Golden-mantled ground squirrels (Callospermophilus lateralis) are elite hibernators. Seasonal torpor as a result of environmental extremes induces a reduction in body temperature (Tb) to 4°C and oxygen consumption rates 1/100th of active rates. Most hibernators are not capable of Tb reduction to this extent; instead, mammalian hibernators employ diverse strategies and perform torpor at Tb’s ranging from cold (rodents) to hot (bears). We performed transcriptomic analysis of brain, heart, liver, and kidney tissues collected from ground squirrels during early torpor across a range of ambient temperatures (4, 12, 20, 25, 30°C). The highest number of differentially expressed genes (DEG’s) in the brain was between the euthermic squirrels and those torpid at 25ºC (3425 DE genes; pFDR< 0.01). The highest number of DEG’s for heart (2742 genes), liver (3586 genes), and kidney tissue (2233 genes) occurred between euthermic squirrels and those torpid at 20ºC. To elucidate human cells responses to metabolic depression, mimicking torpor, a 24-hour temperature exposure was performed at the torpor temperatures listed above. Human cells were chosen to reflect tissues investigated in the ground squirrel model including a human astrocytoma cell line, AC-16 cardiomyocytes, HEK-293T, and HEPG2 cells. Temperature-responsive differential gene expressions was compared between cells kept in 37°C incubators and cold-stressed cells at each experimental temperature. The highest number of DEG’s for heart (7,979), brain (8,339), and kidney cells (8,610) were between cells kept at 37°C and those cold-stressed at 25°C. In the liver, the most DEG’s were found between cells at 20°C and 4°C (8,707), cells kept at 37°C and those stressed at 25°C had (6,421) DEG’s. These results indicate torpid temperatures in warm conditions, around 20-25°C, elicit robust molecular responses, suggesting cellular dysregulation may be occurring. Pathway analysis revealed more enriched pathways in human cells incubated at 37°C when compared to 20°C, more than other pairwise comparisons including 37°C and 4°C. Additionally, the overlap between the pairwise comparisons of 37°C and 20°C, and 20°C and 4°C, saw more enriched pathways. This indicates that 20°C causes larger transcriptomic responses when compared to both extremes and thus more energy to execute torpor-like responses at this temperature. We have observed warm torpid temperatures between 20-25°C induce molecular responses related to cell stress such as ferroptosis, the s100 signaling pathway, and inflammatory cytokine expression. Teasing apart the temperature-specific differences in human cells will provide insight into the molecular strategies mammals engage across wide-ranging hibernation phenotypes. Further investigation of cellular morphological changes post-cold stress may supplement transcriptomic data and highlight cellular pathways necessary for torpor-like conditions such as nuclear condensation, cytoskeletal remodeling, and transcript locality. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Crippen et al. (Fri,) studied this question.