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1. Naked Mole-Rats Demonstrate Profound Tolerance to Low Oxygen, High Carbon Dioxide, and Chemical Pain

   https://doi.org/10.3390/ani13050819  

   Amoroso, Vince G.; Zhao, Aishi; Vargas, Isabel; Park, Thomas J. (March 2023, Animals)

   Naked mole-rats (Heterocephalus glaber) are very unusual among subterranean mammals in that they live in large colonies and are extremely social, spending large amounts of time gathered together in underground nests more than a meter below the surface. Many respiring individuals resting in deep, poorly ventilated nests deplete the oxygen supply and increase the concentration of carbon dioxide. Consistent with living in that atmosphere, naked mole-rats tolerate levels of low oxygen and high carbon dioxide that are deadly to most surface-dwelling mammals. Naked mole-rats appear to have evolved a number of remarkable adaptations to be able to thrive in this harsh atmosphere. In order to successfully survive low oxygen atmospheres, they conserve energy utilization by reducing the physiological activity of all organs, manifest by reduced heart rate and brain activity. Amazingly, they resort to the anaerobic metabolism of fructose rather than glucose as a fuel to generate energy when challenged by anoxia. Similarly, high carbon dioxide atmospheres normally cause tissue acidosis, while naked mole-rats have a genetic mutation preventing both acid-induced pain and pulmonary edema. Together, these putative adaptations and the tolerances they provide make the naked mole-rat an important model for studying a host of biomedical challenges. 

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2. Life without substance P: The naked mole rat

   https://doi.org/10.1016/B978-0-443-22194-1.00013-6  

   Zhao, Aishi; Lee, Jiwon; Gryszkiewicz, Weronika; Park, Thomas J (January 2025, Elsevier)

   Vink, Robert (Ed.)

   The African naked mole rat (Heterocephalus glaber) is a small, eusocial rodent that lives in large colonies consisting of up to 295 individuals. Their skin is pink and translucent, and naked mole rats have a distinct set of incisors that protrude externally from the mouth so that they can close their lips behind their teeth while using the teeth to dig tunnels, toilets, and nest chambers. They construct and inhabit complex underground tunnel systems in the Horn of Africa where they are protected from climate extremes and predators on the surface, but still face limited resources (sparsely distributed food), and a biologically challenging environment where there is a depletion of oxygen and an accumulation of carbon dioxide from many respirating individuals living in an unventilated space. This is particularly an issue in the communal nest chambers where animals gather to huddle and sleep. Data from Zions et al. show that the nest chambers in colonies of captive naked mole rats have significantly, and substantially higher concentrations of CO2 compared to other compartments in the housing system. They also showed that on average, colony members spent more than 70% of their time in the nest chamber, exposed to elevated CO2. Naked mole rats have a multitude of biological adaptations that make them specialized for life in humid, congested, poorly ventilated burrows. Subsequently, this species is a fascinating and important nontraditional model for biomedical research. Studies have focused on topics such as tolerance to hypoxia and hypercapnia, extreme longevity, resistance to cancer, and insensitivity to chemical pain. One remarkable feature that naked mole rats display is the lack of Substance P from their peripheral nerves. Substance P is associated with pain from a variety of irritants such as carbon dioxide (CO2), acid, capsaicin, and ammonia, as well as itch-like pruritogen, like histamines. Lack of Substance P is presumably an adaptation to reduce the negative effects of living in a high CO2 atmosphere, which would cause a burning sensation in the nasal cavity and around the eyes, as well as acidosis in the lungs that causes pulmonary edema. This chapter reviews how this feature affects their physiology and behavior. For example, naked mole rats show a blunted response to inflammatory pain, complete insensitivity to irritants such as capsaicin, ammonia, and acid, and they do not show a scratching response to histamine. 

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3. Naked Mole‐Rats: Blind, Naked, and Feeling No Pain

   https://doi.org/10.1002/ar.23996  

   Browe, Brigitte_M; Vice, Emily_N; Park, Thomas_J (November 2018, The Anatomical Record)

   ABSTRACT Around the world and across taxa, subterranean mammals show remarkable convergent evolution in morphology (e.g., reduced external ears, small eyes, shortened limbs and tails). This is true of sensory systems as well (e.g., loss of object vision and high frequency hearing). The naked mole‐rat (Heterocephalus glaber) displays these typical subterranean features, but also has unusual characteristics even among subterranean mammals. Naked mole‐rats are cold‐blooded, completely furless, very long‐lived (> 30 years), and eusocial (like termites). They also live in large colonies, which is very unusual for subterraneans. Their cortical organization has reduced area for visual processing, utilizing 30% more cortex for tactile processing. They are extremely tolerant to oxygen deprivation, and can recover from 18 min of anoxia. Their pain pathway is reduced and they feel no pain from acidosis. They are the only rodent tested to date whose pheromone‐detecting vomeronasal organ shows no postnatal growth. These features may be a result of this species' “extreme subterranean lifestyle” that combines living underground and living in large colonies. Many respiring animals cramped together in unventilated burrows elevates CO₂levels, high enough to cause acidosis pain, and depletes O₂concentrations low enough to kill other mammals. The naked mole‐rat may be an extreme model of adaptation to subterranean life and provides insights into the complex interplay of evolutionary adaptations to the constraints of subterranean living. Anat Rec, 2018. © 2018 American Association for Anatomy. 

