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Background <p>Malignant hyperthermia (MH) is caused by the dysregulation of calcium (Ca<sup>2+</sup>) in skeletal muscle cells. In this study, we evaluated the accuracy of a method for diagnosing susceptibility to MH using myotubes as an alternative to Ca<sup>2+</sup>-induced Ca<sup>2+</sup> release rate (CICR) test.</p> Methods <p>In this retrospective study, we retrospectively analyzed Ca<sup>2</sup>⁺ kinetics data obtained using fura-2/AM from myotubes that had been cultured from remnant muscle fibers of 98 patients who had previously undergone CICR testing for MH susceptibility in Japan. The 50% effective concentrations (EC<sub>50</sub>) of caffeine and 4-chloro-m-cresol (4-CmC) were calculated from the concentration response curves. The previously calculated cut-off values (caffeine: 3.62&#xa0;mM, 4-CmC: 197&#xa0;μM) were used to diagnose susceptibility to MH. The diagnostic accuracy of myotubes was compared with that of the CICR test. Statistical significance was tested using the Mann–Whitney U test.</p> Results <p>The CICR test identified 76 patients as CICR-Positive and 22 patients as CICR-Negative. The EC<sub>50</sub> for caffeine was 2.9 (2.4–3.3) and 5.0 (4.5–5.5) mM in the CICR-Positive and CICR-Negative groups, respectively (<i>p</i> &lt; 0.0001). The EC<sub>50</sub> of 4-CmC was 130 (116–148) and 249 (226–289) μM in the CICR-Positive and CICR-Negative groups, respectively (<i>p</i> &lt; 0.0001). The sensitivity for caffeine for myotubes was 98.7% (95%CI 92.9–99.9). The specificity for caffeine was 100% (95%CI 85.1–100.0). The sensitivity and specificity for 4-CmC were 100% (95%CI 95.2–100.0) and 100% (84.5–100.0), respectively.</p> Conclusions <p>Myotubes responses to caffeine and 4-CmC can be regarded as a viable alternative to the conventional CICR test; however, further validation is needed before this test supersedes the CICR.</p>

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Primary myotubes as an alternative to the calcium induced calcium release test in diagnosing malignant hyperthermia susceptibility

  • 期刊论文

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  • 发表日期：

    2026年7月6日

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  • Sachiko Otsuki,
  • Keiko Mukaida,
  • Hirotsugu Miyoshi,
  • Kenshiro Kido,
  • Ayako Sumii,
  • Tsuyoshi Ikeda,
  • Takahiro Kato,
  • Toshimichi Yasuda,
  • Yousuke T. Horikawa,
  • Yasuko Ichihara,
  • Yasuo M. Tsutsumi

摘要

Background

Malignant hyperthermia (MH) is caused by the dysregulation of calcium (Ca2+) in skeletal muscle cells. In this study, we evaluated the accuracy of a method for diagnosing susceptibility to MH using myotubes as an alternative to Ca2+-induced Ca2+ release rate (CICR) test.

Methods

In this retrospective study, we retrospectively analyzed Ca2⁺ kinetics data obtained using fura-2/AM from myotubes that had been cultured from remnant muscle fibers of 98 patients who had previously undergone CICR testing for MH susceptibility in Japan. The 50% effective concentrations (EC50) of caffeine and 4-chloro-m-cresol (4-CmC) were calculated from the concentration response curves. The previously calculated cut-off values (caffeine: 3.62 mM, 4-CmC: 197 μM) were used to diagnose susceptibility to MH. The diagnostic accuracy of myotubes was compared with that of the CICR test. Statistical significance was tested using the Mann–Whitney U test.

Results

The CICR test identified 76 patients as CICR-Positive and 22 patients as CICR-Negative. The EC50 for caffeine was 2.9 (2.4–3.3) and 5.0 (4.5–5.5) mM in the CICR-Positive and CICR-Negative groups, respectively (p < 0.0001). The EC50 of 4-CmC was 130 (116–148) and 249 (226–289) μM in the CICR-Positive and CICR-Negative groups, respectively (p < 0.0001). The sensitivity for caffeine for myotubes was 98.7% (95%CI 92.9–99.9). The specificity for caffeine was 100% (95%CI 85.1–100.0). The sensitivity and specificity for 4-CmC were 100% (95%CI 95.2–100.0) and 100% (84.5–100.0), respectively.

Conclusions

Myotubes responses to caffeine and 4-CmC can be regarded as a viable alternative to the conventional CICR test; however, further validation is needed before this test supersedes the CICR.