The naked mole-rat possesses several unique physiological and molecular features that underlie their remarkably and exceptional resistance to tissue hypoxia. Elevated pattern of Epo, an erythropoietin (Epo) factor; c-fos; vascular endothelial growth factor (VEGF); and hypoxia-inducible factors (HIF-1α) contribute to the adaptive strategy to cope with hypoxic stress. Moreover, the naked mole-rat has a lower metabolic rate than any other eutherian mammal of comparable size that has been studied. The ability to actively reduce metabolic rate represents a strategy widely used in the face of decreased tissue oxygen availability. Understanding the different molecular and physiological factors that induce metabolic suppression could guide the development of pharmacological agents for the clinical management of stroke patient.

Recent investigations of hypoxia physiology in the naked mole rat have opened up an interesting line of research into the basic physiological and genomic alterations that accompany hypoxia survival. The extent to which such findings connect the effect of hypoxia to metabolic rate (O2 consumption), core body temperature (Tb), and transcripts encoding the immediate early gene product (such as c-fos) under a constant ambient temperature (Ta) is not well known. We investigated this issue in the current study. Our first sets of experiments measured Tb and metabolic rates during exposure of naked mole rats to hypoxia over a constant Ta. Hypoxia significantly decreased metabolic rates in the naked mole rat. Although core Tb also decreased during hypoxia, the effect of hypoxia in suppressing core Tb was not significant. The second series of experiments revealed that c-fos protein and mRNA expression in the hippocampus neurons (CA1) increased in naked mole rats that were repeatedly exposed to 3% O2 for 60min per day for 5 days when compared to normoxia. Our findings provide evidence for the up-regulation of c-fos and suppression of metabolic rate in hypoxia tolerating naked mole rats under constant ambient temperature. Metabolic suppression and c-fos upregulation constitute part of the physiological complex associated with adaptation to hypoxia.

Being the longest-lived rodent, naked mole-rats (NMR; Heterocephalus glaber) are an exceptional model for biogerontological research. However, unlike other rodents, not much is known about their wound healing process. To investigate that, full-thickness wounds were created in the back skin of naked mole rats. Our initial data confirmed that wound closure in NMR skin was achieved primarily by reepithelialization and granulation tissue formation, with only ~26% wound contraction, making them an excellent model to study human cutaneous wound healing. Similar to mice and human skin, changes in wound epithelial tongue included progressive enlargement of wound epithelium, increased proliferation and changes in the expression pattern of epidermal markers including K14, K17, integrin α6 and E-cadherin. Further analysis revealed characteristics of reduced scarring in NMR wounds including low collagen I to III ratio, increased HA expression (HMW) and increased fibronectin expression. Transcriptional profiling of TGFβ isoforms and different pro/anti-inflammatory cytokines revealed a balance in the expression and repression of different cytokines, potentially contributing into reduced scarring. Comparison of RNA-seq data from NMR and human fullthickness wounds revealed a delay in the activation of important biological processes and pathways in NMR skin in response to injury. Further analysis based on cultured human and NMR cells revealed differential regulation of TGFβ signalling pathway between both species. 3-D collagen gel contraction assay revealed that NMR fibroblast showed noticeable contraction but independently of TGFβ treatment, while human fibroblast showed marked increased in gel contraction in the presence of TGFβ. In conclusion, NMR can serve as a very useful model to study human cutaneous wound healing. The reduced scarring in NMR could be a result of multiple factors including HMW-HA, balanced cytokine expression and differential regulation of different TGFβ cytokines as observed in the in vitro studies.