Exposure to an elevated state of hyperthermia is associated with heat-induced cytotoxicity, which, if left unabated, can cause tissue damage and death. Although activation of autophagy is vital to counter heat-induced cellular injury and promote cellular survival, the dose-dependent autophagic response to controlled elevations in body core temperature has yet to be evaluated in an in vivo human model. Therefore, on separate days, we evaluated cellular responses in 12 young adults [means (SD): 22 (2) yr; 6 women] who were immersed (up to the clavicle) in water set at a temperature to clamp core temperature (esophageal) at either baseline resting (control; 37°C), warm (38°C), or hot (39°C) conditions for 60 min. Autophagy was characterized in peripheral blood mononuclear cells before and after water immersion, as well as following 3 h of seated recovery in a temperate environment (∼22°C). Proteins associated with autophagy and cellular stress pathways (apoptosis, inflammation, and heat shock response) were assessed via Western blot. With increasing levels of hyperthermia, we observed increasing autophagic activation (as indexed via elevated LC3-II and decreasing p62) at end exposure to warm and hot core temperature clamps, with evidence of elevated autophagic activity up to 3 h after exposure to the hot condition. This was paired with significant end exposure elevations in cellular stress proteins including cleaved-caspase-3, TNF-α, and IL-6 in the hottest condition. Taken together, our findings suggest that autophagy is activated with increasing levels of hyperthermia and may be important in restoring cellular homeostasis when exposed to body core temperatures above 38°C in healthy young adults.Our findings suggest that autophagic regulation is stimulated in peripheral blood mononuclear cells associated with elevations in body core temperature induced through warm-to-hot water immersion. Importantly, our findings propose that autophagy may be important in restoring cellular homeostasis when exposed to body core temperatures above 38°C in healthy young adults. Therefore, the use of warm-to-hot water immersion may provide a potent model to study cellular heat stress responses in humans. NEW & NOTEWORTHY
