Skeletal Muscle as the Primary Generator of Post-Exertional Malaise (PEM)

Abstract

Post-exertional malaise (PEM) is the defining clinical feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID ME/CFS, yet its tissue-level origin has remained unresolved. Existing models have emphasized global fatigue, inflammation, or mitochondrial insufficiency, but these frameworks struggle to explain the delayed onset, disproportionate severity, reproducibility, and cumulative progression of PEM following modest physical or orthostatic stress.

Here, we synthesize physiological, structural, and cellular evidence to propose that PEM is primarily generated and amplified within skeletal muscle. Skeletal muscle is uniquely positioned to serve this role because it exhibits the largest and most dynamic perfusion demands in the body and relies heavily on precise microvascular distribution and oxygen extraction. In ME/CFS, invasive cardiopulmonary exercise testing demonstrates preserved cardiac output and arterial oxygenation during exertion alongside impaired peripheral oxygen extraction, localizing the dominant limitation downstream of the heart.

Longitudinal biopsy studies further show that PEM induction is followed by delayed worsening of skeletal muscle pathology, including fiber atrophy, focal necrosis, immune dysregulation, and impaired oxidative metabolism. Structural and capillary studies reveal baseline muscle vulnerabilities—such as altered fiber composition and capillary rarefaction—that prime tissue for perfusion misdistribution and shear stress during exertion. Complementary cellular models demonstrate time-dependent ER–mitochondrial calcium dysregulation and oxidative stress that progress from compensatory hypermetabolism to delayed execution failure.

Integrating these findings, we argue that exertion exposes impaired microvascular control in skeletal muscle, producing inefficient oxygen extraction, ischemia–reperfusion–like stress, and delayed cellular injury that manifest clinically as PEM. This framework does not posit a muscle-only disease, but identifies skeletal muscle as the dominant execution surface where upstream autonomic, immune, endothelial, and metabolic instability is converted into delayed, multi-system dysfunction. The model yields clear, testable predictions and provides a coherent explanation for the timing, severity, and progression of PEM in ME/CFS and post-COVID ME/CFS.

1. Why skeletal muscle is uniquely positioned to generate PEM

Conceptual and physiological framing

1.1 Skeletal muscle as the dominant perfusion-demand organ

Among all organ systems, skeletal muscle exhibits the largest and most dynamic range of perfusion demand. At rest, muscle receives a relatively modest fraction of cardiac output, yet during physical activity—even at low to moderate intensities—local blood flow to active muscle groups can increase by orders of magnitude. This capacity for rapid, high-amplitude perfusion change exceeds that of most other tissues and requires continuous, fine-grained regulation across space and time ( Joseph et al., 2023; Jespersen & Østergaard, 2012 ).

Crucially, skeletal muscle activation during everyday activity is highly localized and variable. Standing, walking, maintaining posture, or performing simple tasks engage small and shifting subsets of muscle fibers, each with distinct metabolic demands. As a result, perfusion must be dynamically redistributed across microvascular networks on a moment-to-moment basis rather than globally increased. This places a uniquely high burden on microvascular control systems, which must precisely match blood flow to local metabolic demand while maintaining overall circulatory stability ( Joseph et al., 2023 ).

Meeting these requirements depends on tight coordination between endothelial signaling, autonomic regulation, capillary recruitment, and erythrocyte transit. Even modest impairments in these control processes can therefore become functionally significant in skeletal muscle long before they would produce overt dysfunction in organs with more stable or homogeneous perfusion requirements. In this sense, skeletal muscle acts as a natural stress test for perfusion regulation during exertion ( Jespersen & Østergaard, 2012 ).

1.2 Skeletal muscle as a shear- and distribution-sensitive tissue

Beyond its large perfusion range, skeletal muscle is particularly sensitive to how blood flow is distributed rather than to absolute flow alone. Muscle tissue contains dense, highly organized capillary networks designed to optimize oxygen diffusion across short distances. Effective oxygen extraction depends not only on sufficient total flow, but on uniform capillary recruitment, appropriate red blood cell transit times, and synchronized endothelial responses ( Jespersen & Østergaard, 2012 ).

