Journal
BIOCHEMISTRY-MOSCOW
Volume 88, Issue 2, Pages 189-201Publisher
MAIK NAUKA/INTERPERIODICA/SPRINGER
DOI: 10.1134/S0006297923020037
Keywords
Duchenne dystrophy; heart; mitochondria; NS1619; calcium-activated potassium channel; BKCa
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In this study, NS1619 was found to improve potassium ion transport and content in the heart mitochondria of DMD mice. This led to a decrease in oxidative stress and fibrosis level. The findings suggest that NS1619 could be a potential approach for correcting the pathology in DMD.
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 (mitoBK(Ca)), 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 mitoBK(Ca) 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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