monocarboxylate transporters. Increased proliferation was not linked to amplified mitochondrial respiration. Instead, L-lactate deviated glucose metabolism to the pentose phosphate pathway, indicated by increased glucose-6-phosphate dehydrogenase activity while glycolysis decreased. Knockout of Hcar1 revealed that the pro-proliferative effect of L-lactate was not dependent on receptor activity although phosphorylation of ERK1/2 and Akt was increased following L-lactate treatment. Together, we show that availability of L-lactate is linked to the proliferative potential of NPCs and add evidence to the hypothesis that lactate influences cellular homeostatic processes in the adult brain, specifically in the context of adult hippocampal neurogenesis.
Full-text available
When viruses infect cells, they almost invariably cause metabolic changes in the infected cell as well as in several host cell types that react to the infection. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Several examples are discussed in this review, which include effects on energy metabolism, glutaminolysis and fatty acid metabolism. The response of the immune system also involves metabolic changes and manipulating these may change the outcome of infection. This could include changing the status of herpesviruses infections from productive to latency. The consequences of viral infections which include coronavirus disease 2019 (COVID-19), may also differ in patients with metabolic problems, such as diabetes mellitus (DM), obesity, and endocrine diseases. Nutrition status may also affect the pattern of events following viral infection and examples that impact on the pattern of human and experimental animal viral diseases and the mechanisms involved are discussed. Finally, we discuss the so far few published reports that have manipulated metabolic events in-vivo to change the outcome of virus infection. The topic is expected to expand in relevance as an approach used alone or in combination with other therapies to shape the nature of virus induced diseases.
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COVID-19, caused by SARS-CoV-2, can involve sequelae and other medical complications that last weeks to months after initial recovery, which has come to be called Long-COVID or COVID long-haulers. This systematic review and meta-analysis aims to identify studies assessing long-term effects of COVID-19 and estimates the prevalence of each symptom, sign, or laboratory parameter of patients at a post-COVID-19 stage. LitCOVID (PubMed and Medline) and Embase were searched by two independent researchers. All articles with original data for detecting long-term COVID-19 published before 1st of January 2021 and with a minimum of 100 patients were included. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. Heterogeneity was assessed using I2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 15 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). All meta-analyses showed medium (n=2) to high heterogeneity (n=13). In order to have a better understanding, future studies need to stratify by sex, age, previous comorbidities, severity of COVID-19 (ranging from asymptomatic to severe), and duration of each symptom. From the clinical perspective, multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.
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Introduction: Muscle pain, fatigue, and concentration problems are common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These symptoms are commonly increased as part of the phenomenon of postexertional malaise (PEM). An increase in the severity of these symptoms is described following physical or mental exercise in ME/CFS patients. Another important symptom of ME/CFS is orthostatic intolerance, which can be detected by head-up tilt testing (HUT). The effect of HUT on PEM has not been studied extensively. For this purpose, we assessed numeric rating scales (NRS) for pain, fatigue, and concentration pre- and post-HUT. As pain is a core symptom in fibromyalgia (FM), we subgrouped ME/CFS patients by the presence or absence of FM. Methods and Results: In eligible ME/CFS patients who underwent HUT, NRS of pain, fatigue, and concentration were obtained pre-HUT, immediately after HUT, at 24 and 48 h, and at 7 days posttest. We studied 174 ME/CFS patients with FM, 104 without FM, and 30 healthy controls (HC). Values for all symptoms were unchanged for HC pre- and post-HUT. Compared with pre-HUT, the three NRS post-HUT were significantly elevated in both ME/CFS patient groups even after 7 days. NRS pain was significantly higher at all time points measured in the ME/CFS patients with FM compared with those without FM. In ME/CFS patients, the maximum fatigue and concentration scores occurred directly post-HUT, whereas pain perception reached the maximum 24 h post-HUT. Conclusion: NRS scores of pain, fatigue, and concentration were significantly increased even at 7 days post-HUT compared with pre-HUT in ME/CFS patients with and without FM, suggesting that orthostatic stress is an important determinant of PEM.
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A metabolic hallmark of many cancers is the increase in glucose consumption coupled to excessive lactate production. Mindful that L-lactate originates only from pyruvate, the question arises as to how can this be sustained in those tissues where pyruvate kinase activity is reduced due to dimerization of PKM2 isoform or inhibited by oxidative/nitrosative stress, posttranslational modifications or mutations, all widely reported findings in the very same cells. Hereby 17 pathways connecting glucose to lactate bypassing pyruvate kinase are reviewed, some of which transit through the mitochondrial matrix. An additional 69 converging pathways leading to pyruvate and lactate, but not commencing from glucose, are also examined. The minor production of pyruvate and lactate by glutaminolysis is scrutinized separately. The present review aims to highlight the ways through which L-lactate can still be produced from pyruvate using carbon atoms originating from glucose or other substrates in cells with kinetically impaired pyruvate kinase and underscore the importance of mitochondria in cancer metabolism irrespective of oxidative phosphorylation.
