ACSL4 contributes to ferroptosis-mediated rhabdomyolysis in exertional heat stroke.
ACSL4 contributes to ferroptosis-mediated rhabdomyolysis in exertional heat stroke.
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DOI：
10.1002/jcsm.12953
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发表时间：
2022-06
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影响因子：
--
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中科院分区：
文献类型：
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横纹肌溶解症（RM）是劳力性中暑（EHS）的常见并发症，并构成死亡的直接原因。然而，EHS后RM的潜在机制仍不清楚。小鼠EHS模型通过我们先前的方案制备。应用RNA测序来鉴定导致EHS后RM的病理途径。在离子霉素加热应激暴露前，通过体外RNA沉默或在热和运动暴露前，通过体内药理学抑制剂实现酰基辅酶A合成酶长链家族成员4（ACSL 4）的抑制。测量骨骼肌组织的组织学变化、铁积累、氧化磷脂酰乙醇胺物质以及组织学评价和脂质代谢产物水平。我们证明，铁凋亡有助于RM的发展以下EHS。EHS发作后立即给予铁凋亡抑制剂ferrostatin-1，可显著改善EHS小鼠的存活率，从35.357%提高至EHS后24 h内的52.288%（与对照组相比，P = 0.0028），并显著抑制EHS诱导的RM发展。通过比较热应激（n = 3）和假热应激（n = 3）小鼠腓肠肌（Gas）组织中Acsl 4基因表达的差异，证实了EHS小鼠Gas肌组织中Acsl 4 mRNA表达水平升高（与SHR相比P = 0.0038），其蛋白水平也升高（与SHR相比P = 0.0001）。随后肌酸激酶（CK）和肌红蛋白（MB）水平升高，不稳定铁积累，谷胱甘肽过氧化物酶4（GPX 4）表达减少，脂质过氧化产物升高。根据体内和体外实验，抑制Acsl 4显著改善由EHS引起的肌细胞死亡，从而改善RM发展，随后CK和MB水平降低30-40%（P < 0.0001; n = 8-10）和40%（P < 0.0001; n = 8-10），GPX 4表达恢复，并且脂质过氧化产物减少。从机制上讲，ACSL 4介导的RM似乎是通过TEA结构域转录因子1/TEA结构域转录因子4依赖的Yes相关蛋白（雅普）。这些发现表明ACSL 4在EHS后RM发展中介导铁凋亡激活的重要作用，并表明靶向ACSL 4可能代表一种新的治疗策略，以限制EHS后骨骼肌细胞死亡并预防RM。
Rhabdomyolysis (RM) is a common complication of exertional heat stroke (EHS) and constitutes a direct cause of death. However, the mechanism underlying RM following EHS remains unclear. The murine EHS model was prepared by our previous protocol. RNA sequencing is applied to identify the pathological pathways that contribute to RM following EHS. Inhibition of the acyl‐CoA synthetase long‐chain family member 4 (ACSL4) was achieved by RNA silencing in vitro prior to ionomycin plus heat stress exposure or pharmacological inhibitors in vivo prior to heat and exertion exposure. The histological changes, the iron accumulation, oxidized phosphatidylethanolamines species, as well as histological evaluation and levels of lipid metabolites in skeletal muscle tissues were measured. We demonstrated that ferroptosis contributes to RM development following EHS. Ferroptosis inhibitor ferrostatin‐1 administration once EHS onset significantly ameliorated the survival rate of EHS mice from 35.357% to 52.288% within 24 h after EHS (P = 0.0028 compared with control) and markedly inhibited RM development induced by EHS. By comparing gene expression of between sham heat rest (SHR) (n = 3) and EHS (n = 3) mice in the gastrocnemius (Gas) muscle tissue, we identified that Acsl4 mRNA expression is elevated in Gas muscle tissue of EHS mice (P = 0.0038 compared with SHR), so as to its protein levels (P = 0.0001 compared with SHR). Followed by increase in creatine kinase (CK) and myoglobin (MB) levels, the labile iron accumulation, decrease in glutathione peroxidase 4 (GPX4) expression, and elevation of lipid peroxidation products. From in vivo and in vitro experiments, inhibition of Acsl4 significantly improves muscle cell death caused by EHS, thereby ameliorating RM development, followed by reduction in CK and MB levels by 30–40% (P < 0.0001; n = 8–10) and 40% (P < 0.0001; n = 8–10), restoration of GPX4 expression, and decrease in lipid peroxidation products. Mechanistically, ACSL4‐mediated RM seems to be Yes‐associated protein (YAP) dependent via TEA domain transcription factor1/TEA domain transcription factor4. These findings demonstrate an important role of ACSL4 in mediating ferroptosis activation in the development of RM following EHS and suggest that targeting ACSL4 may represent a novel therapeutic strategy to limit the skeletal muscle cell death and prevent RM after EHS.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
4.8
作者：
Wang, Yuehong;Yu, Ruihuan;Yang, Guangdong
通讯作者：
Yang, Guangdong
影响因子：
5.8
作者：
Leon, Lisa R.;Bouchama, Abderrezak
通讯作者：
Bouchama, Abderrezak