Charlton, Braeden T, Goulding, Richie P, Jaspers, Richard T et al. · Trends in endocrinology and metabolism: TEM · 2025 · DOI
This article reviews evidence that long COVID symptoms—especially worsening after activity (post-exertional malaise)—may be caused by problems with how muscles produce energy, damage to blood vessel function, and changes in muscle fiber types that make them rely more on less-efficient energy pathways. The authors suggest that physical or mental exertion may trigger rapid muscle damage and immune cell infiltration, which could explain why patients feel worse after activity.
Understanding the muscle-level mechanisms behind post-exertional malaise is critical for developing targeted therapies and validating objective biomarkers in long COVID. This synthesis helps explain why standard exercise advice may worsen symptoms and supports the need for activity management strategies tailored to ME/CFS pathophysiology.
This opinion article does not present new experimental data and cannot establish causation—it proposes mechanisms based on existing evidence. The relative importance of each proposed mechanism (mitochondrial dysfunction, endothelial damage, fiber type shift) remains unclear, and the specific trigger linking exertion to PEM has not been identified.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
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