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Research ArticleDrug Discovery and Translational Medicine

Opening of Intermediate Conductance Ca2+-Activated K+ Channels in C2C12 Skeletal Muscle Cells Increases the Myotube Diameter via the Akt/Mammalian Target of Rapamycin Pathway

Yuzo Iseki, Yuko Ono, Chihiro Hibi, Shoko Tanaka, Shunya Takeshita, Yuko Maejima, Junko Kurokawa, Masahiro Murakawa, Kenju Shimomura and Kazuho Sakamoto
Journal of Pharmacology and Experimental Therapeutics March 2021, 376 (3) 454-462; DOI: https://doi.org/10.1124/jpet.120.000290
Yuzo Iseki
Departments of Bioregulation and Pharmacological Medicine (Y.I., Y.O., S.T., Y.M., K.Sh., K.Sa.) and Anesthesiology (Y.I., M.M.), Fukushima Medical University, School of Medicine, Fukushima, Japan; Department of Disaster and Emergency Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan (Y.O.); and Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi, Shizuoka, Japan (C.H., S.T., J.K., K.Sa.)
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Yuko Ono
Departments of Bioregulation and Pharmacological Medicine (Y.I., Y.O., S.T., Y.M., K.Sh., K.Sa.) and Anesthesiology (Y.I., M.M.), Fukushima Medical University, School of Medicine, Fukushima, Japan; Department of Disaster and Emergency Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan (Y.O.); and Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi, Shizuoka, Japan (C.H., S.T., J.K., K.Sa.)
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Chihiro Hibi
Departments of Bioregulation and Pharmacological Medicine (Y.I., Y.O., S.T., Y.M., K.Sh., K.Sa.) and Anesthesiology (Y.I., M.M.), Fukushima Medical University, School of Medicine, Fukushima, Japan; Department of Disaster and Emergency Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan (Y.O.); and Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi, Shizuoka, Japan (C.H., S.T., J.K., K.Sa.)
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Shoko Tanaka
Departments of Bioregulation and Pharmacological Medicine (Y.I., Y.O., S.T., Y.M., K.Sh., K.Sa.) and Anesthesiology (Y.I., M.M.), Fukushima Medical University, School of Medicine, Fukushima, Japan; Department of Disaster and Emergency Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan (Y.O.); and Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi, Shizuoka, Japan (C.H., S.T., J.K., K.Sa.)
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Shunya Takeshita
Departments of Bioregulation and Pharmacological Medicine (Y.I., Y.O., S.T., Y.M., K.Sh., K.Sa.) and Anesthesiology (Y.I., M.M.), Fukushima Medical University, School of Medicine, Fukushima, Japan; Department of Disaster and Emergency Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan (Y.O.); and Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi, Shizuoka, Japan (C.H., S.T., J.K., K.Sa.)
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Yuko Maejima
Departments of Bioregulation and Pharmacological Medicine (Y.I., Y.O., S.T., Y.M., K.Sh., K.Sa.) and Anesthesiology (Y.I., M.M.), Fukushima Medical University, School of Medicine, Fukushima, Japan; Department of Disaster and Emergency Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan (Y.O.); and Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi, Shizuoka, Japan (C.H., S.T., J.K., K.Sa.)
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Junko Kurokawa
Departments of Bioregulation and Pharmacological Medicine (Y.I., Y.O., S.T., Y.M., K.Sh., K.Sa.) and Anesthesiology (Y.I., M.M.), Fukushima Medical University, School of Medicine, Fukushima, Japan; Department of Disaster and Emergency Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan (Y.O.); and Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi, Shizuoka, Japan (C.H., S.T., J.K., K.Sa.)
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Masahiro Murakawa
Departments of Bioregulation and Pharmacological Medicine (Y.I., Y.O., S.T., Y.M., K.Sh., K.Sa.) and Anesthesiology (Y.I., M.M.), Fukushima Medical University, School of Medicine, Fukushima, Japan; Department of Disaster and Emergency Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan (Y.O.); and Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi, Shizuoka, Japan (C.H., S.T., J.K., K.Sa.)
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Kenju Shimomura
Departments of Bioregulation and Pharmacological Medicine (Y.I., Y.O., S.T., Y.M., K.Sh., K.Sa.) and Anesthesiology (Y.I., M.M.), Fukushima Medical University, School of Medicine, Fukushima, Japan; Department of Disaster and Emergency Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan (Y.O.); and Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi, Shizuoka, Japan (C.H., S.T., J.K., K.Sa.)
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Kazuho Sakamoto
Departments of Bioregulation and Pharmacological Medicine (Y.I., Y.O., S.T., Y.M., K.Sh., K.Sa.) and Anesthesiology (Y.I., M.M.), Fukushima Medical University, School of Medicine, Fukushima, Japan; Department of Disaster and Emergency Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan (Y.O.); and Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi, Shizuoka, Japan (C.H., S.T., J.K., K.Sa.)
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Abstract

