4 Discussion
In this study, we conducted a bidirectional two-sample MR study to explore the causal association between sarcopenia (ASM, LH, RH, WP) and COVID-19. After Bonferroni correction, except for WP, there were no significant associations observed between ASM, LH or RH and COVID-19. Nevertheless, the causal effect of WP on COVID-19 disappeared after adjusting for BMI.
According to the IVW results, slow WP was significantly associated with an increased risk of COVID-19 infection. Consistent with our study, a prospective study indicated that the illness of patients with COVID-19 infection tended to get aggravated more frequently among patients with fatigue and slow WP[37]. The role of WP in the development of COVID-19 may attribute to the decline in immune function caused by low physical activity and longtime of bed rest during the COVID-19 pandemic[38]. Research indicated that SARS-CoV-2 can survive in host cells by evading the host immune mechanism to cause COVID-19 infection[39]. If the immune function of patients with sarcopenia was declined, not only the symptoms of patients may be aggravated, but also the risk of COVID-19 infection may get increased. Studies found that WP can be influenced by age and BMI[40, 41]. Considering that the GWAS data stratified by age were not available, and BMI can reflect physical conditions including age directly or indirectly, we re-analyzed the causal effect of WP on COVID after adjusting for BMI.
As the results showed, after adjusting by BMI, there was no significant relationship between WP and COVID-19, suggesting that BMI is involved in the effect of WP on COVID-19. As we all know, WP and COVID-19 were both associated with BMI [42, 43], and the causal association between them may be due to the mediating role of BMI. An MR study pointed out that genetically predicted higher BMI is significantly linked with an elevated probability of COVID-19 infection and hospitalization[44]. Another prospective community-based cohort study found a linear increase in the risk of hospitalization and death caused by severe COVID-19 at a BMI above 23 kg/m2[45]. Furthermore, some studies found that patients with BMI outside the normal range are more susceptible to COVID-19[46, 47]. Moreover, it was also revealed that too high or low BMI usually led to slow WP in patients with COVID-19[42]. It may attribute to the association of adipose tissue with complement system hyperactivation, chronic inflammation and the presence of other complications[48], which damage skeletal muscle. Therefore, we speculate that the effect of WP on COVID-19 may be caused by the role of BMI.
In this study, we failed to figure out the causal effect of ASM, LH or RH on COVID-19. However, a previous observational study indicated that increased hand grip strength was related to shorter severe COVID-19 inpatient stays[49]. In another retrospective observational study, higher hand grip strength was associated with lower COVID-19 severity, which acted as the protective factor for severe COVID-19[50]. Additionally, due to the reduction of muscle mass of the patients with low ASM, the adipose tissue gradually replaced the muscle fibers[13]. The replacement consumes the adipose tissue, which was suggested to be a probable risk factor for COVID-19 infection[43], and it may be helpful to decrease the prevalence of COVID-19. Due to the studies above almost observational studies, the conclusions cannot completely exclude the possibility of confounding factors, which led to the inconsistency.
Furthermore, the reverse MR study showed that there was no connection between COVID-19 and sarcopenia, which differs from the results of others. In a cross-sectional study, it has been proposed that patients with COVID-19 had lower mean hand grip strength values[51]. It may attribute to the strong injurious stimulation of acute severe inflammation caused by COVID-19 infection[38]. Among the various harmful effects of inflammation, the increased concentration of c-reactive protein (CRP), TNF-alpha and IL-6 have been the strongest connection with the reduction of skeletal muscle fibers[52]; and the high level of inflammatory factors may impact the acute changes of the amount, structure and function of skeletal muscles[53], which causes sarcopenia. The results in this study differed from previous studies possibly because these studies were cross-sectional studies, which only found the short-term, reversible and non-pathogenic effects resulting from fatigue caused by COVID-19, rather than the direct causal relationship.