Synergistic effects of commonly used ICU drugs and high temperature on skeletal muscle at the cellular and tissue levels.

Abstract

BACKGROUND Several drugs are commonly administered to patients with high body temperature in intensive care units (ICUs). However, previous in vitro studies have investigated only the independent effects of high temperatures or drugs on various cultured cells. We explored the hypothesis that pharmacological treatment with representative ICU drugs induces lethal effects on cultured skeletal muscle and engineered muscle tissue at high temperatures. METHODS 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 (LDH) 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 3 times. RESULTS Dexmedetomidine and acetaminophen had no observable adverse effects at high temperatures, whereas propofol treatment at > 200 µM resulted in increased LDH 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 (TUDCA), 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. CONCLUSIONS 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, TUDCA 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.