Fasting-induced decrease in mouse cardiac pyruvate dehydrogenase enzyme activity associated with increased tolerance to lethal hypoxia

Abstract

The global mortality of patients with cardiovascular diseases annually exceeds tens of millions. This study tested the hypothesis that fasting-induced down-regulation of pyruvate dehydrogenase (PDH) enzyme activity preconditions mice to improve survival during acute hypoxia. PDH is a major supplier of substrates to the TCA cycle but also generates toxic reactive oxygen species (ROS). PDH inhibition could inhibit ROS production, thereby contributing to fasting-induced protection against hypoxic death. FVB mice fasted for 48 hr displayed 100% survival during 1 hr 5% oxygen exposure compared to their fed counterparts that perished within 20 min, however, fasted C57BL/6J (B6) survival was minimal. Fasting induced an upregulation of PDH kinase 4 (PDK4) gene expression, increased PDH E1? site 3 phosphorylation, and decreased PDH activity in cardiac tissue of both mouse strains. Therefore, although PDH likely plays a role in hypoxia tolerance, it is not the primary mechanism of survival of the FVB mice.