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GLA — Concept Document

Shear Stress — A PEM Activator

A hypothesis note that reframes post-exertional malaise (PEM) as a shear-activated failure state emerging from baseline membrane control-surface instability, impaired resolution (ER stress / phosphatase efficacy), and mistimed nitric-oxide signaling.

Framework: GLA (v2.4, provisional) Audience: researcher / clinician discussion Status: hypothesis + testable predictions Updated: 2026-01-07

Document purpose

Post-exertional malaise (PEM) is the defining clinical feature of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), yet its triggering mechanism remains poorly explained by models focused solely on exertion load, inflammation, or mitochondrial insufficiency. PEM is notable not for the magnitude of stress required to provoke it, but for the fact that ordinary physiological demands—such as standing, walking, or cognitive effort—can be sufficient to initiate delayed, multi-system dysfunction.

This document reframes post-exertional malaise (PEM) as a shear-activated failure state. Rather than viewing PEM as a consequence of exertion, inflammation, or mitochondrial weakness alone, the core claim is that baseline membrane and endothelial instability renders otherwise-normal shear forces injurious. Everyday physiological demands (standing, walking, heat, cognitive load) then become sufficient to trigger a delayed multi-system collapse.

Key framing: PEM is not “caused by exertion itself.” Exertion is a stress test. The injury is the system’s inability to absorb and resolve flow stress when membrane control and signal termination are fragile.

Figure A — Overview: shear-activated failure state (5-box flow)
Shear Stress as the PEM Activator Baseline instability + normal physiological shear → delayed multi-system collapse BOX 1 Innate immune trigger (IFN / TLR) Viral hit, relapse, stressor — trigger type varies, but the entry point is conserved. Key point: initiation is not the controversy; failure of resolution is. BOX 2 Control & resolution layer ER stress + impaired membrane / phosphatase resolution • ER stress / slow recovery • Impaired receptor internalization • Reduced phosphatase effectiveness • Membranes can’t reorganize cleanly BOX 3 Membrane control surface Phospholipid & lipid-raft stability (SMPDL3B) SMPDL3B Phenotype fork (same upstream stress → different failure modes) Shedding phenotype • Defensive PI-PLC activation • Episodic loss of anchoring • Oscillatory instability Deficient phenotype • Chronically fragile rafts • Low recovery bandwidth • Persistent signal residency BOX 4 Downstream execution Metabolic / autonomic / vascular strain (Ca²⁺ handling, mitochondria, perfusion) Key point: mitochondria belong here (execution), not at the root. BOX 5 Clinical state PEM, crashes, phase progression (output state, not initiating cause) Shear exposure + impaired recovery → delayed symptom amplification.

Figure A. Conceptual overview: baseline resolution failure (membrane + ER) destabilizes the control surface, SMPDL3B failure mode determines phenotype dynamics, and normal shear exposures drive downstream execution strain and clinical PEM.

Section 1 — The baseline abnormalities (the vulnerable state)

1.1 Lipid-raft / membrane instability (control-surface failure)

At baseline, ME/CFS is modeled here as instability of the phospholipid “control surface” of immune and endothelial cells. Phospholipids are not passive building blocks — they determine where receptors sit, how long signals persist, and whether a cell can turn off cleanly after activation.

Interpretation: signals may start normally, but fail to shut off cleanly.

Figure B — The membrane “control surface”: why signals fail to shut off cleanly
Phospholipids are a dynamic control surface (not a wall) They determine receptor location, signal duration, and clean shut-off after activation. LEFT Stable lipid rafts → clean signal termination Membrane surface raft raft R R R R Internalization / recycling endosome Signal shuts off cleanly Short receptor residency → controlled duration → recovery possible RIGHT Unstable rafts → prolonged residency Membrane surface raft raft raft R R R R Prolonged receptor residency Internalization / recycling is slowed or incomplete Signal termination fails Signals may start normally → persist longer → recovery becomes fragile Interpretation: the core abnormality is duration control — “turning off” becomes unreliable.

