Skeletal Muscle in PASC Patients (MUSCLE-PASC)

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  • sponsor
    Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Updated on 13 August 2022
Accepts healthy volunteers


Rationale: A common feature in patients with Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) are skeletal muscle-related symptoms, such as muscle pain, weakness, fatigue and post-exertional malaise.

Objective: The primary aim is to determine markers for skeletal muscle structure and function, and circulating factors, in patients with PASC, and compare with controls. The secondary objective is to determine skeletal muscle structure and function before and after induction of post-exertional malaise, and assess the relationships between the measures obtained from muscle biopsies and parameters of exercise tolerance.

Study design: Case-control observational study Study population: Patients with PASC and healthy human volunteers, 18 - 65 yr old.

Intervention (if applicable): none Main study parameters/endpoints: Primary outcome parameters are markers for local inflammation, viral infiltration, mitochondrial respiratory function and myokine concentrations in a muscle biopsy and venous blood before and after induction of post-exertional malaise. Heart rate variability and measures of exercise performance will also be determined.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Participants will be asked to perform physical exercise tests, give muscle biopsies (2 samples), and various blood samples. There is some extent of burden and risk associated with harvesting muscle biopsies and blood samples, however this will be mitigated by the fact that these procedures will only be carried out by trained physicians. Moreover, the scientific gain from obtaining intracellular information outweighs these relatively quick procedures with minimal discomfort afterwards. The acute risks of the physical exercise measurements are negligible. The main risk for patients is that these patients often suffer from post-exertional malaise, which causes the participants to feel fatigued for some time after the maximal exercise test. It is one of the aims to better understand post-exertional malaise.



Since the end of February 2020, there have been more than 1.5 million infections with the SARS-CoV-2 virus in the Netherlands. Although the majority of patients experience mild complaints and fully recover within a few weeks, approximately 10% continue to experience long-term residual complaints (Huang et al., 2021, Sudre et al., 2021, Nalbandian et al., 2021). In February 2021, the World Health Organization recognized this group and introduced the term Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). Residual complaints mainly include limited exercise tolerance and malaise after exertion, fatigue, shortness of breath, accelerated heartbeat, muscle weakness and cognitive complaints (Huang et al., 2021, Sudre et al., 2021, Nalbandian et al., 2021, Soares et al, submitted). The underlying mechanisms responsible for the exaggerated response to exercise in a large part of the PASC population are currently unclear, which makes it difficult to deploy effective rehabilitation interventions. This project tests the hypotheses that skeletal muscle tissue damage, directly or indirectly caused by the SARS-CoV-2 virus, and/or an impaired immune response, underlies this.

A relatively common feature in all these patients with acute Covid-19 or PASC are skeletal muscle-related symptoms, such as muscle pain (myalgia), muscle weakness, fatigue and exercise intolerance (Soares et al., submitted). Broadly speaking, there are two groups of patients with PASC: one that have been hospitalised (and likely also suffer from hospitalized muscle weakness and fatigue), and those that underwent the Covid-19 infection at home. We particularly focus on the second group in this application.

Muscle weakness and fatigue are key symptoms of patients with Covid-19, and the literature that is currently available suggests that reduced force generating capacity, decreased neural activation, fiber atrophy, necrosis, fibrosis and alterations in metabolic function likely underlie these clinical symptoms in acute Covid-19. Contributing factors will vary between patients, and might include systemic inflammation (cytokine storm), viral infection, and (forced) inactivity. In some (hospitalized) patient populations, malnutrition, hypoxemia and certain medications can worsen skeletal muscle atrophy and metabolic alterations, but are likely not the main contributor, whilst comorbidities could exacerbate symptoms particularly in older patients. The observation that a significant subgroup of patients reports clinical symptoms of exercise intolerance, muscle fatigue and weakness for up to a year post-infection, suggests that this is a multifactorial problem.

The muscle weakness can range from mild to severe, and such symptoms may persist long after the viral infection has resolved. Myalgia and arthralgia are also common persistent symptoms in patients with PASC (24%) and are more notable in patients who were prone positioned during ICU-admission (5). The high prevalence of skeletal muscle-related symptoms hint towards structural and functional alterations in skeletal muscle in patients with PASC. 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 suffer from post-exertional fatigue. Due to the heterogeneity of patients, these muscle-related symptoms may vary dramatically, and is likely multifactorial in nature. Comparing these alterations with other clinical conditions that present with similar symptoms, the aim of the present work is to understand the possible contributing factors.

Whilst long-term consequences of hospitalization are known, the widespread incidence of muscle-related symptoms suggests that skeletal muscle adaptations seen in patients with PASC stand apart from those seen in critical illness myopathy. As such, different contributing factors are likely. Acute systemic inflammation or inactivity may play a smaller role, and other factors such as persistent viral load inside cells and possibly specific genotypes (such as different ACE gene polymorphisms) might play a role. This study will shed light on this.


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


Primary objectives:

• To determine markers for skeletal muscle structure and function (such as mitochondrial ultrastructure and function, viral infiltration, metabolite concentrations, myokine secretion), the immune response and circulating myokines (muscle-derived molecules), in non-hospitalized patients with PASC and healthy controls.

Secondary objectives:

• To determine each of the above variables both before and after induction of post-exertional malaise, and assess the relationships between the measures obtained from muscle biopsies and parameters of exercise tolerance.

3. STUDY DESIGN 3.1. General. Case-control study with assessments before and after an induction of post-exertional malaise. 25 individuals with PASC and 25 matched healthy controls who have recovered from Covid-19 infection will be recruited for the study. Participants are required to visit the laboratory for a total of 4 experimental sessions, for a total duration of approximately 5 hours. Measurements will take place within a time window of 2 weeks.

25 participants with PASC (equal split between sexes) between the ages of 18-65 yrs will be recruited for the study, and 25 healthy control participants matched for age, BMI and physical activity levels.

Participants will be required to visit the laboratory on 4 separate occasions over a 2 week period immediately prior to and following a maximal exercise test. After the first visit, participants will be asked to confirm dates for the subsequent visits over the next 2 weeks face-to-face in the laboratory. Participants will be instructed not to consume alcohol or perform strenuous exercise within the 24 h preceding each exercise test, and to abstain from caffeine consumption for at least 3 h.


4.1 Population Around 10% of all patients with an acute Covid-19 infection suffer from PASC in the Netherlands, and this is the population base from which individuals with PASC will be recruited. 25 non-hospitalized participants with diagnosed PASC and 25 healthy participants of similar sex, age, BMI and preferably current physical activity levels between the ages of 18-65 years old will be recruited to the study. All participants with PASC will be recruited from the outpatient clinic of the Amsterdam UMC, whereas healthy controls will be recruited via specific social media groups, through personal networks and/or posters. All testing will be conducted at the department of Rehabilitation Medicine, Amsterdam UMC location AMC. Therefore, participants should be currently residing in or willing to travel to Amsterdam.

Condition LONG-COVID, Post-acute Sequelae of COVID-19
Treatment Bike exertion test
Clinical Study IdentifierNCT05225688
SponsorAcademisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Last Modified on13 August 2022

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