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Preclinical pharmacological in vitro investigations on low chloride conductance myotonia: effects of potassium regulation

  • Muscle physiology
  • Published:
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A Correction to this article was published on 03 September 2020

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Abstract

In myotonia, reduced Cl− conductance of the mutated ClC-1 channels causes hindered muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. Repetitive contraction temporarily decreases myotonia, a phenomena called “warm up.” The underlying mechanism for the reduction of hyperexcitability in warm-up is currently unknown. Since potassium displacement is known to reduce excitability in, for example, muscle fatigue, we characterized the role of potassium in native myotonia congenita (MC) muscle. Muscle specimens of ADR mice (an animal model for low gCl− conductance myotonia) were exposed to increasing K+ concentrations. To characterize functional effects of potassium ion current, the muscle of ADR mice was exposed to agonists and antagonists of the big conductance Ca2+-activated K+ channel (BK) and the voltage-gated Kv7 channel. Effects were monitored by functional force and membrane potential measurements. By increasing [K+]0 to 5 mM, the warm-up phenomena started earlier and at [K+]0 7 mM only weak myotonia was detected. The increase of [K+]0 caused a sustained membrane depolarization accompanied with a reduction of myotonic bursts in ADR mice. Retigabine, a Kv7.2–Kv7.5 activator, dose-dependently reduced relaxation deficit of ADR myotonic muscle contraction and promoted the warm-up phenomena. In vitro results of this study suggest that increasing potassium conductivity via activation of voltage-gated potassium channels enhanced the warm-up phenomena, thereby offering a potential therapeutic treatment option for myotonia congenita.

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Change history

  • 03 September 2020

    The original article contains an error during online publication. Table 2 was included during production round and now deleted. The Original article has been corrected.

Abbreviations

9-AC:

Anthracene-9-carboxylic acid

ADR:

Arrested development of rightening response

AP:

Action potential

BK channel:

Big conductance Ca2+-activated K+ channel

ClC-1:

Skeletal muscle chloride channel type 1

DMSO:

Dimethylsulfoxide

EDL:

Extensor digitorum longus

RMP:

Resting membrane potential

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Acknowledgments

This work is dedicated to Professor Dr Dr hc Frank Lehmann-Horn, who passed away in May 2018. His enthusiasm, helpfulness, and his bright mind are not forgotten. Part of this work were performed by Sunisa Chaiklieng and presented at the 36th European Muscle Conference in Heidelberg, Germany. Frank Lehmann-Horn and Karin Jurkat-Rott are fellows of the non-profit Hertie Foundation.

Funding

S.C. was supported by a governmental scholarship (“Land Baden-Württemberg”) for the promotion of young scientist and the German Academic Exchange Service (DAAD). We also thank the Deutsche Gesellschaft für Muskelkranke (DGM) for the grant to F.L.H. and K.J.R. for research on myotonia.

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Authors and Affiliations

  1. Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Theodor–Stern–Kai 7, 60590, Frankfurt, Germany

    Kerstin Hoppe

  2. Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital of Wuerzburg, Oberduerrbacher Str. 6, 97080, Wuerzburg, Germany

    Kerstin Hoppe & Frank Lehmann-Horn

  3. Division of Neurophysiology in the Center of Rare Diseases, Ulm University, Albert Einstein Allee 23, 89081, Ulm, Germany

    Sunisa Chaiklieng

  4. Faculty of Public Health, Khon Kaen University, Muang Khon Kaen, Thailand

    Sunisa Chaiklieng

  5. Universtiy Medical Center Ulm, Division of Experimental Anesthesiology, Albert-Einstein-Allee 23, 89081, Ullm, Germany

    Karin Jurkat-Rott

  6. Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, 4059, Australia

    Scott Wearing & Werner Klingler

  7. Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, SRH Clinincs, Hohenzollernstraße 40, 72488, Sigmaringen, Germany

    Werner Klingler

  8. Department of Conservative and Rehabilitation Orthopedics, Faculty of Sport and Health Science, Technical University of Munich, Gerog-Brauchle-Ring 60/62, Munich, Germany

    Scott Wearing & Werner Klingler

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  1. Kerstin Hoppe
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  2. Sunisa Chaiklieng
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Contributions

Intellectual content and study design: WK, KH, FLH, SC. Collection, analysis, and interpretation of data: WK, SC, KH, FLH, KJR. Drafting the manuscript and graphical representation of data: KH, SC, WK, FLH. Critical evaluation of the manuscript: KJR, SW, WK. All authors approved the submission of this version of the manuscript. All persons designated as authors quality for authorship and all those who qualify for authorship are listed.

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Correspondence to Kerstin Hoppe.

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The original version of this article was revised: The original article contains an error during online publication. Table 2 was included during production round and now deleted.

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Hoppe, K., Chaiklieng, S., Lehmann-Horn, F. et al. Preclinical pharmacological in vitro investigations on low chloride conductance myotonia: effects of potassium regulation. Pflugers Arch - Eur J Physiol 472, 1481–1494 (2020). https://doi.org/10.1007/s00424-020-02410-4

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