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

---

Mikhail V. Dubinin^1,a*, Vlada S. Starinets², Yuliya A. Chelyadnikova¹, Natalia V. Belosludtseva², Irina B. Mikheeva², Daria K. Penkina¹, Anastasia D. Igoshkina¹, Eugeny Yu. Talanov², Igor I. Kireev³, Dmitry B. Zorov³, and Konstantin N. Belosludtsev^1,2

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

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

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

^* To whom correspondence should be addressed.

Received November 13, 2022; Revised January 15, 2023; Accepted January 15, 2023

---

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.

---

KEY WORDS: Duchenne dystrophy, heart, mitochondria, NS1619, calcium-activated potassium channel, BK_Ca

DOI: 10.1134/S0006297923020037

---