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Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy

Abstract

Muscular dystrophies comprise a diverse group of genetic disorders that lead to muscle wasting and, in many instances, premature death1. Many mutations that cause muscular dystrophy compromise the support network that connects myofilament proteins within the cell to the basal lamina outside the cell, rendering the sarcolemma more permeable or leaky. Here we show that deletion of the gene encoding cyclophilin D (Ppif) rendered mitochondria largely insensitive to the calcium overload–induced swelling associated with a defective sarcolemma, thus reducing myofiber necrosis in two distinct models of muscular dystrophy. Mice lacking δ-sarcoglycan (Scgd−/− mice) showed markedly less dystrophic disease in both skeletal muscle and heart in the absence of Ppif. Moreover, the premature lethality associated with deletion of Lama2, encoding the α-2 chain of laminin-2, was rescued, as were other indices of dystrophic disease. Treatment with the cyclophilin inhibitor Debio-025 similarly reduced mitochondrial swelling and necrotic disease manifestations in mdx mice, a model of Duchenne muscular dystrophy, and in Scgd−/− mice. Thus, mitochondrial-dependent necrosis represents a prominent disease mechanism in muscular dystrophy, suggesting that inhibition of cyclophilin D could provide a new pharmacologic treatment strategy for these diseases.

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Figure 1: Loss of cyclophilin D reduces pathology in Scgd−/− muscle.
Figure 2: Analysis of skeletal membrane fragility, ultrastructural defects and cardiac defects.
Figure 3: Genetic ablation of cyclophilin D increases lifespan and reduces muscular dystrophy pathology in Lama2−/− mice.
Figure 4: Debio-025 reduces disease progression in mdx mice.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (J.D.M., J.R.), an award from the Jain Foundation (J.D.M.), the Fondation Leducq (J.D.M.) and The Paul Wellstone Muscular Dystrophy Cooperative Research Center of the National Institutes of Health (U54 AR052646 to H.L.S. and E.R.B.). D.P.M. was supported by National Institutes of Health training grant 5 T32 HL07382 (principal investigator A. Schwartz). We would like to thank X. Xiao at the University of Pittsburgh for supplying the Lama2−/− mice under permission from E. Engvall at the Burnham Institute. We would also like to thank E. McNally (University of Chicago) for the Scgd−/− mice.

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Contributions

D.P.M. performed most of the experiments with technical help from M.A.S., C.P.B. and H.O. E.R.B. performed the force measurements in EDL within the Wellstone center grant to H.L.S. G.V. consulted on studies with Debio-025 and provided the compound. J.R. provided support through the use of electron microscopy. J.D.M. planned and supervised all experimentation.

Corresponding author

Correspondence to Jeffery D Molkentin.

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Competing interests

One author, G.V., is an employee of DebioPharm, which supplied us with the Debio-025 compound.

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Millay, D., Sargent, M., Osinska, H. et al. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nat Med 14, 442–447 (2008). https://doi.org/10.1038/nm1736

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