A systems biology approach to dissect the hazardous effects of spaceflight and investigate induced torpor as a therapeutic countermeasure.

  • Tom Cahill

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Humanities quest of interplanetary travel will present significant challenges, relating to crew nutrition, and the long-term exposure to microgravity and radiation, the effects of which have not been fully investigated. Chapter Three focuses on characterizing the response of fast (EDL) and slow (soleus) muscles to spaceflight (SF) which are known to be atrophy resistant (EDL) or atrophy prone (soleus). Notably, a dysregulation of phosphodiesterase (PDE) genes was observed between muscles indicative of increased cAMP signalling in the EDL and decreased signalling in the soleus. cAMP signalling has been implicated in promoting fiber hypertrophy. Additionally, the EDL exhibited an upregulation of a long non-coding RNA (Lncbate10) that protects the PGC1α gene from repression. PGC1α is a master regulator of mitochondrial biogenesis, indicating a transition towards a more oxidative phenotype in EDL. Furthermore, the study explores the use of model organisms in simulating mammalian responses to SF. Intriguingly, C.elegans showed a phenotype more similar to the EDL, while larvae D.melanogaster showed a soleus-like response. The thesis then focuses on defining the effects of low-dose radiation (LDR) in zebrafish and an induced a torpor-like state was tested as a countermeasure, using various tissues. Transcriptomic analysis of the GIT and liver revealed radiation-induced changes involving alterations in stress signalling, circadian rhythm, DNA damage, cell cycle arrest, and lipid dysregulation which was a shared response in space flown mice. The induced torpor group displayed a reduction in metabolic pathways and an increase in anti-apoptotic, pro-survival, and DNA repair genes that persisted even after radiation exposure. The findings point to the involvement of an EMT-like programme, and the hypoxia response, in generating this phenotype. Additionally, a similar anti-apoptotic phenotype was observed in the liver of hibernating bears. In the muscle, LDR resulted in an inflammatory and developmental phenotype, mediated by STAT3 and MYOD1. In contrast, STAT signalling, developmental processes, and the extracellular matrix were downregulated. These changes may offer protection against radiation-induced fibrosis. Notably, mitochondrial-related metabolic pathways were upregulated in the induced torpor groups, which might indicate a shift to a more oxidative metabolism. Given that studies on sarcopenia have shown that slow fibres are more atrophy resistant and that mitochondrial biogenesis occurs in the muscles of certain hibernating animals during torpor, the results suggest that an increase in mitochondrial activity is a cold adaptive strategy to maintain muscle mass during reduced activity. Lastly, the properties of anaesthetic agents were explored in the context of a modern medicine approach to inducing a torpor-like state in humans.

Thesis is embargoed until 31 July 2024.
Date of AwardJul 2023
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsNorthern Ireland Department for the Economy, NASA EPSCoR & National Institutes of Health
SupervisorIan Overton (Supervisor) & Gary Hardiman (Supervisor)

Keywords

  • transcriptomics
  • zebrafish
  • gastrointestinal tract
  • liver
  • muscle
  • space flight
  • microgravity
  • radiation
  • induced torpor
  • countermeasure

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