Figure B. Conceptual “control surface” schematic. Stable lipid-raft organization supports receptor clustering and timely internalization, allowing signals to terminate cleanly. In membrane-unstable states, raft fragmentation increases receptor residency time and impairs coordinated termination, enabling persistent signaling without requiring high cytokine output.

1.2 SMPDL3B-related loss of membrane control capacity

SMPDL3B sits at a critical point in phospholipid biology and raft stability. In this framework it is treated as a membrane stability / signal-gain governor that influences multiple receptor platforms (TLR/IFN, insulin signaling, endothelial shear platforms).

Shedding phenotype

  • Defensive PI-PLC activation
  • Episodic loss of anchoring
  • Oscillatory instability (flares)

Deficient phenotype

  • Chronically fragile rafts
  • Low recovery bandwidth
  • Persistent signal residency
Figure C — SMPDL3B as a membrane stability / signal-gain governor (two failure modes)
SMPDL3B marks membrane control capacity Controls raft stability and signal gain across multiple receptor platforms NORMAL ROLE • Regulates sphingomyelin ↔ phosphatidylcholine balance • Stabilizes lipid-raft platforms (TLR/IFN, insulin, shear platforms) • Dampens innate immune signal gain (prevents over-responsiveness) KEYSTONE SMPDL3B Membrane stability / signal-gain governor at the control surface Same upstream stress → different downstream dynamics Shedding phenotype • Defensive PI-PLC activation • Episodic loss of anchoring • Oscillatory instability (flares) threshold / overshoot Deficient phenotype • Chronically fragile rafts • Low recovery bandwidth • Persistent signal residency baseline / capacity

Figure C. SMPDL3B is treated as a membrane stability and signal-gain governor. Loss of SMPDL3B control can express as (left) episodic defensive shedding with oscillatory instability, or (right) chronic deficiency with fragile rafts and persistent signal residency.

1.3 ER stress & impaired resolution machinery (signal-duration failure)

ER stress compounds membrane instability by slowing the “reset machinery”: receptor recycling, protein folding/turnover, and the post-activation return to baseline architecture. In this model, the outcome is signal-duration failure rather than cytokine excess.

1.4 Mistimed nitric oxide (NO) signaling (shear buffering failure)

Endothelial cells normally convert shear stress into adaptive vasodilation via raft-anchored eNOS signaling. In membrane-unstable states, eNOS becomes mislocalized and its regulators stop lining up in time: Cav-1 braking and Ca²⁺ activation desynchronize.

Crucial point: NO is not necessarily absent — it is mistimed and misplaced.

That means baseline microvascular control is fragile: small flow changes are no longer buffered smoothly.

Figure D — Mistimed nitric oxide: eNOS mislocalization breaks shear buffering
Placement & timing matter more than “total NO” Stable rafts/caveolae align Cav-1 braking + Ca²⁺ activation → localized NO pulse → smooth flow. LEFT Correct localization → timed NO buffering Vessel lumen (flow) Laminar shear → sensed & buffered Glycocalyx (intact shear sensor) Endothelial membrane caveolae / raft eNOS anchored “parking spot” Cav-1 brake restrains → releases locally Ca²⁺ local activation zone timed NO pulse (local) Smooth microvascular adaptation Shear stays informational → RBCs protected RIGHT Mislocalization → mistimed / patchy NO Vessel lumen (flow) Heterogeneous shear (spiky) Glycocalyx (patchy / degraded) Endothelial membrane raft raft raft eNOS drifts / mislocalizes Cav-1 brake not co-located Ca²⁺ activation “elsewhere” poor coupling NO becomes mistimed / spatially incoherent Shear shifts toward injury Under oxidative load, uncoupling risk rises (NO↓, ROS↑) Key idea: eNOS quantity can be “normal,” but misplacement breaks microvascular flow control.