Muscle contraction introduces an additional mechanical constraint: capillaries are intermittently compressed during fiber shortening and relaxation. This creates rapid, cyclic changes in local flow patterns and shear forces, further increasing reliance on precise timing and coordination of vascular responses. Under these conditions, mismatches between perfusion and demand are more likely to arise from distributional or regulatory failures than from simple reductions in total blood flow ( Østergaard et al., 2015 ).

As a result, skeletal muscle performance depends disproportionately on timing precision and microvascular coordination, rather than on maximal oxygen delivery capacity. When perfusion control is impaired—whether through endothelial dysfunction, autonomic instability, altered capillary geometry, or abnormal flow regulation—muscle is the tissue most likely to experience inefficient oxygen extraction and localized metabolic stress during exertion ( Jespersen & Østergaard, 2012; Østergaard et al., 2015 ).

2. Dynamic physiology: exercise unmasks peripheral failure

(Evidence from invasive cardiopulmonary exercise testing)

2.1 Peripheral oxygen extraction failure during exertion

Direct physiological testing demonstrates that exercise intolerance in ME/CFS is not driven by an inability of the heart or lungs to deliver oxygen, but by a failure of oxygen extraction at the tissue level during exertion. Invasive cardiopulmonary exercise testing (iCPET), which directly measures central hemodynamics, arterial and venous oxygen content, and gas exchange, consistently shows preserved or near-normal cardiac output during exercise alongside preserved arterial oxygenation. Thus, central oxygen delivery remains intact ( Joseph et al., 2023 ).

Despite this adequate delivery, patients are unable to effectively utilize oxygen within peripheral tissues. The expected increase in arteriovenous oxygen difference with rising workload fails to occur, indicating that oxygen extraction does not appropriately scale with metabolic demand. This pattern localizes the dominant physiological limitation downstream of the heart, within the peripheral circulation. Exertional capacity is therefore constrained not by insufficient oxygen supply, but by impaired tissue-level utilization during activity ( Joseph et al., 2023 ).

2.2 High-flow, low-extraction physiology

Additional insight comes from venous oxygen measurements obtained during exertion. Patients exhibit abnormally elevated mixed venous oxygen saturation, indicating that oxygenated blood is returning to the heart without being fully extracted by peripheral tissues. This finding rules out global hypoxia and instead points to maldistributed microvascular flow and impaired capillary-level oxygen exchange ( Joseph et al., 2023 ).

The resulting physiological profile resembles high-flow, low-extraction states observed in conditions characterized by impaired capillary recruitment, microvascular shunting, or dysregulated vasoregulation. In such states, total blood flow may be adequate—or even elevated—but oxygen delivery is spatially mismatched to metabolic demand. Importantly, this pattern is inconsistent with primary cardiac disease, pulmonary limitation, or simple deconditioning, all of which produce distinct and contrasting physiological signatures ( Jespersen & Østergaard, 2012; Østergaard et al., 2015 ).

Taken together, these findings demonstrate that exertion exposes a dynamic failure of perfusion regulation and oxygen extraction in skeletal muscle. Exercise intolerance in ME/CFS therefore reflects a breakdown in how blood flow is distributed and utilized at the skeletal muscle–microvascular interface, rather than an inability to deliver oxygen to the periphery. This exertion-time extraction failure represents the physiological trigger that initiates downstream processes culminating in post-exertional malaise.

3. Longitudinal human evidence: PEM worsens muscle pathology

(Biopsy-based PEM induction studies)

3.1 Structural injury after PEM

Longitudinal biopsy studies provide direct evidence that post-exertional malaise is associated with measurable structural injury in skeletal muscle. In designs where PEM is experimentally induced and muscle tissue is sampled before and after exertion, patients demonstrate a significant post-exertional increase in pathological features that are not present, or are less pronounced, at baseline. These include an increased proportion of atrophic muscle fibers and the appearance of focal necrotic lesions following exertion ( Appelman et al., 2024 ).

