Molecular control of protein synthesis, glucose metabolism, and apoptosis in the brain of hibernating thirteen-lined ground squirrels

Abstract

Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) are excellent models for studying acute brain ischemia because they show high resistance to reductions in blood flow and oxygen delivery without evidence of neurological damage. In this study, we analyzed the insulin signaling pathway and regulation of mitochondrial substrate oxidation in three regions of ground squirrel brain (forebrain, cerebellum, and brainstem), comparing summer, late torpor, and interbout arousal conditions. We found select decreases in phospho-Akt in the cerebellum during torpor compared with summer animals, as well as select increases in the forebrain during interbout arousal, suggesting that Akt may influence either metabolism or cytoprotective pathways. The phosphoprotein abundance of glycogen synthase kinase 3 beta (GSK3β) showed the most consistent trend across all three brain regions, with peak increases observed during deep torpor, suggesting a crucial role for this protein during hibernation. Furthermore, all three regions of the brain showed increased phospho-protein abundance of pyruvate dehydrogenase at serine 232 during both deep torpor and interbout arousal, and serine 300 during interbout arousal only, whereas other phosphorylation sites showed a region-specific expression pattern. Information collected from these studies sheds light on the molecular controls governing insulin signaling and fuel utilization in the brain of hibernating ground squirrels.

Transformation of Mitochondrial Architecture and Dynamics in the Chinese Soft-Shelled Turtle (Pelodiscus sinensis) During Hibernation

“…To be adaptable to environmental changes, these hibernating animals radically reduce their metabolic rates (including body temperature, oxygen consumption, and heart rate) and swiftly convert the primary fuel from carbohydrate to lipid (Chazarin et al, 2019). Through omics analysis, previous studies in the greater horseshoe bat (Rhinolophus ferrumequinum) (Xiao et al, 2019), American black bear (Ursus americanus) (Srivastava et al, 2019), and thirteen-lined ground squirrel (Ictidomys tridecemlineatus) (Tessier et al, 2019) have revealed metabolic depression and shifts in metabolic fuel use during hibernation. In our previous studies (Huang et al, 2019(Huang et al, , 2021, RNA-Seq analysis in the liver of Pelodiscus sinensis between nonhibernation and hibernation periods indicated that genes involved in lipid β-oxidation were up-regulated, while genes responsible for carbohydrate catabolism were down-regulated during hibernation.…”

Cytoprotection by a naturally occurring variant of ATP5G1 in Arctic ground squirrel neural progenitor cells

“…Proteomic and transcriptomic investigations have comprehensively catalogued the impact of season, torpor, and hibernation on cellular and metabolic pathways in several different tissues of hibernating ground squirrels, including the brain (6,(10)(11)(12)(13)(14)(15)(16). Although the mechanisms underlying hibernating ground squirrel ischemia and hypothermia tolerance in the brain are not fully elucidated, studies suggest that post-translational modifications, regulation of cytoskeletal proteins, and upregulation of antioxidants play a prominent role (17)(18)(19). Gene expression profiling and bioinformatic analyses also indicate the cytoprotective contributions of mitochondrial and lysosomal pathways in adapting to hypothermia and hypoxia in ground squirrel and marmot species (20,21).…”

Cytoprotection by a naturally occurring variant of ATP5G1 in Arctic ground squirrels

“…Proteomic and transcriptomic investigations have comprehensively catalogued the impact of season, torpor, and hibernation on cellular and metabolic pathways in several different tissues of hibernating ground squirrels, including brain (6, 10-16). Although the mechanisms underlying hibernating ground squirrel ischemia and hypothermia tolerance in the brain are not fully elucidated, studies suggest that post-translational modifications, regulation of cytoskeletal proteins, and upregulation of antioxidants play a prominent role (17-19). Recent studies employing unbiased next-generation sequencing and bioinformatics approaches have also highlighted the cytoprotective contributions of mitochondrial and lysosomal pathways in adapting to hypothermia and hypoxia in ground squirrel and marmot species (20, 21).…”