Dr Graham Exelby. December 2024
Post exertional malaise (PEM) is an interplay between amino acid depletion, mitochondrial dysfunction, post exertional malaise (PEM) hypermetabolism, and brainstem hypoperfusion which creates a “perfect storm,“ one of the common symptoms in POTS, Chronic Fatigue Syndrome, Long COVID, Gulf War Syndrome and Fibromyalgia. Using fatigue and PEM as benchmarks, looking into causes has potentially provided major advances in investigation and management in POTS, Long COVID and their comorbidities.
Figure 1. Comparison of Symptoms Severity among POTS, FMS, GWS and Long COVID
(25)(26)(27)(28)(29)(30)(31) CFS rating is 10/10 in fatigue and PEM.
Coat hanger pain reflects hypoxia in muscle groups in the neck and shoulders associated with mitochondrial dysfunction and muscle weakness. When muscles have inadequate oxygen there is a switch to anaerobic metabolism, with accumulation of lactic acid which causes the characteristic cramping and pain. The relationship between the two is shown with exercise, where in POTS, CFS and many Long COVID even minor exertion increases pain, fatigue and cognitive difficulties which characterize PEM. (1)
The interplay between reduced blood flow, lactic acid accumulation and autonomic dysfunction leads to a snowballing increase in symptoms and prolonged recovery times. Post-exertional malaise (PEM) has been compared to the metabolic changes that a marathon runner may experience following their race. ME/CFS patients have reduced reserves of Adenosine triphosphate (ATP) vital for mitochondrial energy production, and replenishment of ATP may take days.
PEM in ME/CFS involves complex metabolic changes including alterations in amino acid metabolism, with evidence of effects 24 hours after exercise and PEM activation. Non-essential amino acids, particularly those that can fuel the TCA cycle independently of pyruvate dehydrogenase (whose function is impaired in PEM) may become increasingly important for maintaining energy production during PEM episodes,(2)(3)(4) as shown by Fluge et al.(5)
Hypermetabolism appears to play a significant role in PEM characterized by increased excretion of urine metabolities indicating an abnormally high rate of metabolism. The hypermetabolism in PEM is also associated with:
the increased excretion of methylhistidine in urine during PEM indicates elevated muscle protein breakdown. This may also contribute to amino acid depletion as muscle is a significant reservoir of amino acids in the body. (5)
intestinal barrier breakdown,
acetate excretion,
glycolytic abnormalities with altered glucose to lactate ratios,
purine metabolism dysregulation with decreased hypoxanthine,
hypoacetylation affecting multiple cytoplasmic enzymes and DNA histone regulation affecting cellular function and gene expression
metabolite loss most likely from hypermetabolic state and hypoacetylation contributing to the prolonged recovery period in CFS patients after exercise.
The effect of catabolic metabolism from PEM, generally aligned with brainstem hypoperfusion, is associated with:
Muscle Protein Breakdown: PEM triggers muscle catabolism, releasing amino acids that are rapidly utilized, leading to systemic depletion.
Nitrogen Overload and Urea Cycle Stress, where increased utilization of aspartate depletes its systemic levels, impairing nitrogen clearance and contributing to metabolic stress.
Gut Barrier Dysfunction where appropriate: Increased intestinal permeability worsens systemic inflammation and impairs amino acid absorption.
Mitochondrial Dysfunction where reduced energy production forces reliance on amino acids for energy, further depleting their stores.
Neuroexcitation and BBB Breakdown: Elevated glutamate and impaired aspartate in the CNS, coupled with BBB dysfunction, drive excitotoxicity and localized hypermetabolism in the brain.
Brainstem Hypoperfusion
The brainstem, which consists of the midbrain, pons and medulla, has been implicated in ME/CIFS in many studies. It regulates the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be affected by long-COVID and similar disorders eg migraine and ME/CFS.
Griffith University showed in 2023 that the brainstem is larger in Long Covid and ME/CFS patients (8) and the brainstem demonstrates an imbalance of neurochemicals in this same group in 2024. (9) These changes correlate with the SPECT scan findings in ME/CFS, POTS and Long COVID found in our studies. The brainstem hypoperfusion is believed to be part of the same process of hypoperfusion and mitochondrial dysfunction that underpins the coat hanger pain of FMS, Long COVID, Fibromyalgia and POTS.
