The African naked mole-rat's () social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.

Noxious substances, called algogens, cause pain and are used as defensive weapons by plants and stinging insects. We identified four previously unknown instances of algogen-insensitivity by screening eight African rodent species related to the naked mole-rat with the painful substances capsaicin, acid (hydrogen chloride, pH 3.5), and allyl isothiocyanate (AITC). Using RNA sequencing, we traced the emergence of sequence variants in transduction channels, like transient receptor potential channel TRPA1 and voltage-gated sodium channel Nav1.7, that accompany algogen insensitivity. In addition, the AITC-insensitive highveld mole-rat exhibited overexpression of the leak channel NALCN (sodium leak channel, nonselective), ablating AITC detection by nociceptors. These molecular changes likely rendered highveld mole-rats immune to the stings of the Natal droptail ant. Our study reveals how evolution can be used as a discovery tool to find molecular mechanisms that shut down pain.

Energy metabolism follows a diurnal pattern responding to the light/dark cycle and food availability. This study investigated the impact of restricting feeding to the daylight hours and feeding a high fat diet on circadian clock (bmal1, dbp, tef and e4bp4) and metabolic (pepck, fas, ucp3, pdk4) gene expression and markers of energy metabolism in muscle and liver of rats. The results show that in chow-fed rats switched to daylight feeding, the peak diurnal expression of genes in liver was shifted by 6-12h while expression of these genes in muscle remained in a similar phase to rats feeding ad libitum. High fat feeding during the daylight hours had limited effect on clock gene expression in liver or muscle but shifted the peak expression of metabolic genes (pepck, fas) in liver by 6-12h. The differential effects of daylight feeding on gene and protein expression in muscle and liver were accompanied by an 8% reduction in whole body energy expenditure, a 20-30% increased glycogen content during the light phase in muscle of day-fed rats and increased adipose tissue deposition per gram food consumed. These data demonstrate that a mismatch of feeding and light/dark cycle disrupts tissue metabolism in muscle with significant consequences for whole body energy homeostasis.

SummaryThe naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats. The sensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked mole-rats have fully functional TRPV1 channels. We show that exposing isolated naked mole-rat nociceptors to NGF does not sensitize TRPV1. However, the naked mole-rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.

The naked mole‐rat (Heterocephalus glaber) has fascinated zoologists for at least half a century. It has also generated considerable biomedical interest not only because of its extraordinary longevity, but also because of unusual protective features (e.g. its tolerance of variable oxygen availability), which may be pertinent to several human disease states, including ischemia/reperfusion injury and neurodegeneration. A recent article entitled ‘Surprisingly long survival of premature conclusions about naked mole‐rat biology’ described 28 ‘myths’ which, those authors claimed, are a ‘perpetuation of beautiful, but falsified, hypotheses’ and impede our understanding of this enigmatic mammal. Here, we re‐examine each of these ‘myths’ based on evidence published in the scientific literature. Following Braude et al., we argue that these ‘myths’ fall into four main categories: (i) ‘myths’ that would be better described as oversimplifications, some of which persist solely in the popular press; (ii) ‘myths’ that are based on incomplete understanding, where more evidence is clearly needed; (iii) ‘myths’ where the accumulation of evidence over the years has led to a revision in interpretation, but where there is no significant disagreement among scientists currently working in the field; (iv) ‘myths’ where there is a genuine difference in opinion among active researchers, based on alternative interpretations of the available evidence. The term ‘myth’ is particularly inappropriate when applied to competing, evidence‐based hypotheses, which form part of the normal evolution of scientific knowledge. Here, we provide a comprehensive critical review of naked mole‐rat biology and attempt to clarify some of these misconceptions.