Importantly, these changes are observed after a delay—typically one day following the exertional stimulus—rather than immediately at exercise cessation. This temporal pattern aligns with the characteristic delay of PEM and indicates that exertion initiates a pathological process that unfolds during recovery rather than during activity itself. In addition to necrosis, markers consistent with regeneration signaling are observed, suggesting repeated cycles of injury and attempted repair rather than a static or purely degenerative process ( Appelman et al., 2024 ).

3.2 Metabolic deterioration after exertion

Structural injury is accompanied by post-exertional deterioration in muscle metabolic capacity. Following PEM induction, skeletal muscle biopsies show reduced activity of oxidative enzymes, including succinate dehydrogenase (SDH), indicating impaired oxidative phosphorylation capacity. These findings are not attributable to acute exhaustion alone, as they are measured during the recovery phase rather than at peak exertion ( Appelman et al., 2024 ).

Concurrently, muscle tissue exhibits a shift toward greater reliance on glycolytic metabolism, consistent with reduced oxidative efficiency and impaired aerobic energy production. This metabolic shift provides a mechanistic bridge between the physiological oxygen extraction failure observed during exercise and the delayed tissue-level consequences measured after exertion. Together, these findings indicate that PEM is associated with a genuine post-exertional metabolic injury state within skeletal muscle ( Appelman et al., 2024 ).

3.3 Abnormal immune responses in muscle

Biopsy studies also reveal abnormalities in local immune responses within skeletal muscle that accompany post-exertional injury. At baseline, patients demonstrate increased immune cell presence within muscle tissue, including macrophages and lymphocytes, indicating a chronically altered immune milieu. Following exertion, however, the expected post-injury immune and repair responses appear blunted or dysregulated ( Appelman et al., 2024 ).

Rather than mounting a coordinated repair response proportional to tissue damage, muscle in ME/CFS and post-COVID ME/CFS shows altered immune cell dynamics after exertion, consistent with impaired resolution of injury. This dysregulation likely contributes to incomplete repair, cumulative tissue stress, and prolonged symptom persistence following exertion ( Appelman et al., 2024 ).

4. Baseline vulnerability of skeletal muscle

(Structural and capillary studies)

4.1 Structural and fiber-type abnormalities

Independent of acute exertion, skeletal muscle in ME/CFS and post-COVID ME/CFS demonstrates baseline structural abnormalities that predispose it to dysfunction under physiological stress. Multiple studies report alterations in muscle fiber composition, including reduced integrity and cross-sectional area of oxidative (type I) fibers. These changes indicate a diminished baseline capacity for sustained aerobic metabolism, even before exertional demands are applied ( Colosio et al., 2023; Charlton et al., 2025 ).

At the subcellular level, skeletal muscle exhibits mitochondrial structural abnormalities at rest, including altered morphology and distribution. Rather than reflecting uniform mitochondrial failure, these changes suggest reduced robustness of oxidative machinery and impaired resilience to increased metabolic load. Such baseline alterations lower the threshold at which exertion can precipitate metabolic stress, particularly in tissues that rely heavily on precise oxygen utilization ( Colosio et al., 2023 ).

Importantly, these findings are not fully explained by deconditioning alone. The observed patterns are fiber-type–specific and structurally organized, indicating disease-related alterations in muscle architecture rather than nonspecific disuse effects ( Charlton et al., 2025 ).

4.2 Capillary rarefaction and perfusion geometry

In addition to intrinsic muscle fiber changes, skeletal muscle in ME/CFS and post-COVID ME/CFS shows evidence of altered microvascular architecture, most notably capillary rarefaction. Reduced capillary density decreases the number of parallel pathways available for blood flow and oxygen diffusion, fundamentally altering perfusion geometry at the tissue level ( Colosio et al., 2023 ).

When capillary networks are sparse, a given increase in perfusion demand must be accommodated by higher flow velocities through the remaining vessels. This amplifies local shear forces and shortens red blood cell transit times, reducing the efficiency of oxygen extraction even when total blood flow is preserved. Under these conditions, oxygen delivery becomes increasingly sensitive to distributional precision rather than absolute flow magnitude ( Østergaard et al., 2015 ).

