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

Abstract

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 two weeks 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 (Te) during EHS to manipulate heat exposure and exercise performance in the males. Three groups of adult C57BL/6 male mice were studied: 'EHS-34' (Te=34°C), 'EHS-41' (Te=41°C), and EHS-39.5 (Te=39.5°C). Mice ran until symptom limitation (unconsciousness), reaching max core temperature (Tc,max). After a 2-wk, the mice were euthanized, and the ventricles removed for untargeted metabolomics. Results were compared against age-matched non-exercise controls. The EHS-34 mice greatly elevated their exercise performance, but reached lower Tc,max and lower thermal loads. The EHS-41 mice exhibited equivalent thermal loads, exercise times and Tc,max compared to 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.