(Endothelial Timing Failure → Skeletal Muscle Injury → Delayed PEM)
Author: Michael Daniels· Framework: GLA·2.5 · Date: January 14th 2026 · This document presents a systems-level interpretation and is not clinical guidance or a treatment recommendation.
This module defines the core mechanism by which post-exertional malaise (PEM) is generated in ME/CFS: a shear-activated failure state arising from impaired endothelial signal-timing precision that produces skeletal-muscle oxygen-extraction failure during exertion and delayed cellular injury during recovery.
This module addresses how PEM is generated once a vulnerable control state exists; it does not propose shear stress, exertion, or skeletal muscle as the initiating cause of ME/CFS.
Physiological shear stress rises normally in response to everyday demands, including:
These inputs are continuous features of normal human physiology and are present even at low levels of activity.
This framing explicitly excludes post-exertional malaise (PEM) as a consequence of:
Instead, shear stress functions in this module as a physiological activator that reveals an underlying failure of endothelial signal decoding and timing precision.
Endothelial shear sensing and response depend on a precisely organized membrane control surface. This control surface translates mechanical shear into coordinated biochemical signals through tightly regulated spatial and temporal organization.
Together, this system translates mechanical shear into precisely timed, spatially restricted endothelial responses, rather than continuous or diffuse signaling.
In ME/CFS-relevant control states, this membrane-based timing architecture becomes unstable:
This loss of timing control at the membrane–caveolar interface constitutes the root control failure for this module.
Figure 1. Endothelial control surface timing architecture (SMPDL3B → Cav-1 → eNOS)
Shear is decoded into precisely timed, spatially localized responses—not diffuse NO “power.”
Caption. Shear sensing depends on a membrane control surface in which SMPDL3B stabilizes lipid microdomains and caveolar structure, Cav-1 gates timing (brake/release), and eNOS generates localized nitric oxide pulses. In this module, dysfunction reflects loss of timing and localization rather than reduced nitric oxide production capacity.
Mistimed endothelial signaling produces a characteristic failure of microvascular flow topology, rather than a reduction in total blood flow.
As a consequence of impaired Cav-1–eNOS timing, capillary-level flow heterogeneity develops, characterized by:
This pattern reflects a loss of coordinated capillary recruitment and flow smoothing at the microvascular level.
This flow-topology failure does not involve:
Instead, the defining abnormality is misallocation of flow in space and time, setting the conditions for downstream oxygen-extraction failure despite preserved central delivery.
Figure 2. Microvascular flow topology failure despite preserved total flow
Overall inflow can be appropriate while distribution across the microvasculature is incorrect.
Caption. Microvascular dysfunction in this module is defined by flow topology failure: total inflow can remain appropriate while perfusion becomes spatially heterogeneous. Panel A illustrates even recruitment and smooth velocities. Panel B illustrates over-perfused fast channels alongside under-perfused or intermittently silent regions. This topological misallocation sets the stage for tissue-level oxygen extraction failure despite preserved central delivery.
Skeletal muscle is uniquely vulnerable to endothelial timing and distribution failures because it combines extreme perfusion demands with strict spatial precision requirements.
Specifically, skeletal muscle:
As a result, even modest microvascular timing errors can produce disproportionate physiological consequences in contracting skeletal muscle.
This vulnerability positions skeletal muscle as the primary generator of post-exertional malaise (PEM), where endothelial control failure is first converted into tissue-level stress and delayed injury — rather than as a passive downstream recipient of systemic dysfunction.
Skeletal muscle has the largest dynamic perfusion range. This makes it the most sensitive tissue for exposing endothelial timing and distribution failures during activity. Values are approximate and depend on intensity, posture, thermoregulation, and training status.
| Organ / vascular bed | Typical change during exercise | Why it matters for PEM framing |
|---|---|---|
| Skeletal muscle | ~20–50× (rest → maximal, per active muscle) | Largest demand swing → most sensitive to timing/distribution errors and capillary recruitment failure |
| Coronary (heart) | ~3–5× | Tight autoregulation → smaller dynamic range, less likely to expose topology failure at low exertion |
| Brain | ~0.5–1.5× | Relatively stable flow; small distribution errors can still cause symptoms but demand swing is modest |
| Skin | ~0–10× (heat-dependent) | Thermoregulatory variability; can amplify symptoms but is not the dominant extraction bed |
| Splanchnic (GI/liver) | ↓ (often decreases) | Redistribution bed; contributes to post-exertional strain but not the primary site of extraction failure |
| Kidney | ↓ (often decreases) | Perfusion trade-off impacts volume regulation and recovery bandwidth rather than exertion-time extraction |
Interpretation. PEM is most reliably generated where perfusion demand swings are largest and capillary recruitment must be precisely coordinated. Skeletal muscle uniquely meets both conditions, which is why the same endothelial timing error tolerated elsewhere becomes pathological in contracting muscle.
During exertion, systemic oxygen delivery functions appropriately, while local utilization in skeletal muscle fails.
These findings confirm that oxygen is successfully loaded, transported, and delivered at the systemic level.
Despite preserved central delivery:
The result is a failure of localized oxygen extraction at the tissue level.
Figure 3. Preserved oxygen delivery with failed skeletal-muscle extraction
Central delivery rises appropriately, but microvascular distribution and unloading fail at the muscle level.
Caption. During exertion, central oxygen delivery can remain appropriate: cardiac output rises with workload and arterial oxygenation remains normal. However, microvascular distribution in skeletal muscle becomes heterogeneous, shortening red blood cell transit time in over-perfused channels and limiting oxygen unloading. The characteristic iCPET pattern emerges: elevated mixed venous oxygen saturation during effort, indicating preserved delivery but impaired peripheral extraction.
