Mechanisms underlying exercise intolerance in Long COVID: an accumulation of multi-system dysfunction

The pathogenesis of exercise intolerance and persistent fatigue which can follow an infection with the SARS-CoV-2 virus (’Long COVID’) is not fully understood. Cases were recruited from a Long COVID clinic (N=32; 44±12y; 10(31%)men), and age/sex- matched healthy controls (HC) (N=19; 40±13y; 6(32%)men) from University College London staff and students. We assessed exercise performance, lung and cardiac function, vascular health, skeletal muscle oxidative capacity and autonomic nervous system (ANS) function. Key outcome measures for each physiological system were compared between groups using potential outcome means(95% confidence intervals) adjusted for potential confounders. Long COVID participant outcomes were compared to normative values. When compared to HC, cases exhibited reduced Oxygen Uptake Efficiency Slope (1847(1679,2016) vs (2176(1978,2373) ml/min, p=0.002) and Anaerobic Threshold (13.2(12.2,14.3) vs 15.6(14.4,17.2) ml/Kg/min, p<0.001), and lower oxidative capacity on near infrared spectroscopy (τ: 38.7(31.9,45.6) vs 24.6(19.1,30.1) seconds, p=0.001). In cases, ANS measures fell below normal limits in 39%. Long COVID is associated with reduced measures of exercise performance and skeletal muscle oxidative capacity in the absence of evidence of microvascular dysfunction, suggesting mitochondrial pathology. There was evidence of attendant ANS dysregulation in a significant proportion. These multi-system factors might contribute to impaired exercise tolerance in Long COVID sufferers. Key Points The pathogenesis of exercise intolerance and persistent fatigue which can follow an infection with the SARS-CoV-2 virus (’Long COVID’) is not fully understood. We show that Long COVID is associated with reduced measures of exercise performance in line with previous work. In Long COVID cases, we observed reduced skeletal muscle oxidative capacity in the absence of evidence of microvascular dysfunction, suggesting mitochondrial pathology. We also observed evidence of attendant autonomic nervous system (ANS) dysregulation in a significant proportion of Long COVID cases. These multi-system factors might contribute to impaired exercise tolerance in Long COVID sufferers.