Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract

Background: A considerable number of patients who contracted SARS-CoV-2 are affected by persistent multi-systemic symptoms, referred to as Post-COVID Condition (PCC). Post-exertional malaise (PEM) has been recognized as one of the most frequent manifestations of PCC and is a diagnostic criterion of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Yet, its underlying pathomechanisms remain poorly elucidated.

Purpose and methods: In this review, we describe current evidence indicating that key pathophysiological features of PCC and ME/CFS are involved in physical activity-induced PEM.

Results: Upon physical activity, affected patients exhibit a reduced systemic oxygen extraction and oxidative phosphorylation capacity. Accumulating evidence suggests that these are mediated by dysfunctions in mitochondrial capacities and microcirculation that are maintained by latent immune activation, conjointly impairing peripheral bioenergetics. Aggravating deficits in tissue perfusion and oxygen utilization during activities cause exertional intolerance that are frequently accompanied by tachycardia, dyspnea, early cessation of activity and elicit downstream metabolic effects. The accumulation of molecules such as lactate, reactive oxygen species or prostaglandins might trigger local and systemic immune activation. Subsequent intensification of bioenergetic inflexibilities, muscular ionic disturbances and modulation of central nervous system functions can lead to an exacerbation of existing pathologies and symptoms.

Keywords: ME/CFS; Physical activity; Post COVID condition; Post-exertional malaise; SARS-CoV-2.

Fig. 1

Potential drivers of PEM include microvascular alterations and mitochondriopathy that can functionally culminate in reduced systemic oxygen extraction and oxidative phosphorylation capacity upon physical activities (a–b). Altered bioenergetics limit the patients’ ability to be physically active and induce the accumulation of lactate, reactive oxygen species and cations (c). Overexertion could manifest as delayed symptom exacerbation and systemic fatigue through subsequent immune activation that might aggravate bioenergetic inflexibilities and modulate CNS functions (d) (Figure created with biorender.com) ATP adenosine triphosphatem, CNS central nervous system, eNOS endothelial nitric oxide synthase, ETC electronic transport chain, FMD flow-mediated dilation, NO nitric oxide, ROS reactive oxygen species, TCA tricarboxylic acid