Figure D. Mechanistic “zoom” of shear buffering. In healthy endothelium, lipid-raft/caveolae organization anchors eNOS in the shear-sensing neighborhood so Cav-1 braking and Ca²⁺ activation align, producing a localized NO pulse that smooths flow. In membrane-instability states, raft/caveolae disorganization leads to eNOS mislocalization, desynchronized regulation, and mistimed/patchy NO signaling—allowing shear to become focal, spiky, and mechanically/oxidatively stressful downstream. :contentReference[oaicite:1]{index=1}

1.5 Glycocalyx & heparan sulfate: the shear–timing interface

The endothelial glycocalyx—particularly heparan sulfate (HS) proteoglycans—functions as a dynamic shear-sensing and signal-timing interface rather than a passive structural coating. HS participates directly in converting mechanical shear into spatially and temporally precise endothelial signaling.

In this framework, HS dysfunction in ME/CFS is modeled as a secondary consequence of membrane control-surface instability rather than a primary structural loss. SMPDL3B-related lipid-raft disorganization disrupts caveolae geometry and receptor microdomains, increasing mechanical strain on HS proteoglycans and altering their surface residency and sulfation patterning.

Patchy or poorly patterned HS impairs spatial averaging of shear forces, causing local over- or under-sensing. This directly contributes to mislocalized and mistimed eNOS activation, as caveolin-1 braking and Ca²⁺ activation no longer align within stable microdomains.

Key clarification: nitric oxide is not necessarily deficient in ME/CFS. Rather, NO signaling becomes mistimed and spatially incoherent, converting otherwise-normal shear into focal mechanical and oxidative stress.

Interpretation: glycocalyx disruption reflects a reversible control-layer failure driven by membrane instability and impaired signal termination, not fixed endothelial damage.

Heparan sulfate (HS) as the shear–timing interface linking SMPDL3B instability to eNOS mis-timing
Intact control surface HS-rich glycocalyx Stable rafts Timed NO Shear-activated failure Patchy HS Raft instability (SMPDL3B) Mistimed NO

Figure — HS as the shear–timing interface. In ME/CFS, SMPDL3B-related membrane instability disrupts HS residency and patterning, degrading spatial averaging of shear and producing mislocalized, mistimed eNOS activation. The result is heterogeneous microvascular flow and delayed shear injury rather than global NO deficiency.

Section 2 — Shear stress as the activator (the stress test)

2.1 What shear stress normally is

Shear stress is the frictional force of blood flow across the endothelial surface. In healthy physiology, shear is sensed by the glycocalyx and raft-anchored mechanosensors, triggering precisely timed NO release. In that state, shear is information, not damage.

2.2 What changes in ME/CFS (activator meets vulnerability)

When baseline membrane organization, ER resolution, and NO timing are unstable:

This converts normal demands into focal mechanical strain — local velocity spikes, narrowed flow segments, and higher-impact deformation events. Shear becomes the activator that exposes baseline vulnerability.

Figure E — Shear stress as the activator: “information” (buffered) vs “strain” (focal spikes)
Section 2: shear stress acts like a stress test Same shear exposure — different outcome depending on baseline control stability. LEFT Healthy physiology: shear = information Blood flow across endothelium Laminar shear (smooth, layered) Glycocalyx senses shear & smooths stress Endothelial control surface raft sensors Timed NO release Smooth capillary transit Shear → sensing → NO → adaptive dilation → protection Shear is a control signal, not damage. RIGHT ME/CFS vulnerability: shear = focal strain Same flow demand (standing, walking, heat) Heterogeneous shear (micro-scale “spikes”) Shear sensing becomes inaccurate (patchy buffering) Control surface (membrane/ER/NO timing unstable) raft raft raft NO timing “off” patchy / delayed pulses Flow becomes uneven Some segments narrow → velocity jets Others over-dilate → mismatch / pooling Shear becomes the activator that exposes vulnerability. Key idea: exertion is the stress test — the injury is failure to buffer & resolve shear at the microvascular level.

