Metabolic remodelling of mice by hypoxic-hypercapnic environment: imitating the naked mole-rat

Abstract

We hypothesised that hypoxic-hypercapnic environment (HHE) could induce metabolic suppression and associated benefits for health and longevity, as observed in the naked-mole rat (NMR). We developed a model of self-produced HHE (similar to a natural habitat of NMRs), which is simple, reliable and natural, and does not require external sources of gases or complex technical equipment. Here, we showed for the first time that a chronic exposure of mice to HHE could be a unique tool for NMR-like metabolic remodeling, resulting in a long-term and substantial decrease in metabolic rate, body temperature, and food consumption, without significant changes in expression of stress-related genes. Unexpectedly, the HHE accelerated skin wound healing, despite the lower energy expenditure. The self-produced HHE could be considered a model of voluntary calorie restriction. All in all, a chronic exposure to HHE offers a potential of being a lifespan-extending intervention as well as an efficient tool for treating the overweight and associated metabolic disorders.

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Abbreviations

CR:

Calorie restriction

FT3:

Free triiodothyronine

FT4:

Free thyroxine

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HHE:

Hypoxic-hypercapnic environment

HSP90AA1:

Heat Shock Protein 90 Alpha Family Class A Member

i.p.:

Intraperitoneally

MSCs:

Mesenchymal stem cells

NMR(s):

Naked mole-rat(s)

qPCR:

Quantitative real time polymerase chain reaction

Vo2 :

Oxygen consumption

Vco2 :

Carbon dioxide production

UCP2:

Mitochondrial uncoupling protein 2

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Acknowledgements

We thank Dr. Irina Pishel for her assistance in conducting the experiments. This work was supported in part by the Fund in Memory of Dr. Amir Abramovich (to V.E.F.).

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Correspondence to Vadim E. Fraifeld or Khachik K. Muradian.

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a

Online Resource 1 Relationships between Vco2 and atmospheric CO2 in (a) young and (b) old male CBA mice (PPTX 65 kb)

a

Online Resource 2 () The head skin excision model, and (b) time-course of skin wound closure in young male C57Bl/6 mice upon chronic exposure to self-produced HHE. Each mouse was subjected to a single head punch wound. Wound area was expressed as percentage of the original wound size (PPTX 194 kb)

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Tolstun, D.A., Knyazer, A., Tushynska, T.V. et al. Metabolic remodelling of mice by hypoxic-hypercapnic environment: imitating the naked mole-rat. Biogerontology 21, 143–153 (2020). https://doi.org/10.1007/s10522-019-09848-9

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Keywords

  • Hypometabolism
  • Hypothermia
  • Hypoxia
  • Hypercapnia
  • Voluntary calorie restriction
  • Mice
  • Age