by Tamara Carnac 1
1 Independent Researcher
Cite as: Carnac, T. (2023). Hypothesis: Astrocyte dysregulation of sympathetic nervous system causes metabolic dysfunction in subset of Long COVID and ME/CFS patients. Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 36-43
An overactive sympathetic nervous system (SNS) may cause one subtype of Long COVID. People who are genetically at risk for noradrenergic nerve problems may develop an overactive SNS after an infection. Alternatively, genetic or virus-induced dysregulation of astrocytes could lead to overactivation of the SNS. An overactive SNS could disrupt regulation of immune cells, energy metabolism, sleep homeostasis, respiratory rate, gastrointestinal function, and systemic and cerebral blood pressure, causing fatigue and cognitive dysfunction.
Long COVID refers to symptoms that continue for more than four weeks after onset of acute COVID-19 illness. This umbrella term includes a wide variety of symptoms and presentations. Long COVID patients may have different types of biological dysfunction, meaning that there may be distinct subtypes of Long COVID. One possible subtype is sympathetic nervous system (SNS) over-activation. This subtype may exist in both Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)1.
Theoretically, patients with this subtype already have a genetic dysregulation of neuronal norepinephrine (NE) release/clearance or noradrenergic receptor sensitivity2. This latent genetic dysfunction of NE signaling may not cause significant problems unless there is a trigger that causes excess NE release.
As NE affects immune cell signaling, this could result in an over-activation or prolonged activation of the immune system in response to infection with SARS-CoV-2, the virus that causes COVID-193 . This subtype could explain why ME/CFS is often triggered by a virus or brain injury, as these occurrences can trigger noradrenergic signaling3.
Possible mechanisms for the SNS overactivation subtype include viral reservoirs, antibody reaction, and dysregulation of noradrenergic receptor expression. In Long COVID patients, viral antigens and reservoirs that remain in the body long after the initial infection may keep the overactive immune system in an inflammatory state4,5. A healthy person may not react to these SARS-CoV-2 reservoirs, as their functional immune cells should develop immune tolerance. Another possibility is that the immune system is reacting to SARS-CoV-2 antibodies.
Finally, it is possible that excess extracellular NE could keep the SNS and noradrenergic systems in the brain stuck in an overactive state. A prolonged period of increased levels of extracellular NE could lead to dysregulation of noradrenergic receptor expression. The excess extracellular NE may be due to a prolonged release of excess NE during the initial infection, or a failure of the negative feedback mechanisms that should reduce NE release.
An overactive SNS explains many of the symptoms found in Long COVID patients, such as IBS/gastrointestinal symptoms6, heart palpitations7, and sleep disturbance8. Additionally, in orthostatic intolerance, which is common in Long COVID and ME/CFS, the release of NE causes pronounced tachycardia. This rapid heart rate may cause palpitations, breathlessness, and chest pain9.
An important piece of the puzzle is to explain how a dysregulated SNS could lead to chronic fatigue and brain fog (cognitive dysfunction). The most likely explanation is a dysregulation of metabolic function. There are many ways excess NE could affect metabolism, including enhancing aerobic glycolysis and depleting glycogen stores.
ME/CFS researchers have previously suggested that ME/CFS patients have dysfunctional neuroglia in the brain10. Astrocytes are a type of glial cell involved in brain metabolism and the regulation of glutamate and GABA. NE activation of β2 adrenergic receptors (β2ARs) on astrocytes results in increased expression of the glucose transporter GLUT1, leading to increased glucose uptake, enhanced aerobic glycolysis, and increased lactate production11. Increased lactate levels have been found in the brains of ME/CFS patients12.
In the brain, glycogen is primarily stored in astrocytes, and glycogenolysis is activated by NE acting on β2ARs. Increased NE levels could therefore lead to excessive glycogen depletion in astrocytes. It is also possible that the β2ARs themselves are oversensitive (not reducing their sensitivity in response to excess NE levels) due to genetic dysregulation13.