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4. Phylogenetic modeling of enhancer shifts in African mole-rats reveals regulatory changes associated with tissue-specific traits

   https://doi.org/10.1101/gr.277715.123  

   Parey, Elise; Fernandez-Aroca, Diego; Frost, Stephanie; Uribarren, Ainhoa; Park, Thomas J; Zöttl, Markus; St_John_Smith, Ewan; Berthelot, Camille; Villar, Diego (September 2023, Genome Research)

   Changes in gene regulation are thought to underlie most phenotypic differences between species. For subterranean rodents such as the naked mole-rat, proposed phenotypic adaptations include hypoxia tolerance, metabolic changes, and cancer resistance. However, it is largely unknown what regulatory changes may associate with these phenotypic traits, and whether these are unique to the naked mole-rat, the mole-rat clade, or are also present in other mammals. Here, we investigate regulatory evolution in the heart and liver from two African mole-rat species and two rodent outgroups using genome-wide epigenomic profiling. First, we adapted and applied a phylogenetic modeling approach to quantitatively compare epigenomic signals at orthologous regulatory elements and identified thousands of promoter and enhancer regions with differential epigenomic activity in mole-rats. These elements associate with known mole-rat adaptations in metabolic and functional pathways and suggest candidate genetic loci that may underlie mole-rat innovations. Second, we evaluated ancestral and species-specific regulatory changes in the study phylogeny and report several candidate pathways experiencing stepwise remodeling during the evolution of mole-rats, such as the insulin and hypoxia response pathways. Third, we report nonorthologous regulatory elements overlap with lineage-specific repetitive elements and appear to modify metabolic pathways by rewiring of HNF4 and RAR/RXR transcription factor binding sites in mole-rats. These comparative analyses reveal how mole-rat regulatory evolution informs previously reported phenotypic adaptations. Moreover, the phylogenetic modeling framework we propose here improves upon the state of the art by addressing known limitations of inter-species comparisons of epigenomic profiles and has broad implications in the field of comparative functional genomics. 

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5. Physiological responses to hypoxia are constrained by environmental temperature in heterothermic tenrecs

   https://doi.org/10.1242/jeb.245324  

   Devereaux, Maiah E.; Silva Rubio, Claudia; van Breukelen, Frank; Pamenter, Matthew E. (March 2023, Journal of Experimental Biology)

   ABSTRACT Malagasy tenrecs are placental hibernating mammals that seal the entrances to their burrows and hibernate either singly or in groups for 8–9 months, which is likely to create a hypoxic and hypercapnic burrow environment. Therefore, we hypothesized that tenrecs are tolerant to environmental hypoxia and hypercapnia. Many hypoxia- and hypercapnia-tolerant fossorial mammals respond to hypoxia by decreasing metabolic rate and thermogenesis, and have blunted ventilatory responses to both environmental hypoxia and hypercapnia. However, tenrecs exhibit extreme metabolic and thermoregulatory plasticity, which exceeds that of most heterothermic mammals and approaches that of ectothermic reptiles. Thus, we predicted that tenrecs would have abnormal physiological responses to hypoxia and hypercapnia relative to other fossorial mammals. To test this, we exposed common tenrecs (Tenrec ecaudatus) to moderate and severe hypoxia (9 and 4% O2) or hypercapnia (5 and 10% CO2) in either 28 or 16°C while non-invasively measuring metabolic rate, thermogenesis and ventilation. We found that tenrecs exhibit robust metabolic decreases in both hypoxia and hypercapnia. Furthermore, tenrecs have blunted ventilatory responses to both hypoxia and hypercapnia, and these responses are highly temperature sensitive such that they are reduced or absent in 16°C. Thermoregulation was highly variable in 16°C but constrained in 28°C across all treatment conditions and was not impacted by hypoxia or hypercapnia, unlike in other heterothermic mammals. Taken together, our results indicate that physiological responses to hypoxia and hypercapnia in tenrecs are highly dependent on environmental temperature and differ from those of other mammalian heterotherms. 

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