Capillary rarefaction therefore transforms exertion into a mechanically and metabolically challenging state for skeletal muscle, particularly during activities that require rapid or localized recruitment of muscle fibers. The resulting mismatch between perfusion and metabolic demand provides a structural substrate for the oxygen extraction failure observed during exertion ( Colosio et al., 2023; Østergaard et al., 2015 ).

5. Cellular execution failure: ER–Ca²⁺–mitochondrial stress loops

(Cellular and serum-transfer models)

5.1 Compensatory hypermetabolism progressing to fragility

Cellular and serum-transfer models provide mechanistic insight into how skeletal muscle converts exertional stress into delayed failure at the intracellular level. When healthy skeletal muscle cells are exposed to circulating factors derived from ME/CFS or post-COVID patients, they initially exhibit a compensatory metabolic response characterized by increased oxygen consumption rate (OCR), elevated glycolysis, and hypertrophic signaling. This early phase reflects an attempt to maintain force production and metabolic output despite underlying stress ( Mughal et al., 2025 ).

However, this hypermetabolic state is not stable. With continued exposure or repeated stress, muscle cells transition from compensation to fragility. Mitochondria shift from fused or hyperfused networks toward fragmented and depolarized morphologies, indicating loss of bioenergetic resilience. Rather than restoring functional capacity, early metabolic upregulation increases vulnerability to subsequent stressors, lowering the threshold for failure during recovery. This progression mirrors the clinical pattern in which brief periods of perceived capacity are followed by delayed worsening after exertion ( Mughal et al., 2025 ).

5.2 Calcium dysregulation and ROS amplification

A central feature of this execution failure is disruption of calcium homeostasis at the interface between the endoplasmic reticulum (ER) and mitochondria. Experimental models demonstrate imbalance in calcium-handling mechanisms, including altered SERCA-mediated sequestration and impaired sodium–calcium exchange (NCX) dynamics. These changes promote accumulation of cytosolic and mitochondrial calcium during periods of metabolic demand ( Baral et al., 2025 ).

Excess mitochondrial calcium acts as a potent driver of reactive oxygen species (ROS) generation. Elevated ROS, in turn, further impairs calcium-handling proteins, disrupts membrane integrity, and compromises mitochondrial electron transport. This creates a self-reinforcing loop in which calcium overload and oxidative stress amplify one another, progressively degrading cellular energy production and stress tolerance. Importantly, this process does not require complete loss of mitochondrial function; rather, it reflects loss of control precision and recovery capacity under load ( Baral et al., 2025 ).

5.3 Delayed collapse as a cellular analog of PEM

Critically, the transition from compensation to collapse in these models is time dependent. Structural mitochondrial damage, depolarization, and metabolic inefficiency emerge hours to days after the initiating stress rather than immediately. This delayed trajectory provides a cellular-scale analog of post-exertional malaise, in which exertion triggers a pathological cascade that unfolds during recovery ( Mughal et al., 2025; Glass et al., 2025 ).

In this framework, PEM reflects not instantaneous exhaustion but delayed execution failure driven by cumulative intracellular stress. Skeletal muscle cells initially meet demand at the cost of accumulating calcium and oxidative burden, only to enter a state of impaired energy production, structural injury, and prolonged dysfunction after the stressor has ceased. These cellular dynamics provide a mechanistic explanation for the delayed onset, persistence, and amplification of symptoms that characterize PEM.

6. Integrated synthesis: how PEM is generated

The findings outlined in the preceding sections can be integrated into a single, coherent sequence that explains how post-exertional malaise is triggered and subsequently generated. This synthesis does not introduce new mechanisms, but rather connects physiological, structural, and cellular observations into a unified process that distinguishes exertion-time failure from delayed injury ( Joseph et al., 2023; Appelman et al., 2024; Mughal et al., 2025 ).

Exertion initiates the cascade by increasing perfusion demand within skeletal muscle. Because skeletal muscle exhibits the largest and most dynamic range of blood-flow requirements in the body, even modest physical or orthostatic activity requires rapid, localized redistribution of flow. In ME/CFS, exertion exposes underlying impairments in microvascular regulation and autonomic coordination rather than overwhelming an otherwise normal system ( Joseph et al., 2023; Jespersen & Østergaard, 2012 ).