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Recent studies of the ketogenic diet, an extremely high-fat diet with extremely low carbohydrates, suggest that it changes the energy metabolism properties of skeletal muscle. However, ketogenic diet effects on muscle metabolic characteristics are diverse and sometimes countervailing. Furthermore, ketogenic diet effects on skeletal muscle performance are unknown. After male Wistar rats (8 weeks of age) were assigned randomly to a control group (CON) and a ketogenic diet group (KD), they were fed for 4 weeks respectively with a control diet (10% fat, 10% protein, 80% carbohydrate) and a ketogenic diet (90% fat, 10% protein, 0% carbohydrate). After the 4-week feeding period, the extensor digitorum longus (EDL) muscle was evaluated ex vivo for twitch force, tetanic force, and fatigue. We also analyzed the myosin heavy chain composition, protein expression of metabolic enzymes and regulatory factors, and citrate synthase activity. No significant difference was found between CON and KD in twitch or tetanic forces or muscle fatigue. However, the KD citrate synthase activity and the protein expression of Sema3A, citrate synthase, succinate dehydrogenase, cytochrome c oxidase subunit 4, and 3-hydroxyacyl-CoA dehydrogenase were significantly higher than those of CON. Moreover, a myosin heavy chain shift occurred from type IIb to IIx in KD. These results demonstrated that the 4-week ketogenic diet improves skeletal muscle aerobic capacity without obstructing muscle contractile function in sedentary male rats and suggest involvement of Sema3A in the myosin heavy chain shift of EDL muscle.
Full-text available
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and 'post-exertional malaise', exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology. Methods: To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group. Results: A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < -0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation. Conclusions: The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.
Selective destruction of senescent cells Senescent cells are associated with a variety of age-related medical conditions and thus have been proposed as potential targets for therapy, but we do not yet have a full understanding of the underlying mechanisms. Johmura et al. used RNA interference to screen for enzymes essential to the survival of senescent cells (see the Perspective by Pan and Locasale). The authors identified a key role for glutamine metabolism, particularly the enzyme glutaminase 1, and demonstrated that inhibition of this pathway induced the death of senescent cells. Glutaminase targeting also ameliorated aging-related organ dysfunction and obesity-related disorders in mouse models, suggesting the potential therapeutic value of this approach. Science , this issue p. 265 ; see also p. 234
2-Oxoglutarate-dependent dioxygenases (2OGDDs) are a superfamily of enzymes that play diverse roles in many biological processes, including regulation of hypoxia-inducible factor-mediated adaptation to hypoxia, extracellular matrix formation, epigenetic regulation of gene transcription and the reprogramming of cellular metabolism. 2OGDDs all require oxygen, reduced iron and 2-oxoglutarate (also known as α-ketoglutarate) to function, although their affinities for each of these co-substrates, and hence their sensitivity to depletion of specific co-substrates, varies widely. Numerous 2OGDDs are recurrently dysregulated in cancer. Moreover, cancer-specific metabolic changes, such as those that occur subsequent to mutations in the genes encoding succinate dehydrogenase, fumarate hydratase or isocitrate dehydrogenase, can dysregulate specific 2OGDDs. This latter observation suggests that the role of 2OGDDs in cancer extends beyond cancers that harbour mutations in the genes encoding members of the 2OGDD superfamily. Herein, we review the regulation of 2OGDDs in normal cells and how that regulation is corrupted in cancer.
The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the microenvironment of tissues affected by chronic inflammatory disease is pro-inflammatory and anti-resolution. Despite these opposing immunological states, the metabolic states in the tissue microenvironments of cancer and inflammatory diseases are similar: both are hypoxic, show elevated levels of lactate and other metabolic by-products and have low levels of nutrients. In this Review, we describe how the bioavailability of lactate differs in the microenvironments of tumours and inflammatory diseases compared with normal tissues, thus contributing to the establishment of specific immunological states in disease. A clear understanding of the metabolic signature of tumours and inflammatory diseases will enable therapeutic intervention aimed at resetting the bioavailability of metabolites and correcting the dysregulated immunological state, triggering beneficial cytotoxic, inflammatory responses in tumours and immunosuppressive responses in chronic inflammation. Lactate accumulates in cancerous and chronically inflamed tissues, where it has diverse and often opposing effects. Here, the authors review the activities of this metabolite in these distinct circumstances, identifying opportunities for therapeutic modulation of the metabolic signature in tumours and inflammatory diseases.