Abstract
Exertional heat stroke (EHS) is a life-threatening disease characterized by high mortality and incidence of rhabdomyolysis (RM). It would therefore be valuable to establish a stable EHS-induced RM model that accurately reflects the clinical characteristics of EHS patients and provides an objective animal model for further study of the pathogenesis of RM. In the current study, 8∼9-week-old, male, wild-type C57BL/6J mice, at the stage of sexual maturity, were randomly divided into four groups: the EHS group, the classical heat stroke (CHS) group, the sham heat exercise group, and sham heat rest group. The survival rate of mice was determined under relatively high levels of temperature and humidity (37.5°C, 65% relative humidity (RH); 37.5°C, 70% RH; 39.5°C, 65% RH; and 39.5°C, 70% RH) as well as a high core temperature (Tc; 42, 42.5, and 43°C). Results showed that the environmental condition of 39.5°C and 65% RH was most suitable for EHS modeling. The end point of EHS evaluation was exhaustion or an individual’s core temperature reaching 43°C. The survival rate of mice in the EHS group within 24 h under these conditions was 37.34%, which is consistent with the high mortality characteristics noted in EHS patients. Severe RM was observed in the EHS group by H&E staining and transmission electron microscopy. Creatine kinase levels in the EHS group mostly exceeded 10,000 U/L, which was approximately 10 times higher than that in the sham heat rest group. Renal tubules of the EHS group exhibited severe necrosis, and calcium overload in the skeletal muscles of this group was also observed using intravital 2-photon microscopy. In conclusion, we made improvements to a stable EHS-induced RM animal model to truly reflect the clinical characteristics of EHS patients. This new model should be helpful in the further study of RM pathogenesis.
Highlights
Exertional heat stroke (EHS) is the most complicated and dangerous form of heat stroke as it can lead to irreversible injury and even death (Bouchama and Knochel, 2002)
Of all the heat stroke cases in the U.S Army between 1980 and 2002, 25% cases were associated with rhabdomyolysis, and 13% were associated with acute renal failure; mortality of EHS with hypotension was >30%
The creatinine kinase (CK) level mostly exceeded 10,000 U/L at 6 h after EHS which was 10-fold that of the sham heat rest (SHR) group; there was only a slight increase in the classical heat stroke (CHS) group. These findings suggest that skeletal muscle was severely damaged by EHS
Summary
Exertional heat stroke (EHS) is the most complicated and dangerous form of heat stroke as it can lead to irreversible injury and even death (Bouchama and Knochel, 2002). The existing models have limitations in that they cannot fully reflect the key clinical characteristics of EHS patients. EHS is an acute injury associated with high morbidity and mortality, and is commonly encountered within the military, athletes, and construction workers (Adams et al, 2012). Of all the heat stroke cases in the U.S Army between 1980 and 2002, 25% cases were associated with rhabdomyolysis, and 13% were associated with acute renal failure; mortality of EHS with hypotension was >30%. Other reports indicate that the EHS mortality rate over the last 50 years has remained between 10 and 50% at St Louis and Kansas City (Bouchama, 1995). With the high mortality rate and high incidence of RM in EHS patients, it is suggested that existing EHS animal models do not sufficiently encapsulate key clinical characteristics of the condition
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