## 4 Discussion  
In this study, skeletal muscle fiber characteristics were investigated at a cellular and subcellular level throughout the first week of ICU admission in critically ill patients infected with SARS-CoV-2. We observed a large variation in muscle fiber size changes, with some patients showing a substantial increase, as opposed to a decline, in muscle fiber size following one week of ICU stay. Ultrastruct muscle tissue analyses showed evidence of myofibrillar degeneration at T0 and hydropic degeneration and necrosis at T1. This shows that the skeletal muscles of critically ill patients infected with SARS-CoV-2 are degenerative, which could indicate the presence of CIM. CIM in patients with sepsis (diagnosed in 15/22 of the patients) and/or systemic inflammatory response syndrome (SIRS) is often called sepsis induced myopathy (SIM). This myopathy is characterized by atrophy, fibrosis, scattered myofiber necrosis, vacuolization, and phagocytosis, with focal myosin loss [23], which is in accordance with our observations. Figure 7: Electron micrographs of abnormalities of the endomysial capillaries. Abnormal capillaries are characterized by swollen endothelial cells, showing swollen mitochondria (M), numerous pinocytotic vesicles (white arrowhead), and thickened lamina (white arrow), sometimes accompanied by perivascular fibrosis (white #). **(A)** The adjacent degenerative myofiber shows narrowed myofibrils (black # ) with a preserved sarcomere structure, sarcolemmal folds (F), and additional layers of basal lamina (black arrowhead). **(B)** An active macrophage (Ma) is located between the capillary and the degenerative myofiber, showing myosin loss (white *), sarcolemmal folds (F), vacuoles (V), and swollen mitochondria (M). **(C)** This capillary shows proliferation (black arrow) of the endothelial cells, causing obliteration of the capillary lumen. The neighboring necrotic myofiber shows vacuoles (V), swollen mitochondria (M), and extensive myofilament loss (black *). **(D)** The lumen of this capillary contains degranulated platelets (P). Muscle samples of critically ill patients infected with SARS-CoV-2 showed no significant changes in type I and type II muscle fiber size, due to large interindividual variation (Figure 1B). In the present study patients had already been suffering from SARS-CoV-2 infection prior to the need for ICU admission (on average 7 days after the start of symptoms). Therefore, we assume that some level of atrophy had already occurred prior to ICU admission. Interestingly, we observed large increases in muscle fiber size during the 7-day ICU admission in a subset of the patients. As myocyte swelling has been suggested to be part of a degenerative cascade, this may explain the lack of an overall decline in muscle fiber size within our patient sample. Myocyte swelling may be induced by several mechanisms [24]. Ultrastructural observations of patients who displayed a large increase in muscle fiber size showed signs of hydropic degeneration. If not halted, hydropic degeneration will result in lysis and cell death [24]. In the present study 13 out of 17 patients had one or more comorbidities when admitted to the ICU (see Table 1). It is interesting to observe that the post hoc analysis between the group of SARS-CoV-2 infected patients with (n = 13) and without (n = 4) comorbidities showed significant differences in the level of muscle fiber atrophy. Whereas, on average, the patients with comorbidities showed no significant changes in fiber size, patients without comorbidities revealed a significant decline in both type I (\(-\)14%) and type II (\(-\)26%) muscle fiber size following 7 days of ICU admission (see Table A1 in Appendix A). Although observed in a small subpopulation, the increase in muscle fiber size due to swelling may be prevalent in many ICU patients. Whether this is specific for ICU patients with a SARS-CoV-2 infection remains to be assessed.