Multi-tissue profile of NFκB pathway regulation during mammalian hibernation

Comp Biochem Physiol B Biochem Mol Biol. Aug-Sep 2020;246-247:110460. doi: 10.1016/j.cbpb.2020.110460. Epub 2020 May 20.

Abstract

Hibernators have evolved effective mechanisms to overcome the challenges of torpor-arousal cycling. This study focuses on the antioxidant and inflammatory defenses under the control of the redox-sensitive and inflammatory-centered NFκB transcription factor in the thirteen-lined ground squirrel (Ictidomys tridecemlineatus), a well-established model of mammalian hibernation. While hibernators significantly depress oxygen consumption and overall metabolic rate during torpor, arousal brings with it a rapid increase in respiration that is associated with an influx of reactive oxygen species. As such, hibernators employ a variety of antioxidant defenses to combat oxidative damage. Herein, we used Luminex multiplex technology to examine the expression of key proteins in the NFκB transcriptional network, including NFκB, super-repressor IκBα, upstream activators TNFR1 and FADD, and downstream target c-Myc. Transcription factor DNA-binding ELISAs were also used to measure the relative degree of NFκB binding to DNA during hibernation. Analyses were performed across eight different tissues, cerebral cortex, brainstem, white and brown adipose tissue, heart, liver, kidney, and spleen, during euthermic control and late torpor to highlight tissue-specific NFκB mediated cytoprotective responses against oxidative stress experienced during torpor-arousal. Our findings demonstrated brain-specific NFκB activation during torpor, with elevated levels of upstream activators, inactive-phosphorylated IκBα, active-phosphorylated NFκB, and enhanced NFκB-DNA binding. Protein levels of downstream protein, c-Myc, also increased in the brain and adipose tissues during late torpor. The results show that NFκB regulation might serve a critical neuroprotective and cytoprotective role in hibernating brains and selective peripheral tissue.

Keywords: Metabolic rate depression; Neuroprotection; Nuclear factor kappa-light-chain-enhancer of activated B cells; Thirteen-lined ground squirrel; Torpor.

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Brain Stem / metabolism
  • Cerebral Cortex / metabolism
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / metabolism
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • Heart / physiology
  • Hibernation / genetics*
  • Hibernation / physiology
  • Kidney / metabolism
  • Liver / metabolism
  • Male
  • NF-KappaB Inhibitor alpha / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Oxidative Stress
  • Phosphorylation
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Sciuridae / genetics
  • Sciuridae / metabolism*
  • Signal Transduction / genetics*
  • Signal Transduction / physiology
  • Spleen / metabolism

Substances

  • Fas-Associated Death Domain Protein
  • NF-kappa B
  • Proto-Oncogene Proteins c-myc
  • Reactive Oxygen Species
  • Receptors, Tumor Necrosis Factor, Type I
  • NF-KappaB Inhibitor alpha