Abstract
Mitigation of calcium-dependent destruction of skeletal muscle mitochondria is considered as a promising adjunctive therapy in Duchenne muscular dystrophy (DMD). In this work, we study the effect of intraperitoneal administration of a non-immunosuppressive inhibitor of calcium-dependent mitochondrial permeability transition (MPT) pore alisporivir on the state of skeletal muscles and the functioning of mitochondria in dystrophin-deficient mdx mice. We show that treatment with alisporivir reduces inflammation and improves muscle function in mdx mice. These effects of alisporivir were associated with an improvement in the ultrastructure of mitochondria, normalization of respiration and oxidative phosphorylation, and a decrease in lipid peroxidation, due to suppression of MPT pore opening and an improvement in calcium homeostasis. The action of alisporivir was associated with suppression of the activity of cyclophilin D and a decrease in its expression in skeletal muscles. This was observed in both mdx mice and wild-type animals. At the same time, alisporivir suppressed mitochondrial biogenesis, assessed by the expression of Ppargc1a, and altered the dynamics of organelles, inhibiting both DRP1-mediated fission and MFN2-associated fusion of mitochondria. The article discusses the effects of alisporivir administration and cyclophilin D inhibition on mitochondrial reprogramming and networking in DMD and the consequences of this therapy on skeletal muscle health.
Highlights
Muscle hereditary diseases are rare, but rather severe, pathologies
The data obtained in this work suggest that a decrease in the activity and expression of cyclophilin D by alisporivir (MPT pore inhibitor) treatment restores the structure and functions of skeletal muscle mitochondria in dystrophin-deficient mdx mice, improves the functioning of skeletal muscles, and reduces the intensity of destructive processes
We demonstrated that administration of alisporivir at a concentration of 5 mg/kg/day (1) restores the ultrastructure of the skeletal muscle mitochondria in mdx animals and (2) restores the calcium retention capacity and respiratory control ratio, and reduces the lipid peroxidation intensity
Summary
Muscle hereditary diseases are rare, but rather severe, pathologies One of these pathologies is Duchenne muscular dystrophy (DMD), caused by mutations in the gene encoding the dystrophin protein in muscles. This protein provides a link between the cytoskeleton and the sarcolemma, as well as other muscle proteins, by forming the dystrophinassociated glycoprotein complex, playing a key role in muscle contraction. Disorganization of this structure leads to dysfunction of muscle tissue, the development of progressive muscle wasting and weakness, and in the later stages is associated with heart failure [1]. This, in turn, results in dysfunction of the contractile apparatus, leading to reduced muscular strength, dysregulation of intracellular Ca2+ buffering, loss of homeostasis, and rapidly progressive Ca2+-induced degeneration of skeletal muscle
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