Fig. 3: Metabolic and mitochondrial dysfunction in long COVID patients worsens with post-exertional malaise.

A Oxidative phosphorylation (OXPHOS) capacity was significantly lower in patients with long COVID (n = 25) compared to healthy controls (n = 21), and remained lower one day after induction of post-exertional malaise (PEM) in patients (Group: p = 0.003, Time: p < 0.001). B Succinate dehydrogenase (SDH) activity, a marker for mitochondrial density, was not different between groups (p = 0.06) and only reduced (p = 0.0083) after induction of post-exertional malaise in long COVID patients (n = 25) compared to healthy controls (n = 21). A typical example of the SDH activity is shown in panel C. Skeletal muscle (D) and venous (E) metabolome pathways indicate slightly higher levels of metabolites related to glycolysis, and a lower abundance of metabolites related to purine synthesis and the tricarboxylic acid (TCA) cycle, indicative of a lower reliance on oxidative metabolism in patients with long COVID (n = 25, both timepoints) as compared to healthy (n = 19, both timepoints). Faded names were not measured and shown for clarity. A higher effect size in long COVID is shown in red, lower effect size in blue. Continuous parametric longitudinal data (panels A, B, D, E) were analyzed with a generalized linear mixed model with a two-sided ANOVA. Post-hoc tests comparing each group were performed when the interaction term was significant and was performed using emmeans with BH adjustment (panels A and B). Effect sizes (D and E) were calculated with Hedges‘ g *p < 0.05; **p < 0.001; ^†p < 0.05 indicates a significant interaction effect. Bar: 50 μm. PEM post-exertional malaise. Box plots show the median (centerline), the first and third quartiles (the lower and upper bound of the box), and the whiskers show the 1.5× interquartile range. Source data are provided in the Source Data File.