Abstract
The African naked mole-rat (Heterocephalus glaber) is unique among mammals, displaying extreme longevity, resistance to cardiovascular disease and an ability to survive long periods of extreme hypoxia. The metabolic adaptations required for resistance to hypoxia are hotly debated and a recent report provides evidence that they are able to switch from glucose to fructose driven glycolysis in the brain. However, other systemic alterations in their metabolism are largely unknown. In the current study, a semi-targeted high resolution 1H magnetic resonance spectroscopy (MRS) metabolomics investigation was performed on cardiac tissue from the naked mole-rat (NMR) and wild-type C57/BL6 mice to better understand these adaptations. A range of metabolic differences was observed in the NMR including increased lactate, consistent with enhanced rates of glycolysis previously reported, increased glutathione, suggesting increased resistance to oxidative stress and decreased succinate/fumarate ratio suggesting reduced oxidative phosphorylation and ROS production. Surprisingly, the most significant difference was an elevation of glycogen stores and glucose-1-phosphate resulting from glycogen turnover, that were completely absent in the mouse heart and above the levels found in the mouse liver. Thus, we identified a range of metabolic adaptations in the NMR heart that are relevant to their ability to survive extreme environmental pressures and metabolic stress. Our study underscores the plasticity of energetic pathways and the need for compensatory strategies to adapt in response to the physiological and pathological stress including ageing and ischaemic heart pathologies.
Highlights
The naked mole-rat (NMR) (Heterocephalus glaber) is a mouse-sized eusocial African rodent that displays a range of unusual physiological characteristics from resistance to cardiovascular disease to extreme longevity [1,2,3]
High resolution 1H magnetic resonance spectroscopy (MRS) based metabolomic analysis of NMR heart tissue revealed distinctly different metabolomic profiles compared to C57/BL6 hearts and changes in several key metabolites were observed
A significant difference in myocardial glycogen levels was observed in NMRs compared to Wistar rats, the latter was not significantly different to that found in C57/BL6 mice
Summary
The naked mole-rat (NMR) (Heterocephalus glaber) is a mouse-sized eusocial African rodent that displays a range of unusual physiological characteristics from resistance to cardiovascular disease to extreme longevity [1,2,3]. The NMR can undergo rapid increases in metabolic rate to meet energy demand associated with digging through compacted soils in its xeric natural habitat with patchy food distribution [11] They display a low baseline metabolic rate, and a recent study by Pamenter et al [10] has shown that NMRs exhibit a clear decrease in metabolic rate in situations of acute hypoxia, emphasizing their ability to physiologically react to the prevailing conditions. NMRs have low basal cardiac function accompanied by morphological traits such as cardiomyocyte hypertrophy, which is commonly associated with cardiac pathology in the Murinae and in humans [12,13,14,15] They do not develop the cardiac disease and unlike pathologically remodelled hearts have enhanced contractile reserve upon increased demand [12,13,14,15]. What fuels these critical functional adaptations as well as what kind of metabolic adaptations and associated mechanisms render NMR hearts resistant to hypoxic injury and senescence remain unknown
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