During exertion, skeletal muscle does not immediately fail, despite impaired oxygen extraction. Instead, it transitions into a compensated but unstable physiological state that temporarily sustains function while encoding latent injury.
This compensated state is characterized by:
These compensatory responses preserve short-term performance but increase cellular stress and reduce recovery headroom.
This latent, compensated state explains:
The critical transition from compensation to injury occurs after exertion ends, during the recovery phase addressed in Section 7.
Figure 4. Compensated exertion state and latent injury encoding
During exertion, function can be temporarily maintained while cellular stress is encoded for recovery-phase injury.
Caption. During exertion, skeletal muscle can enter a compensated but unstable state that maintains function despite impaired oxygen extraction. Compensation is supported by increased intracellular Ca2+ influx, increased glycolysis, and increased mitochondrial workload. At the same time, ER–mitochondrial coupling tightens and recovery headroom shrinks, encoding latent injury that may not be symptomatic during exertion. This explains the “false OK” window and sets up the recovery-phase amplification described in Section 7.
After exertion ends, systemic demand for perfusion decreases, but the upstream endothelial control failure does not immediately resolve.
During early recovery:
This mismatch converts the previously compensated stress state into active injury.
The persistence of flow heterogeneity during recovery produces:
These processes drive progressive tissue injury after activity has stopped, rather than during exertion itself.
Figure 5. Recovery-phase amplification of microvascular and cellular injury
After activity stops, demand falls—but timing/topology failures can persist, converting compensated stress into injury.
Caption. After exertion ends, perfusion demand decreases, but the upstream endothelial timing failure does not necessarily resolve immediately. Microvascular flow topology can remain heterogeneous, maintaining a mismatch between flow and tissue needs. This persistence converts the compensated exertion state into active injury via micro-ischemia/reperfusion mismatch, reactive oxygen species (ROS) bursts, sustained ER–mitochondrial Ca2+ dysregulation, and impaired repair and resolution signaling. The result is progressive tissue injury during recovery, not during exertion itself.
Over the ensuing hours to days following exertion and recovery-phase injury amplification, structural and metabolic injury accumulates in skeletal muscle, reflecting unresolved cellular stress and impaired repair.
Whole-body symptoms emerge as post-exertional malaise (PEM), including fatigue, pain, cognitive dysfunction, autonomic instability, and reduced functional capacity.
The delayed onset and duration of PEM reflect the time course of tissue injury, stress signaling, and incomplete recovery, rather than acute exertional failure.
The intensity and persistence of PEM are shaped by:
Figure 6. Shear-activated PEM generation timeline
One-panel synthesis: how normal shear input becomes delayed, multi-system PEM via timing failure and recovery-phase injury amplification.
Caption. Integrated synthesis of the module logic. Physiological shear input is decoded by an endothelial control surface that requires timing precision. When timing fails, microvascular flow becomes topologically misallocated, producing skeletal-muscle oxygen extraction failure during exertion (iCPET pattern). Muscle can remain temporarily functional in a compensated state while latent injury is encoded. After exertion ends, persistent flow heterogeneity during recovery drives ischemia/reperfusion mismatch, ROS bursts, sustained ER–mitochondrial Ca2+ dysregulation, and impaired repair—leading to delayed, multi-system post-exertional malaise (PEM).
PEM severity reflects how much injury is amplified during recovery and how long repair and resolution remain incomplete. The same exertional input can produce very different outcomes depending on baseline control state, buffering capacity, and accumulated prior injury.
| Determinant | What it represents in this module | Effect on PEM severity / duration | Typical pattern |
|---|---|---|---|
| Disease phase (baseline control state) | Baseline stability of timing, distribution, and recovery coordination — i.e., how close the system is to a failure threshold before shear input. | Lower baseline control increases likelihood that normal shear triggers topology failure, and lengthens the recovery window required for repair and reset. |
Early-phase: intermittent tolerance with clearer recovery. Late-phase: low threshold, prolonged or continuous instability. |
| Physiological buffering capacity (e.g., haptoglobin) | Ability to absorb downstream consequences of shear-related stress (vascular/RBC buffering, hemoglobin/heme handling, oxidative load containment). | Lower buffering increases oxidative amplification and slows resolution, raising symptom intensity and prolonging PEM duration under the same stressor. |
Better buffering: higher tolerance and faster recovery. Weaker buffering: sharper crashes and longer recovery tails. |
| Prior injury burden (cumulative baseline erosion) | Pre-existing structural/metabolic strain and reduced repair bandwidth from previous episodes — a reduced “recovery reserve.” | Higher prior injury lowers the threshold for subsequent PEM and increases the probability of stepwise worsening, with longer and deeper post-exertional impairment. |
Low burden: clearer “baseline return.” High burden: incomplete return and progressive threshold erosion. |
Interpretation. PEM severity is not determined only by the size of the exertional input. It is determined by whether shear variability exceeds shear tolerance, how strongly recovery-phase injury is amplified, and how much recovery bandwidth remains to complete repair and reset.
The documents listed below define the conceptual and methodological framework used to interpret genetic signals and physiological mechanisms in this paper. Collectively, they establish layer boundaries, phenotype discipline, and phase dependence within the Gut–Liver–Autonomic (GLA) system architecture.
These materials are provided for transparency and interpretive context only. They are not cited as evidentiary sources and should be read as evolving systems-biology models used to organize and constrain interpretation, rather than as claims of mechanism or causation.
Core GLA framework documents
SMPDL3B phenotype frameworks
Control layers & system modulators