As microvascular control fails, blood flow becomes maldistributed at the capillary level. Although total oxygen delivery is preserved through adequate cardiac output and arterial oxygenation, perfusion is no longer precisely matched to local metabolic demand. Oxygen extraction therefore becomes inefficient, with oxygenated blood traversing skeletal muscle without being effectively utilized. This exertion-time extraction failure constitutes the physiological trigger for downstream pathology ( Joseph et al., 2023; Østergaard et al., 2015 ).

The resulting mismatch places skeletal muscle into a state functionally analogous to ischemia–reperfusion stress. Local regions experience intermittent metabolic insufficiency followed by reoxygenation, creating conditions that favor calcium influx, oxidative stress, and metabolic instability rather than uniform hypoxia. Importantly, muscle may transiently maintain function through compensatory mechanisms, masking injury at the time of exertion ( Østergaard et al., 2015; Colosio et al., 2023 ).

At the cellular level, unresolved perfusion mismatch drives ER–mitochondrial calcium dysregulation and reactive oxygen species generation. Calcium overload and oxidative stress reinforce one another, progressively impairing mitochondrial function, membrane stability, and recovery capacity. These processes unfold over hours to days rather than instantaneously, shifting pathology into the recovery phase ( Mughal et al., 2025; Glass et al., 2025; Baral et al., 2025 ).

The end result is delayed structural and metabolic injury within skeletal muscle, manifested as fiber atrophy, focal necrosis, impaired oxidative metabolism, and prolonged dysfunction during recovery. Clinically, this delayed injury state corresponds to post-exertional malaise, explaining its characteristic latency, persistence, and disproportionate severity following otherwise modest exertion ( Appelman et al., 2024 ).

7. What this model explains (and others do not)

Framing post-exertional malaise as a skeletal muscle–generated execution failure explains several defining features of ME/CFS and post-COVID ME/CFS that have remained difficult to reconcile within alternative models.

First, this framework naturally accounts for the delayed timing of PEM. Because exertion initiates a cascade of perfusion misdistribution, calcium dysregulation, and oxidative stress that unfolds during recovery, symptoms do not peak at the moment of activity. Instead, tissue injury and metabolic failure emerge hours to days later, mirroring the delayed onset observed clinically. Models that emphasize immediate energy depletion or acute inflammation struggle to explain this temporal separation ( Joseph et al., 2023; Mughal et al., 2025 ).

Second, the model explains the disproportionate severity of symptoms relative to exertion magnitude. Skeletal muscle in ME/CFS operates close to its physiological threshold due to baseline structural and microvascular vulnerability. As a result, even mild increases in demand—such as slow walking, standing, or combined cognitive–postural tasks—can exceed the system’s capacity for precise perfusion control, triggering the same downstream injury cascade that more intense exertion would provoke in healthy individuals ( Colosio et al., 2023; Charlton et al., 2025 ).

Third, this framework clarifies why crashes occur after activities that minimally tax central cardiopulmonary systems. Standing or light activity imposes relatively small increases in cardiac output, yet it significantly alters skeletal muscle perfusion requirements and microvascular distribution. When control is impaired, these modest demands are sufficient to induce oxygen extraction failure and downstream stress, producing PEM without evidence of central cardiovascular limitation ( Joseph et al., 2023 ).

Fourth, the model reconciles the presence of objective tissue damage in the absence of central failure. Biopsy-based studies demonstrate post-exertional worsening of skeletal muscle pathology despite preserved cardiac output and arterial oxygenation. This dissociation resolves the apparent contradiction between normal central testing and profound functional impairment by localizing the pathological bottleneck to the skeletal muscle–microvascular interface ( Appelman et al., 2024 ).

Fifth, the model explains poor recovery despite rest. Because PEM reflects delayed structural and metabolic injury rather than transient depletion, recovery requires repair and reconstitution of tissue-level function. Simple cessation of activity does not immediately reverse calcium overload, oxidative damage, or impaired mitochondrial dynamics, leading to prolonged symptoms and cumulative deterioration with repeated exertional exposures ( Mughal et al., 2025; Glass et al., 2025 ).

