What Is Myalgic Encephalomyelitis?
A GLA-Based Systems Framework

Myalgic encephalomyelitis (ME) is a multi-system regulatory disorder marked by impaired perfusion, metabolic fragility, autonomic instability, and exaggerated innate immune responsiveness. The GLA model (Gut–Liver–Autonomic Axis) frames ME as a failure of physiological adaptation rather than a dysfunction of a single organ.

Under physical, cognitive, or orthostatic stress, the body should increase:

• endothelial dilation & capillary recruitment,
• mitochondrial ATP generation,
• liver metabolic buffering,
• autonomic cardiovascular compensation.

In ME, these adjustments do not activate appropriately, resulting in:

• microvascular under-perfusion,
• rapid metabolic strain,
• innate immune amplification,
• autonomic instability,
• delayed multi-system flares (PEM).

SMPDL3B, a GPI-anchored membrane stabilizer, sits at the highest level of the GLA hierarchy. Two phenotypes contribute to ME pathophysiology:

• Shedding phenotype: low membrane SMPDL3B, high soluble SMPDL3B, elevated PI-PLC activity, strong IL-6/TLR4 reactivity.
• Deficiency phenotype: globally reduced SMPDL3B capacity, lower PI-PLC tone, greater baseline metabolic fragility.

Both reduce the membrane’s ability to regulate endothelial, immune, and autonomic signalling.

A defining feature of ME is a self-reinforcing inflammatory loop:

This loop increases cellular reactivity and lowers thresholds for PEM.

SMPDL3B loss destabilizes endothelial lipid rafts, impairing:

• NO signalling,
• Ang-2/Tie2 balance,
• ET-1–mediated vasoconstriction,
• capillary recruitment,
• RBC deformability & microclot clearance.

Under impaired perfusion, tissues shift into hypoxic and anaerobic metabolism. ATP depletion leads to:

• Ca²⁺ pump failure,
• intracellular Ca²⁺ overload,
• mitochondrial dysfunction,
• ROS bursts.

ROS then reactivates PKC → PI-PLC, worsening SMPDL3B loss.

This loop explains the 24–72h delay characteristic of PEM.

The liver in ME shows functional metabolic strain despite normal routine labs. Disrupted bile-acid signalling, impaired metabolic switching, and oxidative stress lead to upregulation of FGF21, which correlates with symptom severity and reduced recovery capacity. Hepatic instability propagates instability across the entire GLA axis.

Autonomic dysregulation emerges from:

• impaired baroreflex sensitivity,
• sympathetic overcompensation,
• low circulating blood volume,
• RAAS signalling deficits.

This produces:

• POTS / orthostatic intolerance,
• 20–40% reductions in cerebral blood flow during tilt,
• sensory hypersensitivity.

SMPDL3B contributes to podocyte mechanotransduction.
Reduced SMPDL3B → impaired sodium handling → depressed RAAS response → bradykinin drift → renal hypoxia → further ROS.

This loop explains the improvement some patients experience with volume-expanding therapy.

The GLA model integrates:

• SMPDL3B-PI-PLC–TLR4 immune amplification,
• endothelial/microvascular instability,
• ischemia → Ca²⁺ → ROS loops,
• hepatic metabolic constraint (FGF21 signalling),
• autonomic & RAAS dysregulation.

This architecture explains the clinical hallmarks of ME:

• PEM,
• orthostatic intolerance,
• sensory hypersensitivity,
• exertional energy failure,
• multi-system symptom expression.

ME is a systems-level disorder maintained by interacting loops involving SMPDL3B loss, PI-PLC/TLR4 sensitization, endothelial dysfunction, ischemia-driven ROS signaling, hepatic metabolic constraint, and autonomic–vascular mismatch within the GLA axis.