The activation of potassium channels and the ensuing hyperpolarization in skeletal myoblasts are essential for myogenic differentiation. However, the effects of K+ channel opening in myoblasts on skeletal muscle mass are unclear. Our previous study revealed that pharmacological activation of intermediate conductance Ca2+-activated K+ channels (IKCa channels) increases myotube formation. In this study, we investigated the effects of 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (DCEBIO), a Ca2+-activated K+ channel opener, on the mass of skeletal muscle. Application of DCEBIO to C2C12 cells during myogenesis increased the diameter of C2C12 myotubes in a concentration-dependent manner. This DCEBIO-induced hypertrophy was abolished by gene silencing of IKCa channels. However, it was resistant to 1 µM but sensitive to 10 µM TRAM-34, a specific IKCa channel blocker. Furthermore, DCEBIO reduced the mitochondrial membrane potential by opening IKCa channels. Therefore, DCEBIO should increase myotube mass by opening of IKCa channels distributed in mitochondria. Pharmacological studies revealed that mitochondrial reactive oxygen species (mitoROS), Akt, and mammalian target of rapamycin (mTOR) are involved in DCEBIO-induced myotube hypertrophy. An additional study demonstrated that DCEBIO-induced muscle hypertrophic effects are only observed when applied in the early stage of myogenic differentiation. In an in vitro myotube inflammatory atrophy experiment, DCEBIO attenuated the reduction of myotube diameter induced by endotoxin. Thus, we concluded that DCEBIO increases muscle mass by activating the IKCa channel/mitoROS/Akt/mTOR pathway. Our study suggests the potential of DCEBIO in the treatment of muscle wasting diseases.

Significance Statement Our study shows that 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (DCEBIO), a small molecule opener of Ca2+-activated K+ channel, increased muscle diameter via the mitochondrial reactive oxygen species/Akt/mammalian target of rapamycin pathway. And DCEBIO overwhelms C2C12 myotube atrophy induced by endotoxin challenge. Our report should inform novel role of K+ channel in muscle development and novel usage of K+ channel opener such as for the treatment of muscle wasting diseases.

Footnotes

    • Received August 20, 2020.
    • Accepted December 23, 2020.
  • This study was supported by grants to Y.O. [18K16544], J.K. [19H03380], K.Sh. [17K09840], and K.Sa. [18K06897] from the Japan Society for the Promotion of Science (KAKENHI). This research was also supported by Joint Research of Exploratory Research Center on Life and Living Systems (ExCELLS) [No. 19-204] and the Nakatomi Foundation. No author has an actual or perceived conflict of interest with the contents of this article.

  • https://doi.org/10.1124/jpet.120.000290.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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Research ArticleDrug Discovery and Translational Medicine

IKCa Channels in Muscle Hypertrophy

Yuzo Iseki, Yuko Ono, Chihiro Hibi, Shoko Tanaka, Shunya Takeshita, Yuko Maejima, Junko Kurokawa, Masahiro Murakawa, Kenju Shimomura and Kazuho Sakamoto
Journal of Pharmacology and Experimental Therapeutics March 1, 2021, 376 (3) 454-462; DOI: https://doi.org/10.1124/jpet.120.000290

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Research ArticleDrug Discovery and Translational Medicine

IKCa Channels in Muscle Hypertrophy

Yuzo Iseki, Yuko Ono, Chihiro Hibi, Shoko Tanaka, Shunya Takeshita, Yuko Maejima, Junko Kurokawa, Masahiro Murakawa, Kenju Shimomura and Kazuho Sakamoto
Journal of Pharmacology and Experimental Therapeutics March 1, 2021, 376 (3) 454-462; DOI: https://doi.org/10.1124/jpet.120.000290
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