β2AR autoantibodies have been found in a subset of ME/CFS patients, which could cause dysregulation of astrocytic metabolism via β2ARs14. High levels of CCL2/MCP1 have been found in ME/CFS patients and CCL2/MCP1 can increase β2AR expression15,16.
An imbalance in astrocytes toward increased glycolysis could lead to reductions in glycogen stores in astrocytes. This could lower energy reserves, leading to increased fatigue. Researchers have proposed that brain glycogen decreases with increased periods of wakefulness, and that a major function of sleep is to replenish glycogen stores in the brain17. Therefore, an inability to build up glycogen stores in astrocytes could explain why many ME/CFS patients wake up feeling unrefreshed and tired18.
Excess NE release could also contribute to the post-exertional malaise experienced by ME/CFS and Long COVID patients after exercise. If patients start with depleted glycogen stores, the increased NE release during exercise would further deplete glycogen stores.
It is possible that in some ME/CFS and Long COVID patients, the biological mechanisms are the opposite to what has been suggested in this paper19. Reduced NE or reduced sensitivity of β2ARs could also contribute to fatigue, via a reduction of astrocytic glucose uptake, reduced glycogen synthesis, and a decrease in the lactate supply to neurons. This possibility aligns with research which has suggested that ME/CFS patients can be split into two groups with high and low NE plasma levels20. Reduced astrocytic glucose uptake could lead to a reliance on glutamine oxidation to maintain the tricarboxylic acid cycle.
Desensitized β2ARs on immune cells could lead to an inability to switch from the production of pro-inflammatory cytokines such as tumor necrosis factor-α to anti-inflammatory cytokines. Research has shown that the capacity of monocyte β2ARs to regulate the production of tumor necrosis factor-α is reduced in ME/CFS patients21.
Dysregulation of β2ARs could also cause excessive vasoconstriction of the blood vessels, bronchoconstriction of the lungs, reduced gut peristalsis, and dysregulation of lipolysis and thermogenesis in adipocytes. The β2AR also controls glycogenolysis and gluconeogenesis in the liver, which could lead to depleted liver glycogen stores and a reliance on noncarbohydrate metabolites. In skeletal muscle β2ARs can control translocation of GLUT4, which is normally triggered during exercise in order to increase glucose uptake. A reduced ability to translocate GLUT4 could lead to skeletal muscle fatigue during exercise.
A further theory is that dysfunction of the β2ARs on astrocytes could be solely responsible for causing the symptoms of ME/CFS and Long COVID. Astrocytes that reside alongside central nervous system sympathetic control circuits can regulate cerebral perfusion, systemic arterial blood pressure, heart rate, respiratory rhythm-generating circuits, sleep homeostasis, and glucose metabolism22-24.
Of particular interest is that astrocytes detect falling cerebral perfusion pressure and activate sympathetic control circuits in response. To counter the dropped pressure, the sympathetic control circuits increase heart rate and systemic arterial blood pressure in order to maintain blood flow and oxygen delivery to the brain. This mechanism involves astrocytic calcium-dependent signaling pathways25. Dysregulation of astrocytic calcium signaling due to β2AR dysfunction could lead to an inadequate or excessive SNS response when an ME/CFS patient stands up. A dysregulated SNS response could explain the postural orthostatic tachycardia syndrome (POTS) symptoms of altered heart rate and dizziness experienced by many ME/CFS and Long COVID patients.
An initial overactivation of the SNS could dysregulate astrocytes via adrenergic receptors, which in turn could prevent the astrocytes from being able to effectively control the SNS. Alternatively, genetic or virus-induced dysfunction of astrocytes could be the root cause of SNS dysfunction, an idea given weight by the finding that SARS-CoV-2 is able to infect and replicate in human cortical astrocytes26,27. Research testing these hypotheses is needed in order to better determine the mechanisms of Long COVID and ME/CFS.
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