Skeletal muscle adaptations and post-exertional malaise in long COVID.
Charlton, Braeden T, Goulding, Richie P, Jaspers, Richard T et al. · Trends in endocrinology and metabolism: TEM · 2025 · DOI
Quick Summary
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.
Why It Matters
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.
Observed Findings
Mitochondrial dysfunction has been documented in long COVID muscle tissue
Endothelial abnormalities are present in affected patients
Muscle fiber types show a shift toward more glycolytic (less efficient) metabolism
Rapid skeletal muscle tissue damage occurs following exertion
Intramuscular immune cell infiltration is associated with PEM-related symptoms
Inferred Conclusions
Multiple intrinsic muscle abnormalities converge to reduce exercise capacity in long COVID
Post-exertional malaise likely results from exertion-induced muscle damage combined with immune cell infiltration
Muscle fiber metabolic switching toward glycolysis may represent an adaptive but energy-inefficient response
Current understanding of PEM's mechanistic trigger remains incomplete despite identified contributory factors
Remaining Questions
What is the precise molecular trigger that causes physical or mental exertion to initiate muscle damage and immune infiltration?
Which of the proposed mechanisms (mitochondrial dysfunction, endothelial abnormalities, fiber type shift) is primary versus secondary?
What This Study Does Not Prove
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.