Whole genome transcriptomic profiling reveals distinct sex-specific responses to heat stroke.

IF 3.3 3区 医学 Q1 PHYSIOLOGY
Journal of applied physiology Pub Date : 2025-04-01 Epub Date: 2025-03-11 DOI:10.1152/japplphysiol.00001.2025
Abderrezak Bouchama, Maria Gomez, Mashan L Abdullah, Saeed Al Mahri, Shuja Shafi Malik, Saber Yezli, Sameer Mohammad, Cynthia Lehe, Bisher Abuyassin, Robert Hoehndorf
{"title":"Whole genome transcriptomic profiling reveals distinct sex-specific responses to heat stroke.","authors":"Abderrezak Bouchama, Maria Gomez, Mashan L Abdullah, Saeed Al Mahri, Shuja Shafi Malik, Saber Yezli, Sameer Mohammad, Cynthia Lehe, Bisher Abuyassin, Robert Hoehndorf","doi":"10.1152/japplphysiol.00001.2025","DOIUrl":null,"url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":15160,"journal":{"name":"Journal of applied physiology","volume":" ","pages":"964-978"},"PeriodicalIF":3.3000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of applied physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/japplphysiol.00001.2025","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/11 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
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.

全基因组转录组分析揭示了对中暑的不同性别特异性反应。
与高温有关的死亡仍然是因气候变化而加剧的健康挑战,其结果存在性别差异,但其潜在机制仍知之甚少。本研究检测了19例中暑患者外周血单核细胞对热暴露的转录组反应(男性8例,平均年龄64.8±6.6岁;女性11例,平均年龄49.7±11岁),对照组19例(男性11例,平均年龄48.9±9.6岁;女性8例,平均年龄44.9±11.8岁)。入院时,基因表达显示热休克蛋白基因上调和通路分析,表明热休克激活和未折叠蛋白反应在两性中与蛋白质毒性应激一致。然而,在两性中观察到不同的代谢、氧化应激、细胞周期控制和免疫反应。女性表现出蛋白质合成、氧化磷酸化和代谢途径(包括葡萄糖代谢)的抑制,表明低代谢状态。雄性在冷却前保持代谢活性,冷却后增加ATP的产生。雌性激活nrf2介导的氧化应激反应,抑制DNA复制和有丝分裂,可能减轻基因组的不稳定性,而这些途径在雄性中显示出有限的调控。雌性通过IL-6、炎性体和TREM1信号传导促进先天免疫,而雄性则抑制先天免疫和适应性免疫,包括IL-12、Th1和t细胞受体途径。上游分析在两性中发现了超过100个转录因子。雄性主要依赖于转录机制,而雌性也通过LARP1、FMR1、IGF2BP1和EIF6表现出翻译调控。这些发现表明,不同的、性别特异性的分子适应中暑,强调需要有针对性的治疗策略,以减轻热引起的发病率和死亡率。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
6.00
自引率
9.10%
发文量
296
审稿时长
2-4 weeks
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信