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.

The authors have declared no competing interest.

The study was undertaken as part of a 4-year PhD studentship supported by the British Heart Foundation (grant number FS/19/63/34902). NC and ADH work in a unit that receives support from the UK Medical Research Council (grant number MC_UU_12019/1). HM is supported by the National Institute for Health Research Comprehensive Biomedical Research Centre at University College Hospital London.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Leicester Central Research Ethics Committee gave ethical approval for the recruitment of participants with Long COVID for this work. University College London Research Ethics Committee of University College London gave ethical approval for the recruitment of healthy individuals for this work.

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Due to the sensitive nature of the data collected for this study, data cannot be made publicly available, but requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to Dr Siana Jones at the MRC Unit for Lifelong Health and Ageing at UCL (siana.jones@ucl.ac.uk).