Effect of the Non-Immunosuppressive MPT Pore Inhibitor Alisporivir on the Functioning of Heart Mitochondria in Dystrophin-Deficient <i>mdx</i> Mice
Mikhail V. Dubinin,
Vlada S. Starinets,
Eugeny Yu. Talanov,
Irina B. Mikheeva,
Natalia V. Belosludtseva,
Dmitriy A. Serov,
Kirill S. Tenkov,
Evgeniya V. Belosludtseva,
Konstantin N. Belosludtsev
Affiliations
Mikhail V. Dubinin
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia
Vlada S. Starinets
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia
Eugeny Yu. Talanov
Laboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
Irina B. Mikheeva
Laboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
Natalia V. Belosludtseva
Laboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
Dmitriy A. Serov
Prokhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilov St., 119991 Moscow, Russia
Kirill S. Tenkov
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia
Evgeniya V. Belosludtseva
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia
Konstantin N. Belosludtsev
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia
Supporting mitochondrial function is one of the therapeutic strategies that improve the functioning of skeletal muscle in Duchenne muscular dystrophy (DMD). In this work, we studied the effect of a non-immunosuppressive inhibitor of mitochondrial permeability transition pore (MPTP) alisporivir (5 mg/kg/day), reducing the intensity of the necrotic process and inflammation in skeletal muscles on the cardiac phenotype of dystrophin-deficient mdx mice. We found that the heart mitochondria of mdx mice show an increase in the intensity of oxidative phosphorylation and an increase in the resistance of organelles to the MPT pore opening. Alisporivir had no significant effect on the hyperfunctionalization of the heart mitochondria of mdx mice, and the state of the heart mitochondria of wild-type animals did not affect the dynamics of organelles but significantly suppressed mitochondrial biogenesis and reduced the amount of mtDNA in the heart muscle. Moreover, alisporivir suppressed mitochondrial biogenesis in the heart of wild-type mice. Alisporivir treatment resulted in a decrease in heart weight in mdx mice, which was associated with a significant modification of the transmission of excitation in the heart. The latter was also noted in the case of WT mice treated with alisporivir. The paper discusses the prospects for using alisporivir to correct the function of heart mitochondria in DMD.
