Naked mole-rats to mice: metabolic reprogramming to prevent ischaemic injury

ongoing

The overarching aim of this proposal is to identify unique features of naked mole-rat cardiac metabolism that serve as advantageous adaptations to deal with a hypoxic environment, a state relevant to heart disease. Coronary heart disease is a leading cause of death and its pathogenesis has been linked to metabolic abnormalities. The naked mole–rat has recently emerged as a rodent model of interest to biomedicine due to its extraordinarily long and healthy lifespan (>36 years). Naked mole-rats exhibit various atypical cardiac features including a remodelled metabolism that serve as adaptations to their extremely hypoxic and hypercapnic environment, and also contribute to the negligible decline in heart function with age. I will use “omics” technologies to examine the genetic, epigenetic and post-translational features underlying naked mole-rat rewired metabolism, hypoxia tolerance and myocardial fitness. I have shown that the naked mole-rat can survive extended periods under extreme hypoxia without apparent damage, by switching its metabolism to utilise fructose. Use of fructose in ischaemic conditions could therefore prove beneficial in other mammals. I will assess whether enhancing fructose metabolism via transgenic mouse models is protective under ischaemic conditions. I have shown that the transcriptional landscape of the naked mole-rat myocardium has preserved several neonatal-like features. Since neonatal mammalian heart has regenerative capacity, a quality that is quickly lost after birth, naked mole-rats may be the first adult mammalian model for heart regeneration. This project will measure regenerative capacity of the adult naked mole-rat heart and the mechanisms by which it may retain its proliferative competency. By introducing these features into the mouse I aim to validate and understand the benefit of these unique traits in promoting a healthy myocardium with possibilities for translating these discoveries into novel therapeutic strategies in man.