Passive Heating after Heat‐ and Exercise‐Induced Collapse in Mice Induces a Severe Exertional Heat Stroke Phenotype that More Accurately Recapitulates Human Cases

Abstract

Development of a mouse exertional heat stroke (EHS) model that more accurately recapitulates human EHS cases is essential in characterizing the pathophysiology of the condition and determining potential treatment options for heat stroke sequelae in humans. Previously developed murine heat illness models were either done passively [with or without anesthesia] or had an exertional component with little to no mortality and rapid recovery of mice following removal from the high‐temperature environment, effectively modeling a less severe heat illness, exertional heat injury (EHI). Accordingly, we examined whether leaving mice undisturbed in their environment following heat illness collapse results in an EHS model with a level of mortality that more accurately recapitulates the human condition. Trained mice were placed in a forced‐running wheel that gradually increased from low‐to‐moderate speed (3.0 to 8.5 m/min, increasing 0.5 m/min every 10 minutes). Ambient temperature was set at 25°C for Exercise Controls (ExC) and 37.5°C for EHI and EHS specimens while humidity was set at 30‐70% for all conditions. EHS and EHI mice ran in the wheels until losing consciousness; EHI mice were immediately returned to their home cage (25°C) while EHS mice and a conscious ExC counterpart were left undisturbed in their respective chambers for an additional 20 minutes before being returned to their home cages. Overall, higher mortality rates were observed in the EHS mice (14/63) compared to EHI (0/54) and ExC (0/52) mice. A subset of the mice were sacrificed at 48 hours following the exercise/heat bout (n=10‐12/group); in these mice, student’s T‐tests indicated that serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was elevated in EHS vs. ExC while AST was elevated in EHS vs. EHI, suggesting EHS mice exhibited the most hepatic damage. We have developed a protocol to more accurately model human EHS in mice. Our working hypothesis is that heat 1) in the ambient environment and 2) produced by exertion lead to increased core body temperatures in mice that initiate tissue / organ damage. Inhibiting heat dissipation by leaving mice undisturbed in the warm environment exacerbates tissue / organ damage, resulting in a systemic inflammatory response and mortality in some cases.