Commentaries on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

to the editor: With emerging knowledge regarding the pathogenesis involving SARS-CoV-2, it is becoming apparent that no tissue is spared in the body. Ferrandi et al. (5) suggested a cause for myopathy in COVID-19 via the ACE2 expression that leads to myocytes becoming susceptible to SARS-CoV-2. We would like to add that the muscle involvement in COVID-19 is likely to be early in the infection. We have recently explored the muscles in rheumatoid arthritis (RA) (4) using quantitative MRI measures, which reflect physiological changes regarded as an indirect measure of muscle inflammation (3). These abnormal muscle changes which are present in established RA patients are also noticeable in newly diagnosed untreated RA patients. This suggests that muscle is likely to be sensitive to the inflammatory process and is involved early. COVID-19 also involves multiple proinflammatory cytokines; the muscles may already be affected in susceptible patients at the time of diagnosis, which may then lead to various muscle-related pathologies, including affecting the respiratory muscles as eluded to by Ferrandi et al. Further, Ferrandi et al. highlighted that the aging population is at increased risk of COVID-19; we showed that there are age-related muscle changes on MRI that correlate with frailty and muscle function (2). Our RA patients, when treated to arthritis remission, continued to have persistent abnormal MRI changes and weaker muscles. This is analogous to patients who “recovered” from COVID-19, but continue to manifest various muscular symptoms (1). Therefore therapeutic strategies targeting the muscle may be important throughout the course of COVID-19.

to the editor: We have read with interest the Viewpoint offered by Ferrandi et al. (4). We applaud their thoughtful approach to a situation that is significantly affecting daily life worldwide. We agree that the coronavirus disease 2019 (COVID-19) outbreak has an overwhelming global impact and is one of the world’s leading headlines. We also concur with the idea that concurrently with the infection of pulmonary tissues, there is an evident SARS-CoV-2 potential spread into the skeletal muscle (eventually leading to severe myopathies). However, if it is well-accepted that regular physical activity helps to improve overall health, fitness, and quality of life (3), engaging more people in properly guided physical exercise routines might be an appropriate strategy to prevent skeletal muscle viral susceptibility and avoid muscle failure (1, 3). These training programs should be preferably conducted outdoors (or in closed spaces if respecting proper coronavirus mitigating guidelines), selecting personal rather than group activities even if in low-contact sports the exposure to the virus seems to be minimal (5). In addition to the “exercise is medicine” approach, maintaining wholesome hydration and supplementation, particularly with vitamin C, a powerful antioxidant (2), might be useful for strengthening the immune system for preventing inflammatory reactions that potentially destroy cells and tissues. We believe that, even if in emergency times, we should join efforts to avoid physical inactivity and related diseases like obesity, hypertension, and overall immunodeficiency. Now that seasonal variations are approaching, these strategies might make the difference.

to the editor: We read with interest the recent Viewpoint by Ferrandi, Alway, and Mohamed (1) on the interaction between SARS-CoV-2 and ACE2 with skeletal muscle, and although several relevant points were raised, we would like to present some elements to enrich the debate. Pathologies that affect directly the skeletal muscle (e.g., Duchenne muscular dystrophy) or pulmonary tissue (e.g., idiopathic pulmonary fibrosis), are closely linked to a worse clinical prognostic in the presence of COVID-19 infection. Furthermore, COVID-19 has great potential to promote substantial fibrotic consequences leading to acute lung injury (2). Although a pharmacological treatment would be rational to fight infection, could the systematic practice of moderate-intensity exercises be able to promote both a better health and life quality as well as to accelerate the recovery phase in post-treated COVID-19 patients? Increases in anti-inflammatory (IL-10) and reduction in pro-inflammatory pulmonary cytokines (e. g. IL-1β, IL-6, TNFα, and IGF-1), as well as oxidative stress levels after aerobic exercise (5), were observed during a 4-wk training exercise protocol in rats. Also, lung damage induced by bleomycin (4) was reduced with physical training more then with diminazene (an anti-fibrotic agent), decreasing the expression of TGF-β1 and beta-prolyl-4-hydroxylase, markers related to impaired lung function. Last, but not least, continuous moderate-intensity exercise training seems to improve hematological profile (increasing of leukocyte, lymphocyte, neutrophil, and monocyte), consequently enhancing the subject's immune response, whereas high-intensity training does not (3). Therefore, regular and moderate exercise could be an effective, cost-efficient, and prophylactic collaborative agent during the COVID-19 era.

to the editor: COVID-19, caused by SARS-CoV-2, has represented a significant challenge to healthcare systems around the world (2). It is the role of physiology, and allied health disciplines, to provide answers to better face the current pandemic. In this regard, we believe that the concept of respiratory muscle weakness (RMW) has been vastly overlooked. RMW can be defined as a decline in the force or power that a muscle or muscle group can achieve, provided no prior exercise or significant effort has been made (4). A decrease in respiratory muscle performance commonly manifests itself as dyspnea and can be assessed by measuring the maximal static inspiratory pressure (cut-off point suggestive of RMW: 63 cmH2O in adults < 40 yr, 42 cmH2O in adults > 80 yr) (5).

