In locus coeruleus (LC) neurons, dopamine is transported into the vesicles by vesicular monoamine transporter 2 (VMAT2) and then converted into norepinephrine (noradrenaline, NE) by the enzyme dopamine beta-hydroxylase (DBH) inside the vesicle.
The v-ATPase is needed to move dopamine into the vesicles. Research has shown that sufficient dopamine is not delivered into the vesicles to produce normal amounts of NE in ME/CFS patients (1).
Please read the blog post from Health Rising (1):
Role Reversal: Could a WEAKENED Fight/Flight Response Be Causing ME/CFS and Long COVID? The 2025 IACFS/ME Conference Pt. IDoes this research match the results (impaired systemic oxygen extraction and low right arterial pressure (RAP) in ME/CFS patients) from (2):
I used artificial intelligence (AI) via https://www.google.com/ to get some answers. Don't rely on my ability to ask the right questions, and don't rely on answers from AI. But, please, be inspired to search for more information.
Summary of AI answers
In the context of ME/CFS patients, this LC-NE dysfunction is hypothesized to contribute to key symptoms:
- Impaired Systemic Oxygen Extraction: Dysfunctional microcirculation (due to poor NE regulation) may cause blood to bypass necessary capillaries, leading to an oxygen delivery mismatch in tissues and muscles.
- Low Right Atrial Pressure (RAP): The impaired sympathetic tone contributes to low blood volume and a reduced capacity to maintain venous return and cardiac filling pressure when upright.
My questions and AI answers
Me: What happens to arterioles if vesicles from locus coeruleus have decreased levels of norepinephrine?
AI: If vesicles in neurons from the locus coeruleus (LC) have decreased levels of norepinephrine (NE), the effect on cerebral arterioles is a reduction in vascular contractile tone, leading to passive dilation.
The LC-NE system plays a critical role in generating a baseline level of vasoconstriction (tone) in arterioles and capillary pericytes throughout the brain. When NE levels are reduced:
- Decreased Constriction: Arterioles will experience a reduced level of constriction (vasoconstriction) due to less NE activating alpha-adrenergic receptors on their smooth muscle and on pericytes, which normally induce contraction.
- Reduced Vascular Tone: The overall vascular tone (baseline tension in the vessel walls) decreases, resulting in the arterioles becoming wider, or more dilated, than normal.
- Impaired Blood Flow Regulation: While this dilation might sound beneficial, it actually impairs the brain's ability to regulate blood flow efficiently. The normal function of this NE-mediated tone is to optimize neurovascular coupling: allowing for rapid and focused redirection of blood to areas of high neuronal activity (functional hyperemia).
- Inefficient Oxygen Delivery: With reduced tone and passive dilation, the brain experiences a less spatially focused and more prolonged hyperemic response to activity. This leads to a mismatch between blood volume supply and actual oxygen demand, resulting in inefficient oxygen extraction by active neurons.
- Me: What happens if ME/CFS patients have reduced norepinephrine levels in the neurons from the locus coeruleus?
- AI:: Reduced norepinephrine (NE) levels from the locus coeruleus (LC) in ME/CFS patients can lead to a range of neurological and cognitive symptoms, including brain fog, difficulty concentrating, impaired attention, sleep disturbances, and increased pain sensitivity. This deficiency can also impact the body's stress response, leading to a condition called post-exertional malaise (PEM), which is a hallmark of ME/CFS. The reduced NE may also contribute to neuroinflammation, as NE has been shown to have anti-inflammatory and neuroprotective effects.
Me: Can it also affect skeletal muscles?
AI: Yes, decreased norepinephrine (NE) levels originating from the locus coeruleus can affect skeletal muscles, primarily through their influence on muscle tone and blood flow regulation.
The effects are a combination of central and systemic influences:
- Muscle Tone Regulation (Central): Neurons from the locus coeruleus project to spinal motor neurons and brain structures that modulate muscle tone. The noradrenergic system helps couple muscle tone with the behavioral state (e.g., high tone during waking, low tone during sleep). A decrease in central NE drive to motor neurons can lead to hypotonia (decreased muscle tone) and contribute to fatigue or muscle weakness.
