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

Abstract

ViewpointCommentaries on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathiesPublished Online:07 Oct 2020https://doi.org/10.1152/japplphysiol.00775.2020MoreSectionsPDF (135 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat COMMENTARY ON VIEWPOINT: THE INTERACTION BETWEEN SARS-CoV-2 AND ACE2 MAY HAVE CONSEQUENCES FOR SKELETAL MUSCLE VIRAL SUSCEPTIBILITY AND MYOPATHIESAi Lyn Tan,12 Matthew Farrow,123 and John Biglands14.Author Affiliations1NIHR Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.2Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom.3School of Pharmacy and Medical Sciences, University of Bradford, United Kingdom.4Medical Physics and Engineering, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.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.REFERENCES1. Disser NP, De Micheli AJ, Schonk MM, Konnaris MA, Piacentini AN, Edon DL, Toresdahl BG, Rodeo SA, Casey EK, Mendias CL. Musculoskeletal consequences of COVID-19. J Bone Joint Surg Am 102: 1197–1204, 2020. doi:10.2106/JBJS.20.00847. Crossref | PubMed | ISI | Google Scholar2. Farrow M, Biglands J, Tanner SF, Clegg A, Brown L, Hensor EMA, O’Connor P, Emery P, Tan AL. The effect of ageing on skeletal muscle as assessed by quantitative MR imaging: an association with frailty and muscle strength. Aging Clin Exp Res. doi:10.1007/s40520-020-01530-2. Crossref | PubMed | ISI | Google Scholar3. Farrow M, Biglands J, Alfuraih AM, Wakefield RJ, Tan AL. Novel muscle imaging in inflammatory rheumatic diseases – a focus on ultrasound shear wave elastography and quantitative MRI. Front Med 7: 434, 2020. doi:10.3389/fmed.2020.00434.Crossref | PubMed | ISI | Google Scholar4. Farrow M, Biglands J, Tanner S, Hensor EMA, Buch M, Emery P, Tan AL. Muscle deterioration due to rheumatoid arthritis: assessment by quantitative MRI and strength testing. Rheumatology (Oxford). doi:10.1093/rheumatology/keaa364. Crossref | PubMed | ISI | Google Scholar5. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google ScholarREFERENCES1. Disser NP, De Micheli AJ, Schonk MM, Konnaris MA, Piacentini AN, Edon DL, Toresdahl BG, Rodeo SA, Casey EK, Mendias CL. Musculoskeletal consequences of COVID-19. J Bone Joint Surg Am 102: 1197–1204, 2020. doi:10.2106/JBJS.20.00847. Crossref | PubMed | ISI | Google Scholar2. Farrow M, Biglands J, Tanner SF, Clegg A, Brown L, Hensor EMA, O’Connor P, Emery P, Tan AL. The effect of ageing on skeletal muscle as assessed by quantitative MR imaging: an association with frailty and muscle strength. Aging Clin Exp Res. doi:10.1007/s40520-020-01530-2. Crossref | PubMed | ISI | Google Scholar3. Farrow M, Biglands J, Alfuraih AM, Wakefield RJ, Tan AL. Novel muscle imaging in inflammatory rheumatic diseases – a focus on ultrasound shear wave elastography and quantitative MRI. Front Med 7: 434, 2020. doi:10.3389/fmed.2020.00434.Crossref | PubMed | ISI | Google Scholar4. Farrow M, Biglands J, Tanner S, Hensor EMA, Buch M, Emery P, Tan AL. Muscle deterioration due to rheumatoid arthritis: assessment by quantitative MRI and strength testing. Rheumatology (Oxford). doi:10.1093/rheumatology/keaa364. Crossref | PubMed | ISI | Google Scholar5. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google ScholarCOMMENTARY ON VIEWPOINT: THE INTERACTION BETWEEN SARS-CoV-2 AND ACE2 MAY HAVE CONSEQUENCES FOR SKELETAL MUSCLE VIRAL SUSCEPTIBILITY AND MYOPATHIESRicardo J. Fernandes,12 J. Arturo Abraldes,3 and Flávio Antônio de Souza Castro4.Author Affiliations1Centre of Research, Education, Innovation and Intervention in Sport, Faculty of Sport, University of Porto, Porto, Portugal.2Porto Biomechanics Laboratory, University of Porto, Porto, Portugal.3Department of Physical Activity and Sport, Faculty of Sports Sciences, University of Murcia, Murcia, Spain.4School of Physical Education, Physiotherapy and Dance, Aquatic Sports Research Group, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.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.REFERENCES1. Campbell JP, Turner JE. Debunking the myth of exercise-induced immune suppression: Redefining the impact of exercise on immunological health across the lifespan. Front Immunol 9: 648, 2018. doi:10.3389/fimmu.2018.00648. Crossref | PubMed | ISI | Google Scholar2. Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Med Drug Discov 5: 100028, 2020. doi:10.1016/j.medidd.2020.100028. Crossref | PubMed | Google Scholar3. Denay KL, Breslow RG, Turner MN, Nieman DC, Roberts WO, Best TM. ACSM Call to action statement: COVID-19. Considerations for sports and physical activity. Current Sports Med Rep 19: 326–328, 2020. doi:10.1249/JSR.0000000000000739.Crossref | ISI | Google Scholar4. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar5. Slater SJ, Christiana RW, Gustat J. Recommendations for keeping parks and green space accessible for mental and physical health during COVID-19 and other pandemics. Prev Chronic Dis 17: 200204, 2020. doi:10.5888/pcd17.200204. Crossref | PubMed | ISI | Google ScholarREFERENCES1. Campbell JP, Turner JE. Debunking the myth of exercise-induced immune suppression: Redefining the impact of exercise on immunological health across the lifespan. Front Immunol 9: 648, 2018. doi:10.3389/fimmu.2018.00648. Crossref | PubMed | ISI | Google Scholar2. Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Med Drug Discov 5: 100028, 2020. doi:10.1016/j.medidd.2020.100028. Crossref | PubMed | Google Scholar3. Denay KL, Breslow RG, Turner MN, Nieman DC, Roberts WO, Best TM. ACSM Call to action statement: COVID-19. Considerations for sports and physical activity. Current Sports Med Rep 19: 326–328, 2020. doi:10.1249/JSR.0000000000000739.Crossref | ISI | Google Scholar4. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar5. Slater SJ, Christiana RW, Gustat J. Recommendations for keeping parks and green space accessible for mental and physical health during COVID-19 and other pandemics. Prev Chronic Dis 17: 200204, 2020. doi:10.5888/pcd17.200204. Crossref | PubMed | ISI | Google ScholarCOULD MODERATE-INTENSITY EXERCISE TRAINING BE A PROPHYLACTIC COLLABORATIVE AGENT DURING COVID-19 ERA?Hiago L.R. de Souza, Rhai A. Arriel, Anderson Meireles, and Moacir Marocolo.Author AffiliationsPhysiology and Human Performance Research Group, Department of Physiology, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil.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.REFERENCES1. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar2. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med 8: 807–815, 2020. doi:10.1016/S2213-2600(20)30225-3. Crossref | PubMed | ISI | Google Scholar3. Khammassi M, Ouerghi N, Said M, Feki M, Khammassi Y, Pereira B, Thivel D, Bouassida A. Continuous moderate-intensity but not high-intensity interval training improves immune function biomarkers in healthy young men. J Strength Cond Res 34: 249–256, 2020. doi:10.1519/JSC.0000000000002737. Crossref | PubMed | ISI | Google Scholar4. Prata LO, Rodrigues CR, Martins JM, Vasconcelos PC, Oliveira FM, Ferreira AJ, Rodrigues-Machado MD, Caliari MV. ACE2 activator associated with physical exercise potentiates the reduction of pulmonary fibrosis. Exp Biol Med (Maywood) 242: 8–21, 2017. doi:10.1177/1535370216665174. Crossref | PubMed | ISI | Google Scholar5. Rigonato-Oliveira NC, Mackenzie B, Bachi ALL, Oliveira-Junior MC, Santos-Dias A, Brandao-Rangel MAR, Delle H, Costa-Guimaraes T, Damaceno-Rodrigues NR, Dulley NR, Benetti MA, Malfitano C, de Angelis C, Albertini R, Oliveira APL, Abbasi A, Northoff H, Vieira RP. Aerobic exercise inhibits acute lung injury: from mouse to human evidence Exercise reduced lung injury markers in mouse and in cells. Exerc Immunol Rev 24: 36–44, 2018. PubMed | ISI | Google ScholarREFERENCES1. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar2. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med 8: 807–815, 2020. doi:10.1016/S2213-2600(20)30225-3. Crossref | PubMed | ISI | Google Scholar3. Khammassi M, Ouerghi N, Said M, Feki M, Khammassi Y, Pereira B, Thivel D, Bouassida A. Continuous moderate-intensity but not high-intensity interval training improves immune function biomarkers in healthy young men. J Strength Cond Res 34: 249–256, 2020. doi:10.1519/JSC.0000000000002737. Crossref | PubMed | ISI | Google Scholar4. Prata LO, Rodrigues CR, Martins JM, Vasconcelos PC, Oliveira FM, Ferreira AJ, Rodrigues-Machado MD, Caliari MV. ACE2 activator associated with physical exercise potentiates the reduction of pulmonary fibrosis. Exp Biol Med (Maywood) 242: 8–21, 2017. doi:10.1177/1535370216665174. Crossref | PubMed | ISI | Google Scholar5. Rigonato-Oliveira NC, Mackenzie B, Bachi ALL, Oliveira-Junior MC, Santos-Dias A, Brandao-Rangel MAR, Delle H, Costa-Guimaraes T, Damaceno-Rodrigues NR, Dulley NR, Benetti MA, Malfitano C, de Angelis C, Albertini R, Oliveira APL, Abbasi A, Northoff H, Vieira RP. Aerobic exercise inhibits acute lung injury: from mouse to human evidence Exercise reduced lung injury markers in mouse and in cells. Exerc Immunol Rev 24: 36–44, 2018. PubMed | ISI | Google ScholarRESPIRATORY MUSCLE WEAKNESS: A HIDDEN CAUSE OF POOR CLINICAL OUTCOMES IN COVID-19 PATIENTS WITH COMORBID CONDITIONS?José Manuel González-Rayas,1 Ana Lilia Rayas-Gómez,2 Fadia Norma Mobayed-Vega,3 and José Manuel González-Yáñez4.Author Affiliations1School of Medicine and Health Sciences, Monterrey Institute of Technology and Higher Education, Monterrey, México.2Cardiology/Echocardiography, Hospital San José de Querétaro, Querétaro, México.3Pneumology, Hospital San José de Querétaro, Querétaro, México.4Angiology, Vascular and Endovascular Surgery, Hospital San José de Querétaro, Querétaro, México.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.REFERENCES1. