Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis

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.

Therapeutic Application of Extracellular Vesicles-Capsulated Adeno-Associated Virus Vector via nSMase2/Smpd3, Satellite, and Immune Cells in Duchenne Muscular Dystrophy

“…(2) the therapy of downstream pathological changes, such as transplantation of muscular stem cells, corticosteroids (prednisolone or deflazacort) with highly effective in therapy of concomitant destructive processes (namely inflammation) and an improvement in calcium homeostasis, leading to a decrease in oxidative stress in muscle tissue, and in mitochondrial function and biogenesis [45][46][47][48][49][50][51][52][53][54][55] (Figure 1). Currently, gene editing is attracting attention as a therapeutic strategy for DMD because of the restoration of the dystrophin reading frame in more than 40% of all patients with DMD [56][57][58][59][60][61][62][63].…”

“…(dystriphin-targeted therapies), such as adeno-associated virus (AAV)-mediated micro/minidystrophin gene delivery, synthetic antisense oligonucleotides for exon skipping, nonsense readthrough, CRISPR-Cas9 (clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9)-mediated genome editing, protein replacement therapies, and primarily utropin; (2) the therapy of downstream pathological changes, such as transplantation of muscular stem cells, corticosteroids (prednisolone or deflazacort) with highly effective in therapy of concomitant destructive processes (namely inflammation) and an improvement in calcium homeostasis, leading to a decrease in oxidative stress in muscle tissue, and in mitochondrial function and biogenesis [45][46][47][48][49][50][51][52][53][54][55] (Figure 1). Currently, gene editing is attracting attention as a therapeutic strategy for DMD because of the restoration of the dystrophin reading frame in more than 40% of all patients with DMD [56][57][58][59][60][61][62][63].…”

Analysis of Mitochondrial Function, Structure, and Intracellular Organization In Situ in Cardiomyocytes and Skeletal Muscles

“…Usually, the CRC is quantified in isolated mitochondria spectrophotometrically (light scattering) or using different Ca 2+ -sensitive dyes. For example, along with Ca 2+ -sensitive fluorescent dyes, arsenazo III, a non-membrane-permeant Ca 2+ -sensitive dye [101][102][103][104], and Ca 2+ -sensitive electrodes [104,105] have been used to measure Ca 2+ release/PTP opening in isolated mitochondria. Notably, the estimation of the CRC/PTP opening in isolated mitochondria has several disadvantages [6,49,50].…”

Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0

“…The mitigation of the calcium-dependent destruction of skeletal muscle mitochondria is considered to be a promising adjunctive therapy in Duchenne muscular dystrophy (DMD). The study by Dubinin et al investigated the effect of the intraperitoneal administration of alisporivir, a nonimmunosuppressive inhibitor of the calcium-dependent mitochondrial permeability transition (MPT) pore, on the state of skeletal muscles and the functioning of mitochondria in dystrophin-deficient mdx mice [ 8 ]. The authors showed that treatment with alisporivir reduces inflammation, thus improving muscle function in mdx mice.…”

“…The authors showed that treatment with alisporivir reduces inflammation, thus improving muscle function in mdx mice. These effects of alisporivir were associated with recovery in the ultrastructural alterations of mitochondria; the 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 [ 8 ]. The MPT pore targeting approach may be used as an effective adjunctive strategy in the treatment of DMD.…”