- Blood Flow Regulation (Peripheral): During the "fight-or-flight" response, systemically released NE and epinephrine increase blood flow to skeletal muscles to prepare the body for action. While NE levels in the brain (from the LC) and in the periphery (from the adrenal glands and sympathetic nerves) are regulated differently, a general dysregulation of the noradrenergic system, as hypothesized in ME/CFS, could lead to issues with peripheral blood flow. In ME/CFS patients, this could manifest as an inability to properly increase skeletal muscle blood flow and oxygenation during exertion, contributing to muscle fatigue and post-exertional malaise (PEM).
In summary, a dysfunctional LC-NE system can contribute to the skeletal muscle symptoms in ME/CFS by impairing the central regulation of muscle tone and potentially affecting the peripheral system's ability to ensure adequate blood flow and oxygen extraction during physical activity.
Me: Can it explain impaired systemic oxygen extraction and low right arterial pressure (RAP) in ME/CFS patients?
AI: Yes, decreased norepinephrine (NE) levels related to locus coeruleus (LC) dysfunction can contribute to both impaired systemic oxygen extraction and low right atrial pressure (RAP), as part of a broader systemic autonomic dysregulation in ME/CFS.
Impaired Systemic Oxygen Extraction
Impaired systemic oxygen extraction has been observed in ME/CFS patients during exercise tests, often indicated by a reduced arterial-venous oxygen content difference. A low NE state can contribute to this:
- Microcirculatory Disturbances and Shunting: Dysregulation of the autonomic nervous system, potentially driven by low central NE, can lead to microcirculatory disturbances, including arteriovenous (AV) shunting. This means blood bypasses the capillary beds where oxygen exchange occurs efficiently.
- Inadequate Flow Regulation: The lack of appropriate NE-mediated vascular tone means that blood flow is not optimally regulated to meet the metabolic demands of tissues, especially during exertion. This results in tissue hypoxia, even if the overall blood flow to the limb is normal, because the oxygen is not effectively transferred to the muscle cells.
Low Right Atrial Pressure (RAP)
Low RAP is typically associated with reduced central venous pressure (CVP) and is a key indicator of low cardiac preload or hypovolemia (low blood volume), which is a common finding in a subset of ME/CFS patients.
- Reduced Venous Tone: NE plays a major role in maintaining venous tone through alpha-adrenergic receptors in the peripheral circulation. This tone helps push blood back to the heart, contributing to preload (the volume of blood in the ventricles at the end of diastole). Reduced NE levels can lead to decreased venous tone, causing blood to pool in the peripheral veins.
- Hypovolemia and Preload Failure: This reduced venous return leads to lower end-diastolic volumes in the heart chambers, resulting in a low cardiac output. The lower volume in the right atrium and ventricle directly translates to low RAP.
- Kidney Vasodilation: Autonomic dysfunction may also lead to inappropriate kidney vasodilation and reduced sodium reabsorption, contributing to lower overall blood volume.
In essence, a dysfunctional noradrenergic system starting from the LC can cascade into systemic issues, leading to both the circulatory mechanics that cause low RAP/preload failure and microvascular issues that impair oxygen utilization in muscles
AI: Yes, the "ultraslow mode-switching" mechanism of the brain V-ATPase could potentially be involved in the ME/CFS pathomechanism related to filling vesicles with dopamine (and norepinephrine) in the Locus Coeruleus (LC). This recent neurobiological discovery offers a plausible explanation for how V-ATPase dysfunction could lead to the fluctuating, "on-again, off-again" nature of ME/CFS symptoms, particularly fatigue and cognitive fog.
References
2) Joseph P, Arevalo C, Oliveira RKF, Faria-Urbina M, Felsenstein D, Oaklander AL, Systrom DM. Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Chest. 2021 Aug;160(2):642-651. doi: 10.1016/j.chest.2021.01.082. Epub 2021 Feb 10. PMID: 33577778; PMCID: PMC8727854.https://pubmed.ncbi.nlm.nih.gov/33577778/
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