Finally, this framework explains why PEM tends to worsen with repetition and why recovery becomes progressively less complete over time. Recurrent skeletal muscle injury and metabolic stress do not occur in isolation; they feed back into upstream regulatory systems that govern signal termination and recovery. Prolonged immune signaling, endoplasmic reticulum stress, and impaired cellular reset do not generate PEM directly, but they reduce recovery bandwidth and degrade temporal precision between exertional events. As a result, each episode of PEM leaves skeletal muscle and its supporting regulatory environment less able to absorb subsequent physiological demands, lowering the threshold for future crashes and prolonging recovery even in the absence of additional exertion ( Glass et al., 2025 ).

Together, these explanatory strengths support the view that skeletal muscle functions as the dominant generator and amplifier of PEM, translating upstream regulatory instability into the delayed, multi-system dysfunction characteristic of ME/CFS and post-COVID ME/CFS.

8. Guardrails and scope

This framework does not propose that ME/CFS or post-COVID ME/CFS is a muscle-only disease. While skeletal muscle is identified as the dominant site where post-exertional dysfunction is generated and amplified, multiple physiological systems contribute to disease expression, severity, and progression. Central nervous system processes, autonomic regulation, immune signaling, and hepatic–metabolic function all influence how exertional stress is sensed, distributed, and resolved across the body ( Scheibenbogen & Wirth, 2024 ).

Importantly, skeletal muscle is positioned in this model as the primary execution surface, not the initiating cause of disease. Upstream disturbances—including impaired autonomic coordination, persistent immune activation, endothelial dysfunction, and altered metabolic signaling—shape the baseline state in which muscle operates. These systems modulate perfusion control, recovery bandwidth, and signal termination, thereby determining how readily exertion triggers muscle-level injury and how completely recovery can occur ( Joseph et al., 2023; Glass et al., 2025 ).

Accordingly, skeletal muscle should be understood as the tissue where upstream regulatory instability becomes most visible and damaging under load, rather than as an isolated pathological compartment. This distinction preserves a systems-level view of ME/CFS while clarifying why muscle-centered mechanisms are critical for explaining PEM generation, timing, and progression. Skeletal muscle is therefore the dominant generator of PEM, but not the sole site of dysfunction within the disease process ( Scheibenbogen & Wirth, 2024 ).

9. Testable predictions

This skeletal muscle–centered framework for post-exertional malaise generates several clear, testable predictions that can be evaluated experimentally and clinically.

First, interventions that improve microvascular distribution or oxygen extraction should reduce PEM severity, even if total oxygen delivery or cardiac output remains unchanged. Therapies that enhance capillary recruitment, improve flow distribution, or stabilize microvascular control are predicted to attenuate delayed symptoms by improving tissue-level oxygen utilization during and after exertion ( Joseph et al., 2023; Østergaard et al., 2015 ).

Second, reducing shear stress or perfusion variability during exertion should reduce delayed skeletal muscle injury. Strategies that smooth perfusion transitions, limit abrupt flow redistribution, or reduce mechanical and hemodynamic stress at the microvascular level are expected to decrease downstream ER–mitochondrial stress and attenuate post-exertional structural and metabolic damage ( Østergaard et al., 2015; Colosio et al., 2023 ).

Third, PEM severity should correlate more strongly with markers of skeletal muscle injury and recovery than with central cardiopulmonary metrics. Measures reflecting muscle-level recovery—such as post-exertional changes in muscle metabolism, structural integrity, inflammatory signaling, or mitochondrial function—should better predict symptom severity and duration than resting or peak cardiac output, pulmonary function, or arterial oxygenation ( Appelman et al., 2024; Joseph et al., 2023; Mughal et al., 2025 ).

Together, these predictions provide a framework for empirically distinguishing muscle-centered execution failure models of PEM from explanations based primarily on central cardiovascular limitation, global hypoxia, or nonspecific fatigue.

10. Conclusion

Skeletal muscle is the dominant generator and amplifier of post-exertional malaise, because it is the primary site where exertional perfusion demands collide with impaired microvascular control, leading to oxygen extraction failure, ER–mitochondrial stress, and delayed tissue injury.

Figures

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Interpretive Framework Documents (GLA v2.1 → v2.5)

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