Sugiki Kei, Takahashi Hironobu, Shimizu Tatsuya
Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.
Anesthesiology. 2025 Oct 1;143(4):999-1014. doi: 10.1097/ALN.0000000000005630. Epub 2025 Jun 20.
Several drugs are commonly administered to patients with high body temperature in intensive care units. However, previous in vitro studies have investigated only the independent effects of high temperatures or drugs on various cultured cells. This study explored the hypothesis that pharmacologic treatment with representative intensive care unit drugs induces lethal effects on cultured skeletal muscle and engineered muscle tissue at high temperatures.
Human skeletal muscle cultures were treated with the representative drugs propofol, dexmedetomidine, and acetaminophen at 37°, 39°, and 41°C for various exposure times. To investigate the effects of the drug treatments, cell viability, lactate dehydrogenase activity, caspase activity, and endoplasmic reticulum (ER) stress were analyzed. Conformational changes in myotubes and functional changes in contractile muscle tissue were also assessed. All experiments were repeated at least three times.
Dexmedetomidine and acetaminophen had no observable adverse effects at high temperatures, whereas propofol treatment at greater than 200 μM resulted in increased lactate dehydrogenase activity and myotube detachment. Furthermore, this cellular injury was associated with intracellular calcium overload and upregulation of the ER stress-related genes CHOP, GRP78/Bip, and GRP94. Propofol treatment also decreased the contractile ability of muscle tissues at 39°C ( vs . 37°C propofol; 95% CI, 30.72 to 114.87%; P < 0.001). Additionally, although tauroursodeoxycholic acid, an ER stress inhibitor, alleviated the increase in caspase-3/7 activity at 39°C (95% CI, 38.10 to 145.22%; P < 0.001) and mitigated myotube detachment, it did not result in notable functional improvement in muscle contraction.
These results demonstrate that propofol had harmful effects on skeletal muscle cells and tissues at high temperatures in vitro . As these synergistic effects were closely associated with ER stress, tauroursodeoxycholic acid could mitigate propofol-induced apoptosis at high temperatures. These findings could help improve drug treatment for patients, including their functional prognosis in the clinical setting.
重症监护病房中，几种药物常用于体温过高的患者。然而，以往的体外研究仅探讨了高温或药物对各种培养细胞的单独作用。本研究探讨了如下假说：使用重症监护病房的代表性药物进行药物治疗会在高温下对培养的骨骼肌和工程化肌肉组织产生致死效应。
将人骨骼肌培养物分别在37℃、39℃和41℃下用代表性药物丙泊酚、右美托咪定和对乙酰氨基酚处理不同时间。为研究药物治疗的效果，分析了细胞活力、乳酸脱氢酶活性、半胱天冬酶活性和内质网（ER）应激。还评估了肌管的构象变化和收缩性肌肉组织的功能变化。所有实验均重复至少三次。
右美托咪定和对乙酰氨基酚在高温下未观察到明显不良反应，而丙泊酚浓度大于200μM时处理会导致乳酸脱氢酶活性增加和肌管脱离。此外，这种细胞损伤与细胞内钙超载以及ER应激相关基因CHOP、GRP78/Bip和GRP94的上调有关。丙泊酚处理还降低了肌肉组织在39℃时的收缩能力（与37℃时丙泊酚处理相比；95%CI，30.72至114.87%；P<0.001）。此外，尽管ER应激抑制剂牛磺熊去氧胆酸减轻了39℃时半胱天冬酶-3/7活性的增加（95%CI，38.10至145.22%；P<0.001）并减轻了肌管脱离，但并未使肌肉收缩功能得到显著改善。
这些结果表明，丙泊酚在体外高温下对骨骼肌细胞和组织具有有害作用。由于这些协同效应与ER应激密切相关，牛磺熊去氧胆酸可以减轻丙泊酚在高温下诱导的细胞凋亡。这些发现有助于改善患者的药物治疗，包括临床环境中的功能预后。
