Several mechanisms may explain how exercise training mechanistically confers protection against coronavirus disease 2019 (COVID-19). Here we propose two new perspectives through which cardiorespiratory fitness may protect against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Physical exercise-activated adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling induces endothelial nitric oxide (NO) synthase (eNOS), increases NO bio-availability, and inhibits palmitoylation, leading to specific and immediate SARS-CoV-2 protection. AMPK signaling also induces angiotensin 1-7 release and enhances eNOS activation thus further mediating cardio- and reno-protection. Irisin, a myokine released from skeletal muscles during aerobic exercise, also participates in the AMPK/Akt-eNOS/NO pathway, protects mitochondrial functions in endothelial cells, and antagonizes renin angiotensin system proinflammatory action leading to reductions in genes associated with severe COVID-19 outcomes. Collectively, all the above findings point to the fact that increased AMPK and irisin activity through exercise training greatly benefits molecular processes that mediate specific, immediate, and delayed SARS-CoV-2 protection. Maintaining regular physical activity levels is a safe and affordable lifestyle strategy against the current and future pandemics and may also mitigate against obesity and cardiometabolic disease syndemics. Move more because a moving target is harder to kill.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of the coronavirus disease 2019 (COVID-19), has to date (December 2021) infected over 270 million people worldwide and the death tally approaches 5.5 million[1]. Evolutionary evidence supports the survival of the fittest through natural selection for pathogen resistance, with effects mediated through younger age, lifestyle choices and importantly, genetics[2]. Epidemiological data support a lower COVID-19 incidence and severity in children and adolescents[3], individuals with high cardiorespiratory fitness (CRF) and muscle strength[4] as well as certain protective erythropoietin (EPO) augmenting genetic variants[3]. At the other end of the spectrum, inactivity, obesity, insulin resistance, diabetes, and hypertension, are associated with worse SARS-CoV-2 infection course and disproportionate COVID-19 mortality risk[5,6]. Public policies should promote increased physical activity and endeavor to increase the overall physical fitness in society by all available means. This is especially imperative for the population groups associated with worse SARS-CoV-2 prognosis[7]. The scope of this minireview is to focus on the mechanistical perspectives of two novel pathways, namely adenosine monophosphate (AMP)-activated protein kinase (AMPK) and irisin, through which exercise training may mitigate against SARS-CoV-2 infection and improve COVID-19 prognosis.

We conducted a PubMed literature search for publications in the English language since the start of the pandemic until September 2021, using the keywords: “AMPK”; “Irisin”; “physical exercise”; “renin angiotensin system (RAS)”; “angiotensin-converting enzyme 2 (ACE2)”; “nitric oxide (NO)”; “endothelial nitric oxide (NO) synthase (eNOS)”; “beta common receptor (βcR)”; “SARS-CoV-2”; and “COVID-19”. We noticed a veritable dearth of publications, especially when the keywords “eNOS”, “Irisin”, “AMPK” were used in different combinations together with “physical exercise” and “SARS-CoV-2 or COVID-19” which prompted us to focus on AMPK/eNOS and Irisin. Those pathways are known for their cardiometabolic, and vascular protective properties and suggest concrete mechanisms that offer immediate and delayed SARS-CoV-2 protection[8].

Several reviews have described numerous immune mechanisms which may explain how exercise training mechanistically confers protection against COVID-19. First, exercise downregulates the expression/activation of proinflammatory Toll-like receptors (TLR)[5]. Second, exercise training demonstrates an anti-inflammatory cytokine profile with increased levels of anti-inflammatory interleukin (IL)-10, IL-1 receptor antagonist (IL-1ra), and IL-37, which in turn inhibits the TLR-inflammation pathway and counteracts the inflammatory response induced by the inflammasomes[5]. In general, exercise promotes the recirculation of key immune cells and mediates an anti-inflammatory and antioxidant state through multiple mechanisms[5]. Effective rehabilitation programs for sarcopenia, could reduce inflammation and the need for IL-37 to exert its negative feedback to control the release of inflammatory cytokines[9].

Evolution arms us with ingenious and adaptive defense structures - our immune system, musculature, and cardiovascular system. Increased CRF through regular aerobic exertion and resistance exercise, greatly benefits all the above systems promoting survival and longevity[5]. Regular physical exercise enhances vaccination response and immunoprotection[5]. Maintaining regular physical activity levels along with prudent and balanced nutrition are safe and affordable lifestyle strategies against the current and future pandemics. Physical exercise may also reverse insulin resistance, alleviate hypertension, and mitigate against obesity and cardiometabolic disease syndemics[39]. While observing social distancing, exercise is still possible in public indoor spaces or outdoors. Exercise prescription for vulnerable groups and free or subsidized use of digital technology with online platforms delivering exercise classes could be employed to achieve the recommended exercise guidelines. For greater health benefits, 300 min of aerobic activity is recommended along with strength training exercises for all major muscle groups at least two times a week[40]. “Work from home” directives along with time savings from daily commuting have potentially freed up time for exercise that can be achievable in the home environment. The beneficial effects of exercise training in communicable and non-communicable disease prevention must remain central when deciding appropriate public health policies and subsidies. Government bodies should heed the Damoclean warning in this pandemic of the excess mortality threatening over 500 million people affected with obesity and diabetes worldwide or risk new hecatombs. We may have to learn to live with the virus for many years to come. It is thus imperative, on an individual level, to devise personal strategies for exercise training that do not depend on access to public gymnasiums. The takeaway message is once again to move more because a moving target is harder to kill.