Hibernation vs. hypoxia: an underlying epigenetic,
microRNA, and signaling framework
Abstract:
A myriad of survival strategies have evolved in the animal kingdom to tolerate extreme environmental stress, ranging from freezing temperatures to oxygen deprivation to extreme heat/dehydration. All of these conditions, and the strategies to combat them, necessitate extensive yet reversible phenotypic changes to survive – changes grouped under overarching molecular themes of metabolic rate depression. In this thesis, I focused on cardiac tissue of two mammalian species with robustly evolved survival strategies: hibernation in thirteen-lined ground squirrel Ictidomys tridecemlineatus; and hypoxia tolerance in naked mole-rat Heterocephalus glaber. I examined a representative mode of regulation occurring at each level of the central dogma, illustrating the vast interplay of coordinating molecular mechanisms required for hypometabolism. These included: epigenetic modification via RNA m6A methylation of mRNA transcripts; post-transcriptional regulation via miRNA; protein degradation via the ubiquitin-proteasome system and cullin-RING E3 ligases; and signaling modulation via SMAD proteins. The data I collected forms a network of intricate crosstalk between cardio-metabolic reorganization and cardioprotection during stress. Hypoxia is a subcomponent stress of hibernation; and as such, both species displayed cytoprotective adaptations to hypoxia-induced oxidative stress and ROS generation. Ground squirrels with increased DNA repair capacity to combat oxidative stress during hibernation had an additional layer of crosstalk between hibernation and hypothermia, increasing sensitivity to UV-irradiated DNA which is recognized and facilitated through proteins of the ubiquitin-proteasome system. Naked mole-rats demonstrated increased levels of protein degradation and proteasomal activity, incorporating hypoxia-related oxidative stress tolerance with their extreme longevity. Altered cellular signaling in both species included SMAD, MAPK, mTOR, AMPK, and NFκB pathways. NFκB dysregulation during oxidative stress linked with hypoxia champion HIF-1, and its degradation through the ubiquitin-proteasome system. Continuous inhibition of mTOR was proposed through the torpor-arousal cycle, facilitated by noncanonical eIF3-m6A translation which also serves as an energy saving mechanism. Altered mitochondrial dynamics were a recurring theme in both species and stresses; facets of their regulation were suggested via miRNA targeting and ubiquitin proteasome regulation. Taken together, my work both highlights the complexity of hypometabolic adaptation in cardiac tissue, and suggests globally conserved themes for regulation reflected across the central dogma of biology.