Figure E. Shear stress is the frictional force of blood flow across the endothelium. In healthy physiology it is sensed by the glycocalyx and raft-anchored mechanosensors, producing precisely timed NO release and smooth capillary transit. When membrane/ER resolution and NO timing are unstable, shear sensing becomes inaccurate and flow becomes heterogeneous, producing focal velocity spikes and narrowed segments that act as a mechanical “stress test” exposing baseline vulnerability. :contentReference[oaicite:1]{index=1}

Section 3 — Downstream consequences (why PEM happens)

3.1 Red blood cells as downstream victims

Red blood cells (RBCs) are designed to deform, but only within limits. They also cannot repair membranes. Under pathological shear, RBCs can undergo excessive deformation and membrane stress, producing:

This can coexist with “normal” baseline labs while still producing post-load worsening and delayed symptom peaks.

Figure F — RBC stress under shear: microvesicles + hemoglobin release (low-grade) Conceptual: focal shear spikes can strain RBC membranes, producing microvesicles and a subclinical hemoglobin burden with delayed symptom amplification A. Shear exposure and focal spikes Focal shear spikes → RBC mechanical strain RBCs deform within limits; higher local strain increases membrane stress RBCs cannot “repair” membranes → vulnerability accumulates under load B. Downstream outputs from RBC membrane stress Microvesicle shedding Small membrane fragments released under strain (signals + oxidative load) Hemoglobin release (low-grade) Subclinical burden can rise post-load without abnormal baseline hemoglobin Why baseline labs can look “normal” Events are intermittent and load-dependent; resting values may not capture peaks Signal may appear during recovery window rather than during exertion (timing mismatch = key diagnostic challenge) C. Clinical translation (conceptual timing) Load now → symptoms later RBC strain / hemoglobin burden + endothelial reactivity can amplify during recovery → delayed PEM peaks Note: This is a schematic. It illustrates how intermittent, load-dependent RBC membrane stress can produce microvesicles and a low-grade hemoglobin burden without requiring abnormal baseline labs.

3.2 Microclots as secondary amplifiers (not the initiator)

Endothelial instability plus abnormal flow can promote a “stickier” microvascular environment and abnormal fibrin behavior. Microclots preferentially form in low-flow microregions, persist longer than normal, and further increase local shear.

Interpretation: microclots can strongly amplify PEM dynamics, but in this document they are treated as secondary amplifiers, not the initiating lesion.

Figure G — Microclots amplify shear heterogeneity (secondary amplifier)
Figure G — Microclots amplify shear heterogeneity (secondary amplifier) Microclot “islands” narrow flow channels → local velocity spikes → higher shear → red blood cell stress. Microcirculation segment (conceptual) Blue: bulk flow. Orange: shear hotspots (where impact on RBCs increases). class="g-clot"/> class="g-clot"/> local shear spike microclot island Microclot islands Fibrin-rich obstructions form in low-flow microregions. They narrow channels and reshape local flow paths. Channel narrowing Same flow forced through smaller gaps → velocity rises. Creates patchy perfusion and focal jets. RBC stress ↑ Higher deformation + friction → vesicles / Hb release risk One-way amplification chain (kept linear) Microclots are downstream amplifiers: they worsen shear once baseline flow control is fragile. 1) Low-flow microregion Local stasis pocket forms 2) Microclot forms Fibrin-rich island persists 3) Channel narrows Velocity spike in remaining gaps 4) Shear / impact ↑ RBC deformation + oxidative stress ↑ Interpretation: microclots increase local resistance and make shear more focal, amplifying post-load symptoms without being the initiating lesion.

Figure G. Microclots are treated here as secondary amplifiers: fibrin-rich “islands” form in low-flow microregions, narrowing channels and forcing the same flow through smaller gaps. This produces local velocity spikes and higher focal shear, which can increase RBC deformation and worsen downstream post-load dynamics.

