SARS-COV-2, or COVID-19, is a respiratory virus that enters tissues via the angiotensin-converting enzyme 2 (ACE2) receptor and is primed and activated by transmembrane protease, serine 2 (TMPRSS2). An interesting dichotomy exists regarding the preventative/therapeutic effects of exercise on COVID-19 infection and severity. Although exercise training has been shown to increase ACE2 receptor levels (increasing susceptibility to COVID-19 infection), it also lowers cardiovascular risk factors, systemic inflammation, and preserves normal renin-angiotensin system axis equilibrium, which is considered to outweigh any enhanced risk of infection by decreasing disease severity. The goal of this study was to determine the effects of chronic exercise training, sex, and Western diet on ACE2 and TMPRSS2 mRNA levels in preclinical swine models of heart failure. We hypothesized chronic exercise training and male sex would increase ACE2 and TMPRSS2 mRNA levels. A retrospective analysis was conducted in previously completed studies including: 1) sedentary and exercise-trained aortic banded male, intact Yucatan mini-swine (n = 6 or 7/group); 2) ovariectomized and/or aortic banded female, intact Yucatan mini-swine (n = 5-8/group); and 3) lean control or Western diet-fed aortic banded female, intact Ossabaw swine (n = 4 or 5/group). Left ventricle, right ventricle, and coronary vascular tissue were evaluated using qRT-PCR. A multivariable regression analysis was used to determine differences between exercise training, sex, and Western diet. Chronic exercise training did not alter ACE2 or TMPRSS2 level regardless of intensity. ACE2 mRNA was altered in a tissue-specific manner due to sex and Western diet. TMPRSS2 mRNA was altered in a tissue-dependent manner due to sex, Western diet, and pig species. These results highlight differences in ACE2 and TMPRSS2 mRNA regulation in an experimental setting of preclinical heart failure that may provide insight into the risk of cardiovascular complications of SARS-COV-2 infection.NEW & NOTEWORTHY This retrospective analysis evaluated the impact of exercise, sex, and diet on ACE2 and TMPRSS2 mRNA levels in preclinical swine heart failure models. Unlike normal exercise intensities, exercise training of an intensity tolerable to a patient with heart failure had no influence on ACE2 or TMPRSS2 mRNA. In a tissue-specific manner, ACE2 mRNA levels were altered due to sex and Western diet, whereas TMPRSS2 mRNA levels were sensitive to sex, Western diet, and pig species.
Keywords: ACE2; TMPRSS2; exercise; heart failure; sex.