Metabolomic Analysis of Carbohydrate and Amino Acid Changes Induced by Hypoxia in Naked Mole-Rat Brain and Liver

Hypoxia poses a major physiological challenge for mammals and has significant impacts on cellular and systemic metabolism. As with many other small rodents, naked mole-rats (NMRs; Heterocephalus glaber), who are among the most hypoxia-tolerant mammals, respond to hypoxia by supressing energy demand (i.e., through a reduction in metabolic rate mediated by a variety of cell- and tissue-level strategies), and altering metabolic fuel use to rely primarily on carbohydrates. However, little is known regarding specific metabolite changes that underlie these responses. We hypothesized that NMR tissues utilize multiple strategies in responding to acute hypoxia, including the modulation of signalling pathways to reduce anabolism and reprogram carbohydrate metabolism. To address this question, we evaluated changes of 64 metabolites in NMR brain and liver following in vivo hypoxia exposure (7% O2, 4 h). We also examined changes in matched tissues from similarly treated hypoxia-intolerant mice. We report that, following exposure to in vivo hypoxia: (1) phenylalanine, tyrosine and tryptophan anabolism are supressed both in NMR brain and liver; (2) carbohydrate metabolism is reprogramed in NMR brain and liver, but in a divergent manner; (3) redox state is significantly altered in NMR brain; and (4) the AMP/ATP ratio is elevated in liver. Overall, our results suggest that hypoxia induces significant metabolic remodelling in NMR brain and liver via alterations of multiple metabolic pathways.

Characterization of the Naked Mole Rat Incisors: Chemical Composition, Microstructure and Mechanical Properties

The naked mole rat incisors (NMRI) exhibit excellent mechanical properties, which makes it a good prototype for design and fabrication of bionic mechanical systems and materials. In this work, we characterized the chemical composition, microstructure and mechanical properties of NMRI, and further compared these properties with the laboratory rat incisors (LRI). We found that (1) Enamel and dentin are composed of organic matter, inorganic matter and water. The ratio of Ca/P in NMRI enamel is higher than that of LRI enamel. (2) The dentin has a porous structure. The enamel has a three-dimensional reticular structure, which is more complex, regular and denser than the lamellar structure of LRI enamel. (3) Enamel has anisotropy. Its longitudinal nano-hardness is greater than that of transverse nano-hardness, and both of them are higher than that of LRI enamel. Their nano-hardness and elastic modulus increase with the increment of distance from the enamel-dentin boundary. The nano-hardness of dentin is smaller than that of enamel. The chemical composition and microstructure are considered to be the reasons for the excellent properties of NMRI. The chemical composition and unique microstructure can provide inspiration and guidelines for the design of bionic machinery and materials.

Naked mole-rat brown fat thermogenesis is diminished during hypoxia through a rapid decrease in UCP1

Naked mole-rats are among the most hypoxia-tolerant mammals. During hypoxia, their body temperature (Tb) decreases via unknown mechanisms to conserve energy. In small mammals, non-shivering thermogenesis in brown adipose tissue (BAT) is critical to Tb regulation; therefore, we hypothesize that hypoxia decreases naked mole-rat BAT thermogenesis. To test this, we measure changes in Tb during normoxia and hypoxia (7% O2; 1–3 h). We report that interscapular thermogenesis is high in normoxia but ceases during hypoxia, and Tb decreases. Furthermore, in BAT from animals treated in hypoxia, UCP1 and mitochondrial complexes I-V protein expression rapidly decrease, while mitochondria undergo fission, and apoptosis and mitophagy are inhibited. Finally, UCP1 expression decreases in hypoxia in three other social African mole-rat species, but not a solitary species. These findings suggest that the ability to rapidly down-regulate thermogenesis to conserve oxygen in hypoxia may have evolved preferentially in social species.

The Cost of Reproduction in a Cooperatively Breeding Mammal: Consequences of Seasonal Variation in Rainfall, Reproduction, and Reproductive Suppression