3.3 Buffering determines severity (Hp integration point)

Haptoglobin (Hp) acts as a buffering layer that clears free hemoglobin released into plasma during RBC stress. Hp phenotypes do not “cause” ME/CFS, but can influence crash severity and recovery time under identical stressors by changing how well the system absorbs heme/hemoglobin-related oxidative load.

Figure H — Hp phenotypes as “shock absorbers” for red blood cell stress

Same shear / RBC stress event, different buffering capacity: Hp 1-1 (strong), Hp 2-1 (moderate/variable), Hp 2-2 (weaker). Hp does not cause ME/CFS; it shifts how hard crashes hit once free hemoglobin enters plasma.

Same upstream event (shared) Shear / flow spike → RBC membrane stress → small hemoglobin (Hb) release into plasma Hp 1-1 “Strong shock absorber” Hb binding / clearance Fast + tight → Hb removed quickly Downstream impact Less NO scavenging + less oxidative load Better buffering → milder crashes Hp 2-1 “Moderate / variable absorber” Hb binding / clearance Intermediate → depends on repeat stress Downstream impact Some NO disruption + oxidative carryover Crashes after stacked stressors Hp 2-2 “Weaker shock absorber” Hb binding / clearance Less efficient → Hb lingers longer Downstream impact More NO scavenging + higher oxidative stress Bigger / longer crashes, slower recovery Key point: Hp shifts buffering capacity (severity/duration) — it does not initiate the upstream vascular/membrane instability.

Concept: identical shear-driven RBC stress can yield different symptom impact depending on hemoglobin buffering efficiency.

Section 4 — Clean synthesis (the core claim)

  1. Baseline state: membrane/raft instability + ER-resolution weakness → signals linger and endothelial control is fragile.
  2. Activator: normal shear stress from standing or exertion becomes injurious because buffering (NO timing) is unreliable.
  3. Execution: RBC stress + endothelial microinjury + secondary microclot amplification produce delayed, multi-system symptoms.
  4. Severity modifier: buffering layers (e.g., Hp phenotype) shift the threshold and recovery time.
Figure I — Clean synthesis: baseline vulnerability + shear activator → delayed PEM

One-panel summary of the document’s claim: PEM reflects shear-activated failure when membrane control and signal termination are fragile. Hp phenotype does not initiate disease — it shifts how hard the same event lands.

Baseline vulnerability Control surface + resolution weakness Membrane / raft instability Receptors linger • internalization slowed ER-resolution weakness Reset is slow • termination is fragile Mistimed NO buffering (placement/timing unreliable) Activator Normal shear becomes injurious Standing • exertion • heat • stress Execution (downstream) Mechanical + oxidative double hit RBC stress Microvesicles • small Hb leak Endothelial microinjury Patchy perfusion • NO disruption Secondary amplifier: microclots Fibrin-rich “islands” narrow channels → local velocity spikes → shear heterogeneity increases. narrow gaps amplifies Clinical state (output) PEM • crashes • phase progression Delayed worsening reflects recovery failure, not exertion itself. Severity modifier: Hp buffering layer Same upstream event → different “shock absorber” strength → different injury magnitude, threshold, and recovery time. Hp 1-1 Hp 2-2 strong buffer moderate weaker buffer

Figure I. Baseline membrane/raft instability plus ER-resolution weakness makes endothelial flow control fragile. Normal shear then becomes a stress test that produces RBC stress and microvascular injury; microclots amplify shear heterogeneity. Buffering layers (e.g., Hp phenotype) shift crash threshold and recovery time.

One-sentence takeaway

One-sentence takeaway: PEM is not caused by exertion itself, but by the failure of membrane-mediated flow control to absorb shear stress during recovery.

Interpretive framework documents (GLA v2.1 → v2.4)

The following documents define the conceptual and methodological framework used to interpret genetic signals and physiological mechanisms in this paper. They establish layer boundaries, phenotype discipline, and phase dependence within the GLA system.

These materials are provided for transparency and interpretive context. They are not cited as evidentiary sources and should be read as evolving systems-biology models.