Figure 2. SPECT Scans showing brainstem hypoperfusion and cerebral hyperperfusion
These demonstrate the mixed hyperperfusion and brainstem hypoperfusion typical of POTS.
Green represents normal perfusion. The blue areas reflect hypoperfusion, green normal, yellow, red then white increased metabolic activity/ hyperperfusion. The hyperperfusion is thought to be from endotheiliitis associated with intracranial vascular pressure as there is increasing evidence from our studies of impaired venous return causing a “backup” of venous pressure. Stagnant blood may play a part with its known activation of inflammatory cytokines causing the endotheleiitis. The scan image itself probably reflects increased levels of excitotoxic neurotransmitters affecting the brain through penetration through the dysfunctional BBB from the dysfunctional venous return.
Source: Mermaid Molecular Imaging
In severe ME/CFS, Wirth et al (10) noted the reduction in blood flow in the brainstem from lying to sitting was 24.5%. They described the reduced blood flow to the brainstem causing neurological symptoms including impaired cognitive function or “brain fog.” This hypoperfusion can impact both the global and local regulation of blood flow in the brain. COVID-19 seriously affects the endothelium and there is evidence of chronic endothelial dysfunction in the post-Covid-syndrome similar to that in ME/CFS.(11)
Wirth et al (10) also reported muscle mitochondrial dysfunction, as evidenced by higher levels of pyruvate and lower levels of ATP and phosphocreatine in muscles, suggesting an impairment in muscle energy metabolism, which is also observed in ME/CFS, indicating a likely overlap in the pathophysiological mechanisms of these conditions.
Long Covid research by Appleman et al, (1) has also shown post-exertional malaise (PEM), with associated fatigue, pain and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID.
Impaired Glymphatic Function
The impaired glymphatic function seen in Long COVID with its impairment of the paravascular space function also appears to have far-reaching effects on symptoms such as fatigue, brain fog and head pressure by CSF flow dysfunction. Combining the research into the Glymphatic dysfunction, Intracranial Hypertension by Hulens (12), Bragee (13) and others, with brainstem hypoperfusion and the catabolic metabolism of coat hanger pain and PEM provides a satisfactory hypothesis for much of the symptomatology in all of these.
The use of brain SPECT scans in POTS, Long COVID and ME/CIFS has demonstrated brainstem hypoperfusion which may assist us in determining whether we may be dealing with mitochondrial dysfunction eg after Infectious Mononucleosis, or a vascular/autonomic dysfunction with brainstem hypoperfusion with the sequalae from this, or more commonly, a combination of both. - Brainstem Hypoperfusion, Coat Hanger pain and Post-Exertional Malaise in POTS and Long COVID. (14)
Hoel et al (6) described PEM in ME/CFS involving complex metabolic changes including alterations in amino acid metabolism, with breakdown (burn off) particularly of the branched amino acids leucine, isoleucine and valine, with evidence of affects 24 hours after exercise and PEM activation. Non-essential amino acids, particularly those that can fuel the TCA cycle independently of pyruvate dehydrogenase (whose function is impaired in PEM) may become increasingly important for maintaining energy production during PEM episodes.(15)(16)
This process generates a range of byproducts, some of which directly impact amino acid pathways and the urea cycle. These byproducts can accumulate, contributing to systemic metabolic dysfunction and exacerbating the symptoms of CFS and PEM.
Our findings are discussed in- Amino Acids, Essential Vitamin and Mineral Burn Off in Post Exertional Malaise (23)
Figure 3: Proposed mechanism of ME/CFS linked to amino acid catabolism.
Category I: amino acids are converted to pyruvate, and therefore depend on PDH to be further oxidized. These are alanine (Ala), cysteine (Cys), glycine (Gly), serine (Ser), and threonine (Thr).
Category II: amino acids that enter the oxidation pathway as acetyl-CoA, which directly and independently of PDH fuels the TCA cycle for degradation to CO2. These are isoleucine (Ile), leucine (Leu), lysine (Lys), phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr).
Category III consists of amino acids that are converted to TCA cycle intermediates, thereby replenishing and supporting the metabolic capacity of the cycle- histidine (His), and proline (Pro)
The asterisks indicate the amino acids significantly reduced in ME/CFS patients.