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar2. González-Rayas JM, Rayas-Gómez AL, García-González JJ, González-Yáñez JM, Hernández-Hernández JA, López-Sánchez RC. COVID-19 and ACE -inhibitors and angiotensin receptor blockers-: The need to differentiate between early infection and acute lung injury. Rev Colomb Cardiol 27: 129–131, 2020. doi:10.1016/j.rccar.2020.04.005.Crossref | Google Scholar3. Guidon AC, Amato AA. COVID-19 and neuromuscular disorders. Neurology 94: 959–969, 2020. doi:10.1212/WNL.0000000000009566. Crossref | PubMed | ISI | Google Scholar4. Powers SK, Lynch GS, Murphy KT, Reid MB, Zijdewind I. Disease-induced skeletal muscle atrophy and fatigue. Med Sci Sports Exerc 48: 2307–2319, 2016. doi:10.1249/MSS.0000000000000975. Crossref | PubMed | ISI | Google Scholar5. Severin R, Arena R, Lavie CJ, Bond S, Phillips SA. Respiratory muscle performance screening for infectious disease management following COVID-19: a highly pressurized situation. Am J Med 133: 1025–1032, 2020. doi:10.1016/j.amjmed.2020.04.003. Crossref | PubMed | ISI | Google ScholarREFERENCES1. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar2. González-Rayas JM, Rayas-Gómez AL, García-González JJ, González-Yáñez JM, Hernández-Hernández JA, López-Sánchez RC. COVID-19 and ACE -inhibitors and angiotensin receptor blockers-: The need to differentiate between early infection and acute lung injury. Rev Colomb Cardiol 27: 129–131, 2020. doi:10.1016/j.rccar.2020.04.005.Crossref | Google Scholar3. Guidon AC, Amato AA. COVID-19 and neuromuscular disorders. Neurology 94: 959–969, 2020. doi:10.1212/WNL.0000000000009566. Crossref | PubMed | ISI | Google Scholar4. Powers SK, Lynch GS, Murphy KT, Reid MB, Zijdewind I. Disease-induced skeletal muscle atrophy and fatigue. Med Sci Sports Exerc 48: 2307–2319, 2016. doi:10.1249/MSS.0000000000000975. Crossref | PubMed | ISI | Google Scholar5. Severin R, Arena R, Lavie CJ, Bond S, Phillips SA. Respiratory muscle performance screening for infectious disease management following COVID-19: a highly pressurized situation. Am J Med 133: 1025–1032, 2020. doi:10.1016/j.amjmed.2020.04.003. Crossref | PubMed | ISI | Google ScholarSARS-CoV-2 AND SKELETAL MUSCLE FUNCTION: POTENTIAL LONG-TERM RAMIFICATIONS FOR EXERCISE (IN)TOLERANCEDaniel M. Hirai,1 Michael D. Belbis,1 Michael J. Holmes,1 Nainoa Calvo,2 and Scott K. Ferguson2.Author Affiliations1Department of Health and Kinesiology, Purdue University, West Lafayette, Indiana.2Department of Kinesiology and Exercise Science, College of Natural and Health Sciences, University of Hawaii at Hilo, Hilo, Hawaii.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.REFERENCES1. Cabello-Verrugio C, Morales MG, Rivera JC, Cabrera D, Simon F. Renin-angiotensin system: an old player with novel functions in skeletal muscle. Med Res Rev 35: 437–463, 2015. doi:10.1002/med.21343. Crossref | PubMed | ISI | Google Scholar2. de Gasparo M. Angiotensin II and nitric oxide interaction. Heart Fail Rev 7: 347–358, 2002. doi:10.1023/A:1020714518246. Crossref | PubMed | Google Scholar3. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar4. Motta-Santos D, Dos Santos RAS, Oliveira M, Qadri F, Poglitsch M, Mosienko V, Kappes Becker L, Campagnole-Santos MJ, M Penninger J, Alenina N, Bader M. Effects of ACE2 deficiency on physical performance and physiological adaptations of cardiac and skeletal muscle to exercise. Hypertens Res 39: 506–512, 2016. doi:10.1038/hr.2016.28. Crossref | PubMed | ISI | Google Scholar5. Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, Hou C, Wang H, Liu J, Yang D, Xu Y, Cao Z, Gao Z. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care 24: 422, 2020. doi:10.1186/s13054-020-03120-0. Crossref | PubMed | ISI | Google ScholarREFERENCES1. Cabello-Verrugio C, Morales MG, Rivera JC, Cabrera D, Simon F. Renin-angiotensin system: an old player with novel functions in skeletal muscle. Med Res Rev 35: 437–463, 2015. doi:10.1002/med.21343. Crossref | PubMed | ISI | Google Scholar2. de Gasparo M. Angiotensin II and nitric oxide interaction. Heart Fail Rev 7: 347–358, 2002. doi:10.1023/A:1020714518246. Crossref | PubMed | Google Scholar3. