Effect of the Non-Immunosuppressive MPT Pore Inhibitor Alisporivir on the Functioning of Heart Mitochondria in Dystrophin-Deficient mdx Mice.

Mikhail V Dubinin,Eugeny Yu Talanov,Kirill S Tenkov,Evgeniya V Belosludtseva,Natalia V Belosludtseva,Irina B Mikheeva,Vlada S Starinets,Dmitriy A Serov,Konstantin N Belosludtsev

doi:10.3390/biomedicines9091232

Abstract

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.

Highlights

Duchenne muscular dystrophy (DMD) is a rare (1:3500 male births) inherited X-linked recessive disorder [1,2]
It is known that in Duchenne dystrophy, skeletal muscle mitochondria show a decrease in the intensity of oxidative phosphorylation, ROS overproduction, as well as impairment of the ability to accumulate a large amount of Ca2+ in the matrix due to a decrease in the resistance of organelles to the induction of mitochondrial permeability transition (MPT) pore and rearrangements of calcium-transporting systems [5,6,7]
It is known that the destruction of the cell membranes of mdx mice and the development of the necrotic process leads to the release of intracellular enzymes—creatine kinase, lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) into the serum, and a significant increase in their level [10,11]

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a rare (1:3500 male births) inherited X-linked recessive disorder [1,2]. The cause of the disease is mutations in the gene encoding a set of dystrophin proteins, the largest of which reaches 427 kDa and is involved in the formation of the dystrophin–glycoprotein complex in cardiac and skeletal muscle cells. This complex provides the connection of the cytoskeleton of muscle cells with the extracellular matrix, maintaining the structural integrity of the tissue and its functional activity, and its absence is accompanied by progressive destabilization of the muscle fiber [3]. It is known that in Duchenne dystrophy, skeletal muscle mitochondria show a decrease in the intensity of oxidative phosphorylation, ROS overproduction, as well as impairment of the ability to accumulate a large amount of Ca2+ in the matrix due to a decrease in the resistance of organelles to the induction of mitochondrial permeability transition (MPT) pore and rearrangements of calcium-transporting systems [5,6,7]

Methods

Results

Discussion

Conclusion