###### Abstract  
Many critically ill patients infected with SARS-CoV-2 have been submitted to an intensive care unit (ICU). Patients with a SARS-CoV-2 infection that survive critical illness are confronted with months of physical impairments. To maximize recovery, it is important to understand the musculoskeletal involvement in critically ill patients infected with SARS-CoV-2. The aim of the present study was to assess the myocellular changes in SARS-CoV-2 patients that occur throughout the first week of ICU admission. In n = 22 critically ill patients infected with SARS-CoV-2, a biopsy sample from the vastus lateralis muscle was obtained at day 1-3 and day 5-8 following ICU admission. Fluorescence microscopy was used to assess type I and type II muscle fiber size and distribution, myonuclear content, and muscle tissue capillarization. Transmission electron microscopy was used to support quantitative data at an ultrastructural level. Changes in type I and type II muscle fiber size showed large inter-individual variation. The average change in type I fiber size was +309 \(\pm\) 1834 um2, ranging from \(-\)2129 um2 (-31%) to +3375 um2 (+73%). The average change in type II fiber size was \(-\)224 \(\pm\) 1256 um2, ranging from \(-\)1410 um2 (-36%) to +2592 um2 (+48%). Ultrastruct observations showed myofibrillar and hydrolytic degeneration, and fiber necrosis. This study shows that ICU patients admitted with SARS-CoV-2 suffer from substantial muscle fiber damage during ICU admission. These results are a call for action towards more specialized rehabilitation programs for patients admitted to the ICU with SARS-CoV-2 infection. severe acute respiratory syndrome virus; skeletal muscles; sepsis; respiratory distress syndrome; critical illness +
Footnote †: hypoxemia, septic shock, and multiple organ dysfunction, which result in hospital and/or intensive care unit (ICU) admission [2; 3]. Besides respiratory symptoms, patients with COVID-19 often exhibit musculoskeletal symptoms, including muscle aches, muscle fatigue, and weakness [4]. Patients hospitalized with severe SARS-CoV-2 infection are more likely to develop skeletal muscle injury with myalgia [5]. Survivors of moderate and severe SARS-CoV-2 infection have been shown to suffer from musculoskeletal dysfunction for more than 2-3 months after discharge from the hospital, which impedes rehabilitation and strongly reduces functional capacity and quality of life [6]. To date, the understanding of post-COVID-syndrome remains unclear, due to a lack of knowledge [7]. Critically ill patients commonly develop ICU-acquired weakness (ICUAW), which affects limb and respiratory muscles and adversely affects both short- and long-term clinical outcomes [6]. Critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) are both considered ICUAW [8]. In SARS-CoV-2 infected patients, CIM can accelerate age-related muscle loss and results in poor prognosis and worsens the clinical outcome and rehabilitation capacity [9]. So far, there is no evidence that the muscle tissue of SARS-CoV-2 positive patients shares unique features, other than those previously reported in critically ill patients. Like many different diseases, SARS-CoV-2 enters cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Skeletal muscle tissue expresses ACE2 on different cell types (e.g., satellite cells, fibroblasts, endothelial cells), which allows a possible pathway for viral destruction of skeletal muscle tissue [10; 11; 12]. However, until now, SARS-CoV-2 has not been identified in skeletal muscle tissue, suggesting that other pathways may be involved in COVID-19-related myopathy [13]. Infection with SARS-CoV-2 is known to increase circulating pro-inflammatory cytokine levels [14]. These elevated cytokine levels induce systemic inflammation, exacerbating the viral pathogenesis, and causing sepsis, ARDS, and multiple organ damage, including skeletal muscle loss [14; 15]. Until now, there have been few data on the impact of SARS-CoV-2 infection on skeletal muscle tissue.