The importance of RMW rests in the fact that it is a prevalent condition in elderly patients with comorbidities such as obesity, smoking history, physical inactivity, and chronic diseases (such as heart failure, COPD, and neuromuscular disorders) (3, 4). Surprisingly these are some of the factors that have been extensively associated with a worse prognosis in patients infected with SARS-CoV-2. We thus believe that RMW could be a potential determinant of poor outcomes in severe COVID-19 patients, who often present with several of the above-mentioned comorbidities. Furthermore, according to Ferrandi et al., SARS-CoV-2 could likely infect muscle tissue, which would further complicate the prognosis of the patients (1). Therefore, we consider that new risk-stratification scores for COVID-19 should take into account RMW, evaluated by means of the maximal static inspiratory pressure. This could hopefully lead to early intervention and better outcomes in the treatment of complicated COVID-19 patients.

to the editor: The recent article by Ferrandi, Alway, and Mohamed (3) reminds us that, although we no longer live in the age of continental exploration, we are still in uncharted waters when it comes to the pathophysiology of the novel SARS-CoV-2 (COVID-19) virus. At the onset of exercise, elevated O2 demand (V̇o2) of skeletal muscle requires a commensurate increase in O2 delivery (Q̇o2) by the simultaneous increase in cardiac output and vasodilation within the peripheral arteriolar network. Considering that COVID-19 downregulates angiotensin-converting enzyme 2 [ACE2, which the virus uses to infiltrate cells (5)] and that reduced ACE2 expression results in the accumulation of the potent vasoconstrictor angiotensin II (1), it is possible that COVID-19 impairs Q̇o2/V̇o2 matching within skeletal muscle during exercise. Angiotensin II has also been associated with an increase in expression and activation of NADPH oxidases and the formation of reactive oxygen species, which ultimately degrade nitric oxide bioavailability [a critical contributor to exercise hyperemia (2)], further shifting the vasculature to a more pro-constrictive state. Furthermore, ACE2 downregulation also prevents the production of Ang(1-7), which plays a protective role against insulin resistance via its inhibitory effect on angiotensin II (1). While ACE2 deficiency impairs muscular adaptations to exercise training (4), it is unclear whether COVID-19 reductions in ACE2 persist long-term or whether the degree of endothelial dysfunction results in vascular and/or metabolic dysregulation during exercise. These questions underscore the importance of applied investigations into the physiological underpinnings of this disease and its impact on muscle function and exercise (in)tolerance.

to the editor: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which invades cells through the angiotensin-converting enzyme 2 (ACE2) receptor, is a systemic disease with major events in the lungs and involvement of various organs and tissues (5). Ferrandi et al. (1) showed that these patients are prone to developing skeletal muscle myopathy associated with atrophy, weakness, and disability, culminating in loss of quality of life. In addition, patients with underlying cardiovascular disease and muscle dystrophy infected with SARS-CoV-2 may suffer more severe symptoms and worsened mortality outcomes. Thus, it is expected that SARS-CoV-2 induced skeletal muscle abnormalities either due to direct infection of ACE2-rich cell-types, and/or indirectly through systemic cytokine release and subsequent homeostatic perturbation (1). ACE2 is an enzyme homologous to ACE1 that cleaves the peptide Angiotensin (Ang) II to generate Ang-(1-7). We were the first to show the skeletal muscle ACE2 expression and activity in healthy animals (3). Further, we showed the ACE2/Ang-(1-7)/Mas axis represents a significant protective system in physiological and pathological conditions (2, 4). Considering that skeletal muscle is highly responsive to exercise, we addressed the benefits of exercise training to counteract skeletal myopathy in heart failure (4), suggesting a lower ACE/ACE2 ratio may reduce the risk of worse outcomes in SARS-CoV-2 infection (5). Thus, exercise training can delay the onset or minimize the consequences of cardiac and skeletal muscle myopathy in SARS-CoV-2 by rescuing ACE2 activity and increasing Ang-(1-7) levels in at-risk populations. Further investigations in SARS-CoV-2 patients are encouraged because these patients suffer from impaired functional capacity and could benefit from exercise training.

to the editor: The skeletal myopathy in coronavirus disease 2029 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (2) could be as a consequence of systemic disease rather-specific rich expression of angiotensin-converting enzyme 2 (ACE2) or host surface protease transmembrane protease serine 2 (TMPRSS2). The skeletal myopathy should be characterized as per different disease stages, i.e., asymptomatic SARS-CoV-2 infection, mild COVID-19, and severe COVID-19, especially with acute lung injury. Should there be global skeletal myopathy with general weakness, fatigue, and prolonged inactivity among asymptomatic or mildly symptomatic SARS-CoV-2-infected patients, it is likely due to ACE2 expression distribution. However, if it is significantly limited to severe COVID-19 patients with acute lung injury, myocarditis, acute kidney injury, or central nervous system involvement, the pathophysiological basis of skeletal muscle myopathy should be interpreted as a part of a multi-system disorder. First, many COVID-19 patients suffer from profound hypoxemia: either it is classical acute respiratory distress syndrome (ARDS) or atypical ARDS or so-called “happy hypoxemia,” i.e., hypoxia without associated dyspnea (1, 5). Second, although the pathophysiological basis of COVID-19 lung injury and hypoxemia is yet to be clearly known, there are strong signals pointing toward cytokine storm, endothelial dysfunction, platelet activation, and resultant micro-thromboembolism (4). The severe hypoxemia, the prolonged period under ventilator in the intensive care unit, and physical inactivity could be playing a major role in myopathy. Third, several asymptomatic and severe COVID-19 patients report loss of smell and taste, which could be part of autonomic dysfunction (3), which may also cause myopathy.