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar4. Motta-Santos D, Dos Santos RAS, Oliveira M, Qadri F, Poglitsch M, Mosienko V, Kappes Becker L, Campagnole-Santos MJ, M Penninger J, Alenina N, Bader M. Effects of ACE2 deficiency on physical performance and physiological adaptations of cardiac and skeletal muscle to exercise. Hypertens Res 39: 506–512, 2016. doi:10.1038/hr.2016.28. Crossref | PubMed | ISI | Google Scholar5. Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, Hou C, Wang H, Liu J, Yang D, Xu Y, Cao Z, Gao Z. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care 24: 422, 2020. doi:10.1186/s13054-020-03120-0. Crossref | PubMed | ISI | Google ScholarSARS-CoV-2 AND SKELETAL MUSCLE ACE2: EXERCISE CONTRIBUTIONTiago Fernandes and Edilamar Menezes Oliveira.Author AffiliationsLaboratory of Biochemistry and Molecular Biology of Exercise, School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil.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.REFERENCES1. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar2. Fernandes T, Hashimoto NY, Magalhães FC, Fernandes FB, Casarini DE, Carmona AK, Krieger JE, Phillips MI, Oliveira EM. Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7). Hypertension 58: 182–189, 2011. doi:10.1161/HYPERTENSIONAHA.110.168252. Crossref | PubMed | ISI | Google Scholar3. Fernandes T, Hashimoto NY, Oliveira EM. Characterization of angiotensin-converting enzymes 1 and 2 in the soleus and plantaris muscles of rats. Braz J Med Biol Res 43: 837–842, 2010. doi:10.1590/S0100-879X2010007500088. Crossref | PubMed | ISI | Google Scholar4. Gomes-Santos IL, Fernandes T, Couto GK, Ferreira-Filho JCA, Salemi VMC, Fernandes FB, Casarini DE, Brum PC, Rossoni LV, de Oliveira EM, Negrao CE. Effects of exercise training on circulating and skeletal muscle renin-angiotensin system in chronic heart failure rats. PLoS One 9: e98012, 2014. doi:10.1371/journal.pone.0098012. Crossref | PubMed | ISI | Google Scholar5. Pagliaro P, Penna C. ACE/ACE2 ratio: a key also in 2019 Coronavirus Disease (Covid-19)? [Lausanne]. Front Med (Lausanne) 7: 335, 2020. doi:10.3389/fmed.2020.00335. Crossref | PubMed | ISI | Google ScholarREFERENCES1. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar2. Fernandes T, Hashimoto NY, Magalhães FC, Fernandes FB, Casarini DE, Carmona AK, Krieger JE, Phillips MI, Oliveira EM. Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7). Hypertension 58: 182–189, 2011. doi:10.1161/HYPERTENSIONAHA.110.168252. Crossref | PubMed | ISI | Google Scholar3. Fernandes T, Hashimoto NY, Oliveira EM. Characterization of angiotensin-converting enzymes 1 and 2 in the soleus and plantaris muscles of rats. Braz J Med Biol Res 43: 837–842, 2010. doi:10.1590/S0100-879X2010007500088. Crossref | PubMed | ISI | Google Scholar4. Gomes-Santos IL, Fernandes T, Couto GK, Ferreira-Filho JCA, Salemi VMC, Fernandes FB, Casarini DE, Brum PC, Rossoni LV, de Oliveira EM, Negrao CE. Effects of exercise training on circulating and skeletal muscle renin-angiotensin system in chronic heart failure rats. PLoS One 9: e98012, 2014. doi:10.1371/journal.pone.0098012. Crossref | PubMed | ISI | Google Scholar5. Pagliaro P, Penna C. ACE/ACE2 ratio: a key also in 2019 Coronavirus Disease (Covid-19)? [Lausanne]. Front Med (Lausanne) 7: 335, 2020. doi:10.3389/fmed.2020.00335. Crossref | PubMed | ISI | Google ScholarCOVID-19 SKELETAL MYOPATHY: ROLE OF HAPPY HYPOXIAMatiram Pun1 and Sanjeeb S Bhandari2.Author Affiliations1Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.2Virginia Tech Carilion Department of Emergency Medicine, Roanoke, Virginia.