Skeletal Muscle Structure and Function in Relation to Post-exertional Malaise in Patients With PASC and ME/CFS

1. INTRODUCTION AND RATIONALE Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are severely debilitating diseases mainly characterized by chronic fatigue, post-exertional malaise (PEM) and cognitive impairment with autonomic, neuro-endocrine, immunological and cognitive involvement(Davis et al. 2021; Deumer et al. 2021; Soares et al. 2022). The clinical presentation of both diseases is remarkably overlapping. Particularly, skeletal muscle-related complaints, such as extreme fatigue, muscle weakness and muscle pain, are symptoms that tremendously decrease the patients quality of life and overlap in both patient groups, The key symptom, PEM, distinguishes PASC and ME/CFS from other more common fatigue conditions and is characterized by worsening or relapse of symptoms (including sleep dysfunction, cognitive impairment and extreme skeletal muscle fatigue) after physical activity, which can last for days or weeks(Davis et al. 2021; Soares et al. 2022; Stussman et al. 2020). We recently reviewed the skeletal muscle alterations in both acute SARS-CoV-2 infection and patients with Long COVID, and concluded that post-exertional malaise in patients with Long COVID cannot be explained by current knowledge on skeletal muscle structure and function(Soares et al. 2022).

A possible lead to the understanding of PEM in Long COVID and ME/CFS pathophysiology is provided by the observation that most cases appear to have an infectious onset(Choutka et al. 2022; Magnus et al. 2015; Tsai et al. 2014). Following SARS-CoV-2 infection, 10-30% of patients exhibit post-infectious fatigue syndrome, called Long COVID or post-COVID condition(Ballering et al. 2022). PEM is the hallmark symptom of Long COVID and ME/CFS and a criterion for CCC, ICCC and IOM case definitions. Little is known about the underlying pathophysiology of skeletal muscle abnormalities, including PEM. No treatment options are available, apart from the advice to patients to avoid exercise or exercise below an (unknown) threshold.

Due to the heterogeneity of patients, these muscle-related symptoms may vary dramatically, and is likely multifactorial in nature. Whilst long-term consequences of hospitalization are known, the widespread incidence of muscle-related symptoms suggests that skeletal muscle adaptations seen in non-hospitalized patients with PASC and ME/CFS stand apart from those seen in critical illness myopathy.

The muscle weakness can range from mild to severe, and such symptoms may persist long after the viral infection has resolved. The high prevalence of skeletal muscle-related symptoms hint towards structural and functional alterations in skeletal muscle in patients with PASC and ME/CFS(Kerkhoff et al. 2022; McGregor et al. 2019; Noor et al. 2021). In this study, we aim to study alterations in intracellular skeletal muscle structure and function and the immune response that will help to explain why patients with PASC and ME/CFS suffer from post-exertional fatigue. 2. OBJECTIVES

To obtain insight whether skeletal muscle adaptations can explain post-exertional fatigue malaise in patients with PASC and ME/CFS, the present study will address the following objectives: