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 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 overloadinduced 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.The muscular dystrophies are inherited disorders that mostly affect striated muscle tissue, resulting in progressive muscle weakness, wasting and, in many instances, premature death 1 . Many characterized mutations in humans that result in muscular dystrophy cause alterations either in structural proteins that attach the underlying contractile proteins to the basal lamina, which provides rigidity to the skeletal muscle cell membrane (sarcolemma), or in proteins that HHMI Author ManuscriptHHMI Author Manuscript HHMI Author Manuscript directly stabilize or repair the cell membrane 1-3 . For example, loss of dystrophin or other components of the dystrophin-glycoprotein complex leads to a fundamental alteration in the physical properties of the sarcolemma, permitting contraction-induced microtears and the unregulated exchange of ions, increasing the influx of calcium 2-4 . Moreover, total intracellular calcium or subsarcolemmal calcium levels have been found to be elevated in skeletal muscle cells or fibers from dystrophic mice 5,6 .In response to sustained increases in intracellular calcium concentrations, such as after ischemic injury, mitochondria undergo a so-called 'permeability transition' 7 . This process results in the regulated formation of a large pore complex that spans the outer and inner mitochondrial membranes, leading to an irreversible loss of matrix and intermembrane contents and swelling of the mitochondria. If this transition state is not reversed in a timely manner, the mitochondria can rupture, causing necrotic and/or apoptotic cell death. Cyclophilin D is a mitochondrial matrix prolyl cis-trans isomerase that directly regulates calcium-and reactive oxygen specie...

In mito veritas ?

“…Deux articles, parus simultanément en mars 2008, illustrent ce type de démarche en proposant de traiter certaines dystrophies musculaires par une thérapeutique ciblée sur la mitochondrie [2,3].…”

“…En substituant sur la molécule de CsA le résidu sarcosine en position 3 par une N-méthyle-D-ala, et le résidu N-méthyle-leucine en position 4 par un reste N-éthyle-val, les chimistes de la firme DebioPharm de Lausanne (Suisse) sont justement parvenus à obtenir un analogue (Debio-025) qui ne cible plus que CypD, ce qui en fait un médi-cament purement mitochondrial, dépourvu de tout effet immunosuppresseur [19]. Pour démontrer que CypD est une cible thérapeutique intéressante dans certaines DM, Millay et al [2] ont dans un premier temps croisé des souris Scgd -/-ou des souris Lama2 -/-(voir Tableau I) avec des souris dont le gène de CypD a été invalidé par KO de topographie subcellulaire très variées. Schématiquement, on distingue les DM se manifestant après la naissance (une trentaine de phénotypes cliniques différents, et 20 gènes identifiés), et les DM congé-nitales (une vingtaine de phénotypes, 12 gènes identifiés).…”

Treatments for muscular dystrophy: Increased treatment options for Duchenne and related muscular dystropies

“…2 The final category involves modifying the disease process downstream of the dystrophin deficiency and a number of disease-modifying agents such as angiotensin II type 1 receptor blockade (Losartan), a blockade of TNF-a and coenzyme Q10 have been tested and shown to be effective in the mouse model of DMD. 5,6 The results presented by Millay et al 1 are an important addition to this latter category and present a novel treatment target.…”

“…7 Millay et al demonstrate that crossing these Ppif À/À mice with mice lacking d sarcoglycan (Scgd À/À , a mouse model of limb girdle muscular dystrophy 2F) or laminin a2 (Lama2 À/À , a mouse model of congenital muscular dystrophy 1A), markedly attenuated the disease process, although it did not prevent it entirely. 1 They also showed that two times daily treatment for 6 weeks with Debio-025, a cyclophilin inhibitor, substantially reduced the disease in mdx and Scgd À/À mice.…”

“…The recent paper by Millay et al 1 makes an important contribution as it opens up a new area of disease modification by reducing mitochondrial-dependent necrosis to alleviate the effects of muscular dystrophy in mice. Potentially, this could also be helpful for other conditions involving mitochondrial-dependent necrosis.…”