Effect of physical activity on COVID-19 and underlying mechanisms

The infection of the cytopathic virus, like SARS-CoV-2, initiates with viral entry, in which the virion recognizes a host cell receptor and fuses its membrane with the host cell membrane.[6] Several studies identified that cells with high ACE2 and transmembrane protease serine 2 (TMPRSS2) have strong SARS-CoV-2 binding capacity and are vulnerable to infection.[7] ACE regulates the renin-angiotensin-aldosterone system (RAS), which contains renin, angiotensinogen (ANG), angiotensin I (Ang I), Ang II, and ACE10. Hence, it has been proven that the spike glycoprotein (S) of SARS-CoV-2 binds to ACE2 expressed in epithelial cells of the lung and small intestine.[8] Such that ACE2 serves as a receptor for the virus causing COVID-19.[9] The coronavirus S protein is constituted of S1 and S2 functional subunits with the S1/S2 cleavage site.[9] The viral S glycoprotein interacts with the ectodomain of ACE2 and the complex is endocytosed, leading to decreased surface ACE2 expression.[9] The N-terminal S1 subunit interacts with the ACE2 receptor for initial docking, while the carboxyl-terminal S2 subunit induces the proteolytic fusion between the viral envelope and the cellular membrane by conformational reconfiguration.[10] Subsequently, TMPRSS2 cleaved the multibasic S1/S2 site of the S glycoprotein protein.[10] The association between ACE2 downregulation with the systemic RAS imbalance stimulates the development of multiorgan impairment from SARS-CoV-2 infections.[11]

As COVID-19 was caused by a novel coronavirus, people only counted on their innate immune system in the early COVID-19 pandemic.[12] However, given that the defense against viral infection depends upon a competent adaptive response, understanding adaptive immunity in SARS-CoV-2 immune responses is critical. The immune systems contain the innate immunity activation and memory of three adaptive response compartments; B cells (antibodies synthesis), CD8+ (killer T cells), and CD4+ (helper T cells) lymphocytes.[12] Those CD8+ and CD4+ T lymphocytes recognize viral peptides attached to human leukocyte antigen (HLA) class I and II molecules, respectively.[13] CD8+ T cells directly attack and kill infected cells, whereas CD4+ T lymphocytes help B cells and CD8+ T cells and differentiate into helper and effector cells. CD4+ T cells also take charge of cytokine production to drive immune cell recruitment and migration through cytokine secretion. Dysregulation of innate immune response with excessive inflammatory cytokine production causes severe COVID-19 disease.[11] For SARS-CoV-2 infection, TNF-α, interleukin (IL)-6, and IFN-α/-γ pro-inflammatory cytokines are secreted. As COVID-19 deteriorates, CD4+ T lymphocytes and CD8+ T lymphocytes gradually decline.[14] Indeed, lymphopenia and reduced CD4+ and CD8+ cell counts are significant manifestations of SARS-CoV-2 infection.[14]

In the first months of the epidemic, it was confined to China, and its impact on the Chinese economy caused production disruptions and declines. Consequently, the global supply chain was disrupted. A few months later, the outbreak spread worldwide, and eventually, the COVID-19 pandemic became a severe threat to the world and negatively affected most aspects of our lives. Especially measures to prevent the spread of COVID-19, such as social distancing and home confinement, changed lifestyle behavior for children and adolescents.[15] Children could not access school-based physical activities (PAs), including physical education, recess, and commuting to and from school. Besides, classes for youth physical education and activities such as gymnastics, dance, and martial arts have also been canceled or postponed. Several studies confirmed that the COVID-19 outbreak reduced PA and increased prolonged sedentary behavior.[16] Those radical changes in lifestyle behaviors make the loss of muscular and cardiorespiratory fitness, weight gain, poor sleep quality, and poor academic achievements.[16]

Indeed, the ACE2 protein mediates the SARS-CoV-2 entry and regulation of angiotensin II. Still, the mechanism underlying that PA positively influences the progression of COVID-19 is unknown. One of the studies reported that PA causes chronic alteration in the concentration of ACE2 serum.[28] The result of the study showed that PA makes higher skeletal muscle ACE2 expression and lower flowing ACE2 levels.[28] Thereupon, ACE2 proteins expressed in skeletal muscle would not be bound to SARS-CoV-2 inhaled through the nasal or lung. Therefore, decreased concentration of ACE2 on the epithelial cell of the lung and small intestine would reduce the risk of COVID-19 infection.

According to the studies, the most prominent characteristic of confirmed cases of COVID-19 in China was lymphocytopenia (83.2%).[29] Because the white blood cell (WBC) counts in peripheral blood decreased.[29] Also, SARS-CoV-2 attacks the respiratory system, causing pneumonia and lymphopenia in infected individuals. Among the WBC, neutrophils and lymphocytes are critical components of the immune response to coordinate inflammation. It is known that the concentration of neutrophils, leukocytes, and all lymphocyte subsets increases, but the magnitude varies based on the PA intensity and duration throughout the workout period.[30] Moderate-intensity PA facilitates cellular immunity, while prolonged and vigorous-intensity PA without proper rest can activate decreased cellular immunity, increasing the propensity for diseases[30]. Both the number of CD4+ T and CD8+ T lymphocytes increase during PA, protecting against SARS-CoV-2 by attacking the virus and memorizing it. A relatively more significant increase in CD8+ T lymphocytes than CD4+ T resulted in depressed CD4/CD8 ratios. For cytokines, PA induces the release of a cascade of inflammatory cytokines such as IL-6, IL-1 receptor antagonists, TNF receptors, and IL-10.[30] With these increased lymphocyte populations throughout the PA, the immune system would be improved to help to fight against COVID-19.