alisporivir and Muscular-Dystrophy--Duchenne

We studied the effect of the mitochondrial calcium-dependent pore (MPT pore) inhibitor alisporivir (5 mg/kg per day for 4 weeks) on the parameters of calcium ion transport and the intensity of mitophagy in mitochondria of the heart and skeletal muscles of dystrophin-deficient C57BL/10ScSn-mdx mice. Alisporivir increased the rate of calcium uptake by skeletal muscle mitochondria of mdx mice, which was accompanied by changes in the level of the MCU and MCUb subunits of the calcium uniporter. At the same time, the intensity of calcium uniport in the heart mitochondria did not change. Alisporivir was found to reduce the expression of Pink1 and Parkin genes regulating the intensity of mitophagy in skeletal muscles of mdx mice, but did not affect the expression of these genes in the heart. This effect of alisporivir was accompanied by fragmentation and a decrease in the mean size of organelles. Possible mitochondrion-related mechanisms of the protective effect of alisporivir on the skeletal muscle and heart cells are discussed.

Topics: Animals; Calcium; Cyclosporine; Dystrophin; Ion Transport; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Mitochondria, Heart; Mitophagy; Muscle, Skeletal; Muscular Dystrophy, Duchenne

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

Topics: Animals; Cyclophilins; Cyclosporine; Dynamins; Dystrophin; Gene Expression Regulation; GTP Phosphohydrolases; Humans; Mice; Mice, Inbred mdx; Mitochondria; Mitochondria, Muscle; Mitochondrial Dynamics; Mitochondrial Permeability Transition Pore; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

Duchenne muscular dystrophy (DMD) is a severe muscle disease of known etiology without effective, or generally applicable therapy. Mitochondria are affected by the disease in animal models but whether mitochondrial dysfunction is part of the pathogenesis in patients remains unclear. We show that primary cultures obtained from muscle biopsies of DMD patients display a decrease of the respiratory reserve, a consequence of inappropriate opening of the permeability transition pore (PTP). Treatment with the cyclophilin inhibitor alisporivir - a cyclosporin A derivative that desensitizes the PTP but does not inhibit calcineurin - largely restored the maximal respiratory capacity without affecting basal oxygen consumption in cells from patients, thus reinstating a normal respiratory reserve. Treatment with alisporivir, but not with cyclosporin A, led to a substantial recovery of respiratory function matching improved muscle ultrastructure and survival of sapje zebrafish, a severe model of DMD where muscle defects are close to those of DMD patients. Alisporivir was generally well tolerated in HCV patients and could be used for the treatment of DMD.

Topics: Animals; Cell Respiration; Cells, Cultured; Cyclosporine; Disease Models, Animal; Humans; Membrane Potential, Mitochondrial; Mitochondria; Muscle Cells; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Oxygen Consumption; Zebrafish

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by the absence of the cytoskeletal protein dystrophin. This leads to muscle cell death accompanied by chronic inflammation. Cyclosporin A (CsA) is a powerful immunosuppressive drug, which has been proposed for DMD treatment. CsA also directly regulates the mitochondrial permeability transition pore (mPTP), which participates in cell death pathways through the inhibition of cyclophilin D. Here, we evaluated whether Debio 025, a cyclophilin inhibitor with no immunosuppressive activity, improves the dystrophic condition in a mouse model of DMD, through regulation of mPTP.. The potency of Debio 025 to protect mouse dystrophic cells against mitochondria-mediated death was assessed by caspase-3 activity and calcium retention capacity assays. Mdx(5Cv) mice (3-week-old) were treated daily by gavage for 2 weeks with Debio 025 (10, 30 or 100 mg kg(-1)), CsA (10 mg kg(-1)) or placebo. The effects on muscle necrosis and function were measured.. In vitro investigations showed protective effect of low concentrations of Debio 025 against cell death. Histology demonstrated that Debio 025 partially protected the diaphragm and soleus muscles against necrosis (10 and 100 mg kg(-1), respectively). Hindlimb muscles from mice receiving Debio 025 at 10 mg kg(-1) relaxed faster, showed alteration in the stimulation frequency-dependent recruitment of muscle fibres and displayed a higher resistance to mechanical stress.. Debio 025 partially improved the structure and the function of the dystrophic mouse muscle, suggesting that therapies targeting the mPTP may be helpful to DMD patients.

Topics: Animals; Animals, Newborn; Cell Death; Cyclophilins; Cyclosporine; Diaphragm; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Delivery Systems; Female; Hindlimb; Male; Mice; Mice, Inbred mdx; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Muscle, Skeletal; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Necrosis