Heart Metabolic Responses to Exertional Heat Stroke Are Dependent Upon Sex
Authors: Laitano Orlando , Garcia Christian K. , Ingram Brian , Robinson Gerard P. , Mattingly Alex J. , Ippolito Danielle L. , Leon Lisa R. , Clanton Thomas L. 
Published: June 2021

In virtually all eukaryotic organisms, sex is an important variable affecting many physiological functions. In exertional heat stroke (EHS), the cardiac muscle plays a dual role to pump blood to the active skeletal muscles and to the periphery for heat exchange, but whether the metabolic responses occurring in the cardiac muscle after EHS are sex‐dependent remains unknown. In our pre‐clinical model of EHS, female mice run longer in the heat and this advantage seems to be regardless of body size. Our aim was to determine sex differences in cardiac muscle's metabolic biomarkers in response to a single session of EHS. Sixteen male and 16 female C57BL6J mice were trained to run on an incremental forced running wheel and were exposed to 37.5°C/~40% relative humidity while running to induce EHS. Hearts were harvested 3 h after the EHS trial. Control mice ran for the same relative duration and were sacrificed 4 days after the trial. Metabolites were extracted from the heart and analyzed by mass spectrometry. Metabolites were matched to a library of standards for identification and quantification. Time to achieve EHS was 121.16 ± 22 min for males and 189.25 ± 35 for females (p<0.05). Glucose‐6‐phosphate (G‐6‐P) increased 2‐fold in males after EHS in comparison to control and remained unchanged in females. Males had a 2‐fold higher G‐6‐P concentration after EHS in comparison to females (p<0.05). These changes highlight a greater reliance on glycolytic pathways in the heart for males after EHS. While pyruvate was unchanged in males compared to control, we observed an increase after EHS in females compared to their matched controls (p<0.05). After EHS, females exhibited a higher pyruvate content in comparison to males (p<0.05). The accumulation of pyruvate in females suggests a greater reliance on fatty acid metabolism in the heart after EHS. All branched chain amino acids (leucine, isoleucine and valine) increased in both sexes after EHS (p<0.05), but we did not observe differences between sexes. While the content of palmitoylcarnitine decreased 0.5‐fold after EHS in males, we observed the reverse in females, a 0.5‐fold increase (p<0.05). Likewise, stearoylcarnitine increased in females after EHS, but remained unchanged in males (p<0.05). Because both carnitine metabolites may serve as a substrate for carnitine palmitoyl transferase enzymatic system, which is critical for fatty acid metabolism, we interpret this as evidence of greater reliance on fatty acid metabolism in female heart in comparison to males. In conclusion, we observed relevant and distinct metabolic changes in males versus females after EHS, consistent with female heart having a greater capacity to rely on fatty acid metabolism in comparison to males. Whether these differences explain the more resistant phenotype observed in females during EHS remains to be determined. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or reflecting the views of the Army or the DoD.Support or Funding InformationDOD Grant W81XWH‐15‐2‐0038This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.