Journal Article

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

Vuagniaux, Grégoire, Robbins, Jeffrey, Sweeney, H Lee, Barton, Elisabeth R, Sargent, Michelle A, Millay, Douglas P, Molkentin, Jeffery D, Baines, Christopher P, Osinska, Hanna

2008

Overview

Muscular dystrophies comprise a diverse group of genetic disorders that lead to muscle wasting and, in many instances, premature death 1 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Calcium / Cancer Research / Cyclophilins - antagonists & inhibitors / Cyclophilins - deficiency / Cyclophilins - genetics / Cyclosporine - pharmacology / Dystrophy / Gene therapy / Humans / Infectious Diseases / Inhibitor drugs / Laminin - deficiency / Laminin - genetics / letter / Medical research / Metabolic Diseases / Mice / Mice, Inbred C57BL / Mice, Inbred mdx / Mice, Knockout / Mitochondria, Muscle - drug effects / Mitochondria, Muscle - pathology / Mitochondrial Swelling - drug effects / Molecular Medicine / Muscle, Skeletal - drug effects / Muscle, Skeletal - pathology / Muscular dystrophy / Muscular Dystrophy, Animal - drug therapy / Muscular Dystrophy, Animal - genetics / Muscular Dystrophy, Animal - pathology / Mutation / Myocardium - pathology / Necrosis / Neurosciences / Peptidyl-Prolyl Isomerase F / Proteins / Rodents / Sarcoglycans - deficiency / Sarcoglycans - genetics