Naked mole rats (NMRs, Heterocephalus glaber) are among the most hypoxia-tolerant mammals known. They can reduce their metabolic rate (>85%) under severe hypoxia, remain moderately active and recover with no obvious signs of damage. Hence, NMRs are an excellent model for studying mammalian hypoxia tolerance. The current study characterized the involvement of posttranslational modifications in regulating the Akt/mTOR pathway that regulates protein synthesis, and the responses of key ribosomal proteins in order to assess tissue-specific responses to 4 h exposure to 7% O2 (compared to controls at 21% O2). Results showed a tissue-specific regulation of the Akt/mTOR pathway via differential phosphorylation. Relative amounts of p-TSC(S939) in brain and of p-TSC(S939), p-Akt(473) and p-PTEN(S380) in liver increased under hypoxia, whereas levels of IGF1R(Y1135/1136) in liver decreased. In skeletal muscle, levels of p-Akt(S473) and p-PTEN(S380) decreased during hypoxia, whereas lungs showed an increase in p-mTOR(S2884) content but a decrease in p-RPS6(S235–236) under the same conditions. Analysis of the phosphorylation states of ribosomal proteins revealed increases in p-4E-BP1(T37/46) content in brain and lungs under hypoxia, as well as a rise in total 4E-BP1 protein level in liver. Phosphorylated eIF-4B(S422) content also increased in liver while levels of p-eIF-2α(S51), and eIF-4E(S209) decreased during hypoxia in liver. Overall, hypoxia altered the Akt/mTOR pathway, which correlated with a general decrease in activity of the ribosomal protein biosynthesis machinery in muscle, lung, and brain of NMRs. However, the increase in eIF-4B in liver suggests the potential promotion of cap-independent mRNA translation mechanism operating under hypoxic stress.

Evolution has produced animals that survive extreme fluctuations in environmental conditions including freezing temperatures, anoxia, desiccating conditions, and prolonged periods without food. For example, the wood frog survives whole-body freezing every winter, arresting all gross physiological functions, but recovers functions upon thawing in the spring. Likewise, many small mammals hibernate for months at a time with minimal metabolic activity, organ perfusion, and movement, yet do not suffer significant muscle atrophy upon arousal. These conditions and the biochemical adaptations employed to deal with them can be viewed as Nature’s answer to problems that humans wish to answer, particularly in a biomedical context. This review focuses on recent advances in the field of animal environmental stress adaptation, starting with an emphasis on new areas of research such as epigenetics and microRNA. We then examine new and emerging technologies such as genome editing, novel sequencing applications, and single cell analysis and how these can push us closer to a deeper understanding of biochemical adaptation. Next, evaluate the potential contributions of new high-throughput technologies (e.g. next-generation sequencing, mass spectrometry proteomics) to better understanding the adaptations that support these extreme phenotypes. Concluding, we examine some of the human applications that can be gained from understanding the principles of biochemical adaptation including organ preservation and treatments for conditions such as ischemic stroke and muscle disuse atrophy.

Non-genetic inheritance of metabolic state over multiple generations has been widely reported in insects. The present study uses the fruit fly, Drosophila melanogaster, to assess whether lifespan, physiological traits and metabolism are affected by the dietary protein-to-carbohydrate ratio (P:C) of the prior adult generation. Groups of parental flies were fed diets with different P:C ratios. Their progeny groups were raised on the same diet so the only variable in the experiments was the diet fed to the parents. Parental P:C affected the lifespan of female offspring, however had no impact on F1 males survival. Low parental P:C increased feeding rate in progeny. An increase in the P:C ratio from 0.03 to 0.65 decreased the levels of body glucose and trehalose in the offspring and a similar tendency was observed in the levels of circulating hemolymph glucose and trehalose. Offspring also accumulated less triglycerides but more glycogen when parents were fed a low P:C diet. Our study indicates that the parental dietary P:C ration has a strong impact on the lifespan, reproduction, appetite and metabolism in the offspring generation.