Source: Fluge et al., Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. 2016 Dec 22;1(21):e89376. doi: 10.1172/jci.insight.89376. PMID: 28018972; PMCID: PMC5161229.(5)
The combination of low GABA, low aspartic acid, elevated glutamate, ethanolamine, and lysine, alongside abnormal histidine, which I describe as the “Perfect Storm,” reflects a convergence of increased urea cycle utilization, muscle protein breakdown, mitochondrial dysfunction, and systemic inflammation. Similar amino acid abnormalities can be seen in a range of metabolic, inflammatory, and neurological conditions.
Mitochondrial Dysfunction with impairments in the TCA cycle and amino acid metabolism.
Neurotransmitter Imbalance, with excess excitatory signalling (glutamate) and reduced inhibitory signalling (GABA).
Metabolic Stress with dysregulation in nitrogen balance (aspartate, glutamate) and membrane metabolism (ethanolamine).
Ethanolamine is a component of cell membranes and involved in lipid metabolism. It is a precursor for phosphatidylethanolamine synthesis to phosphatidylcholine. Found very frequently in our amino acid studies, low urinary ethanolamine and high phosphoethanolamine levels suggest disruptions in phospholipid metabolism, potentially causing altered cell membrane composition, which could affect neuronal membrane stability and function, potentially impacting pain signalling.
Ethanolamine is involved in choline synthesis, which is important for acetylcholine production, a neurotransmitter involved in pain modulation. This dysfunction exacerbates the metabolic stress, neuroinflammation, and barrier breakdown observed in conditions like PEM, CFS, and brain hypoperfusion, and is associated with phospholipid dysfunction.
Lysine in preliminary studies is the most commonly effected amino acid. Lysine intake is crucial for maintaining healthy collagen function, which supports the structural integrity of skin, tendons, bones, and other connective tissues. Deficiencies can lead to weakened connective tissues, delayed wound healing, and other related health issues.
Sirtuin 4 (SIRT4) is a mitochondrial protein that inhibits mitochondrial glutamate dehydrogenase 1(GDH) activity, thereby downregulating insulin secretion in response to amino acids, as well as PDH activity. This regulation prevents overactivation of PDHC under nutrient surplus conditions, preserving mitochondrial homeostasis.
Nicotinamide, as a precursor for NAD⁺, directly influences SIRT4 activity and mitochondrial metabolism. The interplay between nicotinamide, NAD⁺, and SIRT4 can influence the observed amino acid imbalances. Nicotinamide, by restoring NAD⁺ levels and modulating SIRT4, could break this "perfect storm" by enhancing mitochondrial efficiency, normalizing amino acid metabolism, and balancing neurotransmitter levels. Nicotinamide is available in a number of forms, eg normal Vitamin B3, nicotinamide, has been used for skin cancer modulation for many years.
Other amino acids may be abnormal, such as proline. Proline is a major component of collagen, and high plasma levels may signal increased collagen turnover or connective tissue remodelling. High proline also contributes to glutamate accumulation, exacerbating excitotoxicity and limiting downstream utilization in the TCA cycle.
Restoring the NAD+ levels can enhance the proline oxidation pathway, helping to regulate the proline-glutamate interconversion. NAD+ also supports the malate-aspartate shuttle, helping to address aspartate depletion. NAD+ supports urea cycle efficiency, helping clear ammonia that may accumulate from amino acid imbalances (e.g., proline and lysine dysregulation).
Clinic studies have found introducing liposomal nicotinamide riboside has positive effects on fatigue and amino acid patterns, including stabilizing of ethanolamine function. Liposomal delivery systems significantly enhance the bioavailability and clinical efficacy of supplements, including nicotinamide riboside (NR) for mitochondrial and metabolic dysfunction (as seen in CFS) and vitamin B3 (nicotinamide/niacin) for skin health and cancer prevention.
Therapeutic Potential of Nicotinamide and SIRT4 Modulation
Restores NAD⁺ Levels by boosting NAD⁺ which supports mitochondrial metabolism, improving TCA cycle function, amino acid metabolism, and neurotransmitter balance.
Inhibits SIRT4 (Indirectly) at high concentrations, relieving GDH inhibition and enhancing glutamate clearance.
Supports Neurotransmitter Balance as improved glutamate metabolism increases GABA synthesis, addressing excitotoxicity and anxiety.
Supports urea cycle efficiency, potentially reducing brain fog.
