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Effect of Large-Conductance Calcium-Dependent K+ Channel Activator NS1619 on Function of Mitochondria in the Heart of Dystrophin-Deficient Mice

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Abstract

Dystrophin-deficient muscular dystrophy (Duchenne dystrophy) is characterized by impaired ion homeostasis, in which mitochondria play an important role. In the present work, using a model of dystrophin-deficient mdx mice, we revealed decrease in the efficiency of potassium ion transport and total content of this ion in the heart mitochondria. We evaluated the effect of chronic administration of the benzimidazole derivative NS1619, which is an activator of the large-conductance Ca2+-dependent K+ channel (mitoBKCa), on the structure and function of organelles and the state of the heart muscle. It was shown that NS1619 improves K+ transport and increases content of the ion in the heart mitochondria of mdx mice, but this is not associated with the changes in the level of mitoBKCa protein and expression of the gene encoding this protein. The effect of NS1619 was accompanied by the decrease in the intensity of oxidative stress, assessed by the level of lipid peroxidation products (MDA products), and normalization of the mitochondrial ultrastructure in the heart of mdx mice. In addition, we found positive changes in the tissue manifested by the decrease in the level of fibrosis in the heart of dystrophin-deficient animals treated with NS1619. It was noted that NS1619 had no significant effect on the structure and function of heart mitochondria in the wild-type animals. The paper discusses mechanisms of influence of NS1619 on the function of mouse heart mitochondria in Duchenne muscular dystrophy and prospects for applying this approach to correct pathology.

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Abbreviations

DMD:

Duchenne muscular dystrophy

DNP:

2,4-dinitrophenol

MDA:

malondialdehyde

mitoBKCa :

Ca2+-activated mitochondrial potassium channel

MPT pore:

mitochondrial permeability transition pore

mtDNA:

mitochondrial DNA

nDNA:

nuclear DNA

ROS:

reactive oxygen species

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Acknowledgments

The authors acknowledge the Lomonosov Moscow State University development program (PNR 5.13) and Nikon center of Excellence at Belozersky Institute of Physico-Chemical Biology for providing access to the equipment and technical support.

Funding

This work was financially supported by the Russian Science Foundation (project no. 20-75-10006).

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Authors and Affiliations

  1. Mari State University, 424001, Yoshkar-Ola, Mari El, Russia

    Mikhail V. Dubinin, Yuliya A. Chelyadnikova, Daria K. Penkina, Anastasia D. Igoshkina & Konstantin N. Belosludtsev

  2. Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290, Pushchino, Moscow Region, Russia

    Vlada S. Starinets, Natalia V. Belosludtseva, Irina B. Mikheeva, Eugeny Yu. Talanov & Konstantin N. Belosludtsev

  3. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    Igor I. Kireev & Dmitry B. Zorov

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  1. Mikhail V. Dubinin
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  11. Konstantin N. Belosludtsev
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Contributions

M. V. Dubinin and K. N. Belosludtsev – conceived and supervised the study; M. V. Dubinin, V. S. Starinets, Yu. A. Chelyadnikova, N. V. Belosludtseva, I. B. Mikheeva, D. K. Penkina, A. D. Igoshkina, E. Yu. Talanov, I. I. Kireev – carried out experiments; M. V. Dubinin, K. N. Belosludtsev, D. B. Zorov – discussed the results of experiments with input from all authors; M. V. Dubinin – wrote the manuscript; M. V. Dubinin, K. N. Belosludtsev, D. B. Zorov – edited the manuscript.

Corresponding author

Correspondence to Mikhail V. Dubinin.

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The authors declare no conflict of interest in financial or any other sphere. The work with laboratory animals was carried out in accordance with the European Convention for the Protection of Vertebrates used for experimental and other purposes (Strasbourg, 1986) and the principles of the Helsinki Declaration (2000). All mouse experimentation was approved by the Mari State University Ethics Committee (Protocol No. 01/2021 of 18 October 2021).

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Dubinin, M.V., Starinets, V.S., Chelyadnikova, Y.A. et al. Effect of Large-Conductance Calcium-Dependent K+ Channel Activator NS1619 on Function of Mitochondria in the Heart of Dystrophin-Deficient Mice. Biochemistry Moscow 88, 189–201 (2023). https://doi.org/10.1134/S0006297923020037

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