African Naked Mole-Rats Demonstrate Extreme Tolerance to Hypoxia and Hypercapnia.

Naked mole-rats are extremely tolerant to low concentrations of oxygen (hypoxia) and high concentrations of carbon dioxide (hypercapnia), which is consistent with the environment that they inhabit. Naked mole-rats combine subterranean living with living in very densely populated colonies where oxygen becomes depleted and carbon dioxide accumulates. In the laboratory, naked mole-rats fully recover from 5 h exposure to 5% O2 and 5 h exposure to 80% CO2, whereas both conditions are rapidly lethal to similarly sized laboratory mice. During anoxia (0% O2) naked mole-rats enter a suspended animation-like state and switch from aerobic metabolism of glucose to anaerobic metabolism of fructose. Additional fascinating characteristics include that naked mole-rats show intrinsic brain tolerance to anoxia; a complete lack of hypoxia-induced and CO2-induced pulmonary edema; and reduced aversion to high concentrations of CO2 and acidic fumes. Here we outline a constellation of physiological and molecular adaptations that correlate with the naked mole-rat's hypoxic/hypercapnic tolerance and which offer potential targets for ameliorating pathological conditions in humans, such as the damage caused during cerebral ischemia.

Auditory-vocal coupling in the naked mole-rat, a mammal with poor auditory thresholds.

Naked mole-rats are extremely social and extremely vocal rodents, displaying a wide range of functionally distinct call types and vocalizing almost continuously. Their vocalizations are low frequency, and a behavioral audiogram has shown that naked mole-rats, like other subterranean mammals, hear only low frequencies. Hence, the frequency range of their hearing and vocalizations appears to be well matched. However, even at low frequencies, naked mole-rats show very poor auditory thresholds, suggesting vocal communication may be effective only over short distances. However, in a tunnel environment where low frequency sounds propagate well and background noise is low, it may be that vocalizations travel considerable distances at suprathreshold intensities. Here, we confirmed hearing sensitivity using the auditory brainstem response; we characterized signature and alarm calls in intensity and frequency domains and we measured the effects of propagation through tubes with the diameter of naked mole-rat tunnels. Signature calls-used for intimate communication-could travel 3-8 m at suprathreshold intensities, and alarm calls (lower frequency and higher intensity), could travel up to 15 m. Despite this species' poor hearing sensitivity, the naked mole-rat displays a functional, coupled auditory-vocal communication system-a hallmark principle of acoustic communication systems across taxa.

Blockade of Vascular Endothelial Growth Factor Receptor-1 (Flt-1), Reveals a Novel Analgesic For Osteoarthritis-Induced Joint Pain.

Osteoarthritis (OA) is a painful and debilitating disease. A striking feature of OA is the dramatic increase in vascular endothelial growth factor (VEGF) levels and in new blood vessel formation in the joints, both of which correlate with the severity of OA pain. Our aim was to determine whether anti-VEGF monoclonal antibodies (mAbs) - MF-1 (mAb to VEGFR1) and DC101 (mAb to VEGFR2) - can reduce OA pain and can do so by targeting VEGF signaling pathways such as Flt-1 (VEGFR1) and Flk-1 (VEGFR2). After IACUC approval, OA was induced by partial medial meniscectomy (PMM) in C57/BL6 mice (20 g). ln the first experiment, for validation of VEGFR1 in DRG, the mouse dorsal root ganglion (DRG) was stimulated with NGF for 48 hours to find the relative gene induction for VEGFR1 vs. 18S by RT-PCR. In the second experiment, Biotin-conjugated VEGFA (1 µg/knee joint) was administered in the left knee joint of mice with advanced OA in order to characterization of VEGFR1 and VEGFR2. pVEGFR1/VEGFR2 was detected by immunostaining in DRGs. Finally, MF-1 and DC101 were administered in OA mice by both intrathecal (IT) and intraarticular (IA) injections, and the change in paw withdrawal threshold (PWT) was measured. Retrograde transport of VEGF was confirmed for detection of pVEGFR1/VEGFR2 in the DRG. PMM surgery led to development of OA and mechanical allodynia, with reduced paw withdrawal thresholds (PWT) (P<0.0001). IT injection of MF-1 led to a reduction of allodynia in advanced OA, but injection of DC101 did not. IA injection of MF-1 or DC101 at one week after PMM injury did not reduce allodynia, but when injected in advanced OA mice joints at 12 weeks, both Mabs increased PWT an indicator of analgesia. Our data show that MF-1 (VEGR1 inhibition) decreases pain in advanced OA after IT or IA injection. Activation of MF-1 or DC101 may ameliorate OA-related joint pain.

Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat.

The African naked mole-rat's (Heterocephalus glaber) 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.