Exertional heat stroke causes long-term skeletal muscle epigenetic reprogramming, altered gene expression, and impaired satellite cell function in mice.

IF 2.2 3区 医学 Q3 PHYSIOLOGY
Kevin O Murray, Jason O Brant, Ray A Spradlin, Trace Thome, Orlando Laitano, Terence E Ryan, Alberto Riva, Michael P Kladde, Thomas L Clanton
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引用次数: 0

Abstract

The effect of exertional heat stroke (EHS) exposure on skeletal muscles is incompletely understood. Muscle weakness is an early symptom of EHS but is not considered a major target of multiorgan injury. Previously, in a preclinical mouse model of EHS, we observed the vulnerability of limb muscles to a second EHS exposure, suggesting hidden processes contributing to declines in muscle resilience. Here, we evaluated the possible molecular origins of EHS-induced declines in muscle resilience. Female C57BL/6 mice [total n = 56; 28/condition, i.e., EHS and exercise control (EXC)] underwent forced wheel running at 37.5°C/40% relative humidity until symptom limitation (unconsciousness). EXC mice exercised identically at room temperature (22-23°C). After 1 mo of recovery, the following were assessed: 1) specific force and caffeine-induced contracture in soleus (SOL) and extensor digitorum longus (EDL) muscles; 2) transcriptome and DNA methylome responses in gastrocnemius (GAST); and 3) primary satellite cell function (proliferation and differentiation). There were no differences in specific force in either SOL or EDL from EXC. Only EHS solei exhibited lower caffeine sensitivity. EHS GAST exhibited higher RNA expression of genes encoding structural proteins of slow fibers, heat shock proteins, and myogenesis. A total of ∼2,500 differentially methylated regions of DNA that could potentially affect many cell functions were identified. Primary satellite cells exhibited suppressed proliferation rates but normal differentiation responses. Results demonstrate long-term changes in skeletal muscles 1 mo after EHS that could contribute to declines in muscle resilience. Skeletal muscle may join other, more recognized tissues considered vulnerable to long-term effects of EHS.NEW & NOTEWORTHY Exertional heat stroke (EHS) in mice induces long-term molecular and functional changes in limb muscle that could reflect a loss of "resilience" to further stress. The phenotype was characterized by altered caffeine sensitivity and suppressed satellite cell proliferative potential. This was accompanied by changes in gene expression and DNA methylation consistent with ongoing muscle remodeling and stress adaptation. We propose that EHS may induce a prolonged vulnerability of skeletal muscle to further stress or injury.

劳累性中暑导致小鼠骨骼肌长期表观遗传重编程、基因表达改变和卫星细胞功能受损。
劳累性中暑(EHS)暴露对骨骼肌的影响尚不完全清楚。肌肉无力是EHS的早期症状,但不被认为是多器官损伤的主要目标。此前,在EHS的临床前小鼠模型中,我们观察到肢体肌肉对第二次EHS暴露的易感性,这表明隐藏的过程导致了肌肉恢复能力的下降。在这里,我们评估了ehs诱导的肌肉恢复力下降的可能分子起源。雌性C57BL/6小鼠[总n =56;28/条件,即EHS和运动控制(EXC)]在37.5°C/40%相对湿度下进行强制车轮运行,直到症状限制(无意识)。EXC小鼠在室温(22-23℃)下运动相同。恢复一个月后,进行以下评估:(1)比目鱼肌(SOL)和指长伸肌(EDL)肌肉的比力和咖啡因引起的挛缩;(2)腓肠肌(GAST)的转录组和DNA甲基组反应;(3)初级卫星细胞功能(增殖和分化)。与EXC相比,SOL和EDL的比力没有差异,只有EHS solei对咖啡因的敏感性较低。EHS GAST表现出较高的慢纤维结构蛋白、热休克蛋白和肌生成基因的RNA表达。总共鉴定了约2500个可能影响许多细胞功能的DNA差异甲基化区域。原代卫星细胞增殖速率受到抑制,但分化反应正常。结果表明,EHS后一个月骨骼肌的长期变化可能导致肌肉弹性下降。骨骼肌可能会加入其他更容易受到EHS长期影响的组织。
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来源期刊
CiteScore
5.30
自引率
3.60%
发文量
145
审稿时长
2 months
期刊介绍: The American Journal of Physiology-Regulatory, Integrative and Comparative Physiology publishes original investigations that illuminate normal or abnormal regulation and integration of physiological mechanisms at all levels of biological organization, ranging from molecules to humans, including clinical investigations. Major areas of emphasis include regulation in genetically modified animals; model organisms; development and tissue plasticity; neurohumoral control of circulation and hypertension; local control of circulation; cardiac and renal integration; thirst and volume, electrolyte homeostasis; glucose homeostasis and energy balance; appetite and obesity; inflammation and cytokines; integrative physiology of pregnancy-parturition-lactation; and thermoregulation and adaptations to exercise and environmental stress.
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