Endothelin-1 (ET-1) is a very potent vasoactive peptide released from endothelial cells, and ET-1 plays an important role in the maintenance and regulation of blood pressure in mammals. ET-1 signaling is mediated by two receptors: ETA and ETB. In mammals, ETA receptors are located on vascular smooth muscle where they mediate vasoconstriction. ETB receptors located on the endothelium mediate vasodilatation through the release of nitric oxide, whereas stimulation of ETB receptors placed on vascular smooth muscle leads to vasoconstriction. Less is known about ET-1 signaling in reptiles. In anaesthetized alligators, ET-1 elicits a biphasic blood pressure with a long-lasting initial decrease followed by a smaller increase in systemic blood pressure. In anaesthetized freshwater turtles, ET-1 causes a dose-dependent systemic vasodilatation mediated through ETB receptors. In the present study, we investigated the cardiovascular effects of ET-1 on the systemic and pulmonary vasculature of pythons. The presence of ETA and ETB receptors in the vasculature of pythons was verified by means of immunoblotting. Myography on isolated vessels revealed a dose-dependent vasoconstrictory response to ET-1 in both mesenteric and pulmonary arteries. Pressure measurements in recovered specimens revealed an ET-1-induced rise in systemic blood pressure supporting our in vitro findings. In conclusion, our study shows that ET-1 induces a strong pressor effect in the systemic circulation.

Preparation for oxidative stress (POS), i.e., the upregulation of endogenous antioxidants, is a widespread response of animals exposed to extreme conditions. This response has been described for more than 80 animal species belonging to eight phyla during hypometabolism or situations that limit oxygen availability. The pattern of the typical POS-response, in which a mild redox imbalance triggers antioxidant adjustments that results in increased tolerance to subsequent oxidative insults, roughly follows the curve of hormetic phenomena. A similar pattern has been reported for various animal species exposed to ultraviolet radiation (UVR) – these studies, on animals from six phyla, are discussed herein. In the light of the similarities in the redox-response of animals exposed to either oxygen restriction or UVR, we argue in this essay that UVR elicits a type of response that fits the POS theory. Exposure to UVR induces both reactive species formation and antioxidant adaptation, which is the essence of typical POS-responses. Thus, antioxidant response to UVR in animals can be categorized as a POS-type mechanism. Moreover, considering that animals are exposed to multiple stressors simultaneously in nature, this would represent an ecologically relevant process, by which one stressor (e.g., UV or ionizing radiation) may enhance the tolerance to other. We also discuss a possible role of low doses of ionizing radiation as inductor of POS-like responses in animals.

Postnatally, during hypoxia the decrease in oxygen consumption (V̇O2) can exceed what expected from the limitation in O2 availability, meaning that V̇O2 -downregulation exceeds O2-conformism. We questioned whether a similar phenomenon could occur prenatally, in chicken embryos at mid- (E11, out of 20.5 days) or near end- (E18) incubation. V̇O2 was measured with an open-flow system in the sequence of normoxia-normothermia (21% O2, 37 °C, 30 min), hypoxia in normothermia (Hx-NT, either 18, 15, 12 or 9% O2, 37 °C, 1 hour), hypoxia in hyperthermia (Hx-HT, up to 43 °C, 1 hour) and return to normoxia-normothermia (30 min). During Hx-NT V̇O2 invariably decreased in a [O2]-dependent fashion. The hypoxic drop in V̇O2 did not require a post-hypoxic payment of the O2-debt, implying that the decrease in V̇O2 reflected hypometabolism. V̇O2 did not differ significantly between Hx-HT and Hx-NT for [O2] = 15% or less, as expected by O2-conformism. Differently, with milder hypoxia (18% O2), V̇O2 during Hx-HT significantly exceeded that in Hx-NT, meaning that the value of V̇O2 in Hx-NT was not limited by O2 supply. We conclude that a phenomenon of hypoxic V̇O2 downregulation like that observed in postnatal mammals can occur also prenatally, in the chicken embryos. The mechanisms at the basis of the downregulation remain unresolved and could combine physiological and cellular processes.