Stabilizes Amino Acid Metabolism as replenished mitochondrial function improves aspartate production, lysine metabolism, and ethanolamine utilization.
Reduces Mast Cell Activation by reducing inflammatory signalling, stabilizing histidine/histamine balance.
GABA and low Aspartic acid
In managing CFS patients with abnormal amino acid profiles, the addition of nicotinamide riboside has shown promise in restoring levels of lysine, ethanolamine, and valine to normal ranges. However, the persistently low urinary aspartic acid levels, believed to be reflective of underlying hypoxia during post-exertional malaise (PEM), remain a challenge. This imbalance with glutamate can lead to neuroexcitation, and while lowering dietary glutamate intake can be beneficial, additional pathways and management strategies may be helpful.
To address low aspartic acid levels, Dunstan et al (17) proposed supplementation with N-acetylcysteine (NAC) may help increase aspartate levels by promoting the conversion of cysteine to cystine, which can then be used to synthesize aspartate. (18) The potential benefits of NAC for ME/CFS patients, particularly in addressing oxidative stress and potentially improving symptoms, are promising. However, the risks, while generally mild, should not be overlooked. (19)
Supporting the urea cycle with supplements like arginine or citrulline may help increase aspartate production, although the important research by Weigel et al (18) found that the role of nutritional intake and supplement use on ME/CFS patients’ health-related quality of life remains unclear, dietary changes and the use of supplements appear to be of value to ME/CFS patients.
With the addition of GABA to the amino acid assays, low levels of GABA are being consistently seen. There is evidence supports the idea that increasing GABA levels can help counteract the excitatory effects of glutamate and potentially reduce neuroexcitation. There may be insufficient conversion of glutamate to GABA due to impaired glutamate decarboxylase (GAD) activity or pyridoxal-5’-phosphate (active B6) deficiency. If B6 levels are low (and care must be taken to ensure avoiding neurotoxicity from excess B6, Pyridoxal-5’-phosphate (P5P) starting at 25 to 50 mg daily may be helpful.
Additionally, there is evidence for the role of magnesium in glutamate regulation. Magnesium plays a significant role in regulating glutamate activity, as magnesium acts as a natural NMDA receptor antagonist, which can help regulate glutamate activity, and by blocking the NMDA receptor channel, magnesium can reduce excessive glutamate signalling.
Magnesium's action at NMDA receptors can protect against glutamate-induced excitotoxicity, which is implicated in various neurological disorders. (20) Magnesium can influence the release of neurotransmitters, including glutamate, potentially helping to maintain proper excitatory/inhibitory balance.(20) The impact of magnesium supplementation may vary depending on an individual's baseline magnesium levels and overall neurological health. Suggested is magnesium glycinate form, 200 to 400mg daily.
While the evidence supports the potential benefits of increasing GABA levels (and magnesium supplementation) in regulating glutamate activity, the relationship between these neurotransmitters is complex and context-dependent. While increasing GABA levels and magnesium supplementation show promise in regulating glutamate excitation, their effects can be nuanced and dependent on various factors. For example, in some cases, GABA can be excitatory, particularly during early development or in certain pathological conditions. (97) The effectiveness of GABA in counteracting glutamate excitation can depend on factors such as intracellular chloride concentrations and the expression of specific transporters. (21)(22)
CoQ10 at 100 to 300 mg daily has been shown may support mitochondrial function alongside nicotinic acid, the combination more effective than each alone in neuroprotection, blocking ATP deletions and lactate increases.(24) Yet nicotinamide and NAD+, nor randomly applied supplementation, while may improve fatigue, will not solve the metabolic problems.
While detailed family history can provide some genetic risk information, individualized DNA through Dr Vittone provides far more information into the various gene mutations than the normal commercially available products, and have been providing valuable insights into these complex pathways. These can provide a springboard into nutraceutical treatments.
Targeted diagnostics and personalized therapeutic approaches, which include dietary and nutraceutical protocols combined with mitochondrial and mast cell support, offers a promising strategy for addressing these complex biochemical disturbances. The targeted approach may help address the underlying metabolic imbalances and mitigate their clinical consequences. For the future, there is a peptide product currently highly regulated in Australia, which if used appropriately, in combination with a targeted management protocol, could yield significant improvements in many areas, thus warranting formal research.
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