Abderrezak Bouchama, Maria Gomez, Mashan L Abdullah, Saeed Al Mahri, Shuja Shafi Malik, Saber Yezli, Sameer Mohammad, Cynthia Lehe, Bisher Abuyassin, Robert Hoehndorf
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引用次数: 0
Abstract
Heat-related mortality remains health challenges exacerbated by climate change, with sex-based differences in outcomes, yet underlying mechanisms remain poorly understood. This study examined transcriptomic responses to heat exposure in peripheral blood mononuclear cells from 19 patients with heat stroke (HS; 8 males, mean age 64.8 ± 6.6 yr; 11 females, mean age 49.7 ± 11 yr) and 19 controls (11 males, mean age 48.9 ± 9.6 yr; 8 females, mean age 44.9 ± 11.8 yr). At admission, gene expression revealed upregulation of heat shock protein genes, and pathway analysis demonstrated activation of heat shock and unfolded protein responses across both sexes consistent with proteotoxic stress. However, distinct metabolic, oxidative stress, cell cycle control, and immune responses were observed within each sex. Females displayed inhibition of protein synthesis, oxidative phosphorylation, and metabolic pathways, including glucose metabolism, indicative of a hypometabolic state. Males maintained metabolic activity precooling and enhanced adenosine triphosphate production postcooling. Females activated nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress responses and inhibited DNA replication and mitosis, potentially mitigating genomic instability, whereas these pathways showed limited regulation in males. Females promoted innate immunity via interleukin (IL)-6, inflammasome, and triggering receptor expressed on myeloid cells 1 (TREM1) signaling, whereas males showed suppression of both innate and adaptive immunity, including IL-12, Th1, and T-cell receptor pathways. Upstream analysis identified over 100 transcription factors in both sexes. Males primarily relied on transcriptional mechanisms, whereas females also exhibited translational regulation via La ribonucleoprotein 1 (LARP1), fragile X messenger ribonucleoprotein 1 (FMR1), insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), and eukaryotic translation initiation factor 6 (EIF6). These findings suggest distinct, sex-specific molecular adaptations to heat stroke, underscoring the need for targeted therapeutic strategies to mitigate heat-induced morbidity and mortality.NEW & NOTEWORTHY Heat-related mortality continues to rise with climate change. Our transcriptomic analysis reveals distinct sex-specific metabolic strategies to heat stroke: females enter a hypometabolic state, an evolutionary adaptation that conserves energy, whereas males sustain metabolic activity. Transcription factors and a subset of translation regulators in females modulate proteostasis and bioenergetics, driving these sex-specific pathways. These novel findings highlight the critical need to consider sex-specific differences in heat-related illnesses and inform carefully targeted interventions to improve patient outcomes.
期刊介绍:
The Journal of Applied Physiology publishes the highest quality original research and reviews that examine novel adaptive and integrative physiological mechanisms in humans and animals that advance the field. The journal encourages the submission of manuscripts that examine the acute and adaptive responses of various organs, tissues, cells and/or molecular pathways to environmental, physiological and/or pathophysiological stressors. As an applied physiology journal, topics of interest are not limited to a particular organ system. The journal, therefore, considers a wide array of integrative and translational research topics examining the mechanisms involved in disease processes and mitigation strategies, as well as the promotion of health and well-being throughout the lifespan. Priority is given to manuscripts that provide mechanistic insight deemed to exert an impact on the field.