Letter abstract
Nature Medicine 14, 442 - 447 (2008)
Published online: 16 March 2008 | doi:10.1038/nm1736
Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy
Douglas P Millay1,2, Michelle A Sargent1, Hanna Osinska1, Christopher P Baines1, Elisabeth R Barton3, Grégoire Vuagniaux4, H Lee Sweeney5, Jeffrey Robbins1 & Jeffery D Molkentin1
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 
-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 
-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.
- Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
- Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, Ohio 45267, USA.
- Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, 240 South 40th Street, Philadelphia, Pennsylvania 19104, USA.
- DebioPharm S.A., Chemin Messidor 5-7, 1002 Lausanne, Switzerland.
- Department of Physiology, University of Pennsylvania School of Medicine, 3700 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA.
Correspondence to: Jeffery D Molkentin1 e-mail: jeff.molkentin@cchmc.org
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