Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome.

Observed Findings

• Patients with PCC and ME/CFS exhibit reduced systemic oxygen extraction and decreased oxidative phosphorylation capacity during physical activity.
• Mitochondrial dysfunction and microcirculatory impairments are evident in both conditions and appear maintained by latent immune activation.
• Physical exertion triggers accumulation of metabolites including lactate, reactive oxygen species, and prostaglandins that activate immune responses.
• Patients frequently experience tachycardia, dyspnea, and early activity cessation during exertional episodes.
• Metabolic dysfunction appears coupled with ionic disturbances in muscle and modulation of central nervous system function.

Inferred Conclusions

• Post-exertional malaise arises from interconnected deficits in tissue perfusion, oxygen utilization, and bioenergetic flexibility triggered by physical activity.
• Latent immune activation perpetuates both mitochondrial and microvascular dysfunction, creating a self-sustaining cycle of reduced energy production.
• Accumulation of metabolic byproducts and reactive oxygen species intensifies immune activation and symptom exacerbation during and after exertion.
• The pathophysiology involves multiple organ systems (muscular, vascular, immune, neurological) in a coordinated dysregulation rather than a single primary defect.

Remaining Questions