Biological investments, such as reproduction, are influenced by both biotic and abiotic factors and their interactions. The trade-off between reproduction and survival has been well established. Seasonally breeding species, therefore, may exhibit variations in these trade-offs, but there is a dearth of knowledge concerning this. This study investigated the physiological cost of reproduction (measured through oxidative stress) across seasons in the cooperatively breeding highveld mole-rat (Cryptomys hottentotus pretoriae), one of the few seasonal breeding mole-rats. Oxidative stress indicates elevated reactive oxygen species (ROS) levels, which can overwhelm antioxidant defences resulting in damaged proteins, lipids and DNA, which overall can reduce longevity and compromise reproduction. Oxidative markers such as total oxidant status (TOS-measure of total peroxides present), total antioxidant capacity (TAC), oxidative stress index (OSI), and malondialdehyde (MDA) are utilised to measure oxidative stress. In this study, breeding and non-breeding male (NBM) and female mole-rats were captured during the dry season (breeding period) and wet season (non-breeding period). There was an apparent cost of reproduction in the highveld mole-rat; however, the seasonality pattern to the cost of reproduction varied between the sexes. Breeding females (BFs) had significantly higher MDA during the breeding period/dry season in comparison to the non-breeding period/wet season; this is possibly a consequence of bearing and nursing offspring. Contrastingly, breeding males (BMs) showed increased oxidative damage in the non-breeding/wet season compared to the breeding/dry season, possibly due to increased activities of protecting their mating rights for the next breeding/dry season, but this was not significant. Interestingly, during the non-breeding period/wet season, non-breeding females (NBFs) are released from their reproductive suppression, which resulted in increases in TOS and OSI, which again indicated that just the mere ability to be able to breed results in a cost (oxidative stress). Therefore we can speculate that highveld mole-rats exhibited seasonal variation in redox balance brought about by variation in abiotic variables (e.g., rainfall), physiology and behaviour. We conclude that physiological changes associated with reproduction are sufficient to induce significant acute oxidative stress in the plasma of female highveld mole-rats, which become alleviated following transition to the non-breeding season/wet period suggesting a possible hormetic effect.

An Enhanced Naked Mole Rat Algorithm for Optimal Cross-Layer Solution for Wireless Underground Sensor Networks

Nature-inspired algorithms serve as the backbone of modern computing technology, and over the past three decades, the field has grown enormously. Many applications were solved by such algorithms and are replacing the traditional classical optimization processes. A recent naked mole-rat algorithm (NMRA) was proposed based on the mating patterns of naked mole-rats. This algorithm proved its worth in terms of competitiveness and application to various domains of research. The aim was to propose an algorithm based on NMRA, named enhanced NMRA (ENMRA), by mitigating the problems that this algorithm suffers from: slow convergence, poor exploration, and local optima stagnation. To enhance the exploration capabilities of basic NMRA, grey wolf optimization (GWO)-based search equations were employed. Exploitation was improved using population division methods based on local neighborhood search (LNS) and differential evolution (DE) equations. To avoid the local stagnation problem, a neighborhood search strategy around the best individual was utilized. Such improvements help the new variant to solve highly challenging optimization problems in contrast to existing algorithms. The efficacy of ENMRA was evaluated using CEC 2019 benchmark test suite. The results were statistically analyzed by the Wilcoxon rank-sum test and Friedman rank (f-rank) test. The resulting analysis proved that ENMRA is superior to the competitive algorithms for test functions CEC 2019 with overall effectiveness of 60.33%. Moreover, the real-world optimization problem from underground wireless sensor networks for an efficient cross-layer solution was also used to test the efficiency of ENMRA. The results of comparative study and statistical tests affirmed the efficient performance of the proposed algorithm.

Isolation and characterization of neural stem/progenitor cells in the subventricular zone of the naked mole-rat brain

Background The naked mole-rat (NMR) is the longest-lived rodent with a maximum lifespan of more than 37 years and shows a negligible senescence phenotype, suggesting that tissue stem cells of NMRs are highly capable of maintaining homeostasis. However, the properties of NMR tissue stem cells, including neural stem cells (NSCs), are largely unclear. Methods Neural stem/progenitor cells (NS/PCs) were isolated from the subventricular zone of the neonate NMR brain (NMR-NS/PCs) and cultured in neurosphere and adherent culture conditions. Expression of NSC markers and markers of neurons, astrocytes, and oligodendrocytes was analyzed by immunocytochemistry. In adherent culture conditions, the proliferation rate and cell cycle of NMR-NS/PCs were assessed and compared with those of NS/PCs from mice (mouse-NS/PCs). The DNA damage response to γ-irradiation was analyzed by immunocytochemistry and reverse transcription-quantitative PCR. Results NMR-NS/PCs expressed several NSC markers and differentiated into neurons, astrocytes, and oligodendrocytes. NMR-NS/PCs proliferated markedly slower than mouse-NS/PCs, and a higher percentage of NMR-NS/PCs than mouse-NS/PCs was in G0/G1 phase. Notably, upon γ-irradiation, NMR-NS/PCs exhibited a faster initiation of the DNA damage response and were less prone to dying than mouse-NS/PCs. Conclusions NMR-NS/PCs were successfully isolated and cultured. The slow proliferation of NMR-NS/PCs and their resistance to DNA damage may help to prevent stem cell exhaustion in the brain during the long lifespan of NMRs. Our findings provide novel insights into the mechanism underlying delayed aging of NMRs. Further analysis of NMR tissue stem cells may lead to the development of new strategies that can prevent aging in humans.