Role of mTORC1 in BDK-Mediated Improvements in Cardiometabolic Parameters

Abstract

Multiple recent studies from various labs have shown improvements in several endpoints in pre-clinical models after treatment with the branched chain ketoacid dehydrogenase kinase (BDK) inhibitor BT2, yet there is still a lack of mechanistic understanding underlying these improvements. Because BT2 leads to decreased plasma and skeletal muscle levels of branched chain amino acids (BCAAs) and branched chain ketoacids (BCKAs) (Neinast et al. 2019), which activate the mammalian target of rapamycin complex 1 (mTORC1), there may also be a decrease in mTORC1 signaling with BT2 in in vivo models of cardiometabolic disease. Increased mTORC1 activity has been implicated in many metabolic disorders (Cheon and Cho 2021; Liu and Sabatini 2020). The goal of this research was to understand whether positive effects seen in multiple animal models of cardiovascular and metabolic disorders with BDK inhibition such as reduced hyperglycemia and hyperinsulinemia may be due to decreased mTORC1 activity. Here, it is demonstrated that in a mouse model of cardiometabolic disease, mTORC1 signaling is decreased as measured by phosphorylation of the mTORC1 downstream target, S6 ribosomal protein, in heart tissue after chronic treatment of BT2. However, compared to healthy mice on standard chow diet, mice with cardiometabolic disease on 60% high fat diet (HFD) had a decrease in mTORC1 activity, which may be explained by the differences in diet (Kimball et al. 2015). Mice treated with BT2 displayed improvements in glycemia and hyperinsulinemia, but acute co-treatment of mice with BT2 and mTORC1 activator NV-5138 resulted in a trending increase in glucose and insulin compared to mice treated with BT2 alone. These results suggest that BT2 and BDK inhibition-mediated positive effects observed in metabolic disease may be in part due to decreased mTORC1 activity.