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.REFERENCES1. Archer SL, Sharp WW, Weir EK. Differentiating COVID-19 pneumonia from acute respiratory distress syndrome and high altitude pulmonary edema: Therapeutic implications. Circulation 142: 101–104, 2020. doi:10.1161/CIRCULATIONAHA.120.047915. Crossref | PubMed | ISI | Google Scholar2. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar3. González-Duarte A, Norcliffe-Kaufmann L. Is “happy hypoxia” in COVID-19 a disorder of autonomic interoception? A hypothesis. Clin Auton Res 30: 331–333, 2020. doi:10.1007/s10286-020-00715-z.Crossref | PubMed | ISI | Google Scholar4. Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of Coronavirus Disease 2019. Crit Care Med 48: 1358–1364, 2020. Crossref | PubMed | ISI | Google Scholar5. Wadman M, Couzin-Frankel J, Kaiser J, Matacic C. A rampage through the body. Science 368: 356–360, 2020. doi:10.1126/science.368.6489.356. Crossref | PubMed | ISI | Google ScholarREFERENCES1. Archer SL, Sharp WW, Weir EK. Differentiating COVID-19 pneumonia from acute respiratory distress syndrome and high altitude pulmonary edema: Therapeutic implications. Circulation 142: 101–104, 2020. doi:10.1161/CIRCULATIONAHA.120.047915. Crossref | PubMed | ISI | Google Scholar2. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). doi:10.1152/japplphysiol.00321.2020. Link | ISI | Google Scholar3. González-Duarte A, Norcliffe-Kaufmann L. Is “happy hypoxia” in COVID-19 a disorder of autonomic interoception? A hypothesis. Clin Auton Res 30: 331–333, 2020. doi:10.1007/s10286-020-00715-z.Crossref | PubMed | ISI | Google Scholar4. Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of Coronavirus Disease 2019. Crit Care Med 48: 1358–1364, 2020. Crossref | PubMed | ISI | Google Scholar5. Wadman M, Couzin-Frankel J, Kaiser J, Matacic C. A rampage through the body. Science 368: 356–360, 2020. doi:10.1126/science.368.6489.356. Crossref | PubMed | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation CollectionsAPS Cross-Journal CollectionsCoronavirus-Related Papers Related ArticlesThe interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies 07 Oct 2020Journal of Applied PhysiologyLast Word on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies 07 Oct 2020Journal of Applied PhysiologyCited ByAngiotensin II Promotes Skeletal Muscle Angiogenesis Induced by Volume-Dependent Aerobic Exercise Training: Effects on miRNAs-27a/b and Oxidant–Antioxidant Balance28 March 2022 | Antioxidants, Vol. 11, No. 4Last Word on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathiesPeter J. Ferrandi, Stephen E. Alway, and Junaith S. Mohamed7 October 2020 | Journal of Applied Physiology, Vol. 129, No. 4 More from this issue > Volume 129Issue 4October 2020Pages 868-871 Copyright & PermissionsCopyright © 2020 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00775.2020PubMed33027604History Received 8 September 2020 Accepted 8 September 2020 Published online 7 October 2020 Published in print 1 October 2020 Metrics