Delayed metabolic disturbances in the myocardium after exertional heat stroke: contrasting effects of exertion and thermal load

Epidemiological studies report higher risks of cardiovascular disease in humans exposed to heat stroke earlier in life. Previously, we explored mechanistic links between heat stroke and developing cardiac abnormalities using a preclinical mouse model of exertional heat stroke (EHS). Profound metabolic abnormalities developed in the ventricles of females but not males after 2 wk of recovery. Here we tested whether this lack of response in males could be attributed to the lower exercise performances or reduced thermal loads they experienced with the same running protocol. We systematically altered environmental temperature (T_e) during EHS to manipulate heat exposure and exercise performance in the males. Three groups of adult C57BL/6 male mice were studied: "EHS-34" (T_e = 34°C), "EHS-41" (T_e = 41°C), and "EHS-39.5" (T_e = 39.5°C). Mice ran until symptom limitation (unconsciousness), reaching max core temperature (T_c,max). After a 2-wk recovery, the mice were euthanized, and the ventricles were removed for untargeted metabolomics. Results were compared against age-matched nonexercise controls. The EHS-34 mice greatly elevated their exercise performance but reached lower T_c,max and lower thermal loads. The EHS-41 mice exhibited equivalent thermal loads, exercise times, and T_c,max compared with EHS-39.5. The ventricles from EHS-34 mice exhibited the greatest metabolic disturbances in the heart, characterized by shifts toward glucose metabolism, reductions in acylcarnitines, increased amino acid metabolites, elevations in antioxidants, altered TCA cycle flux, and increased xenobiotics. In conclusion, delayed metabolic disturbances following EHS in male myocardium appear to be greatly amplified by higher levels of exertion in the heat, even with lower thermal loads and max core temperatures.NEW & NOTEWORTHY Epidemiological data demonstrate greater cardiovascular risk in patients with previous heat stroke exposure. Using a preclinical mouse model of exertional heat stroke, male mice were exposed to one of three environmental temperatures (T_e) during exercise. Paradoxically, after 2 wk, the mice in the lowest T_e, exhibiting the largest exercise response and lowest heat load, had the greatest ventricular metabolic disturbances. Metabolic outcomes resemble developing left ventricular hypertrophy or stress-induced heart disease.