Effect of the large-conductance calcium-dependent k⁺ channel activator NS1619 on the function of mitochondria in the heart of dystrophin-deficient mice

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 a decrease in the efficiency of potassium ion transport and the total content of this ion in 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 the content of the ion in the heart mitochondria of mdx mice, but this is not associated with changes in the level of the mitoBKCa protein and the expression of the encoding gene. The effect of NS1619 was accompanied by a 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, expressed in a 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 wild-type animals. The paper discusses the mechanisms of influence of NS1619 on the function of mouse heart mitochondria in Duchenne muscular dystrophy and the prospects for applying this approach to correct pathology.