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

Nature medicine | Apr 8, 2008

http://www.ncbi.nlm.nih.gov/pubmed/18345011

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

Pubmed ID: 18345011 RIS Download

Mesh terms: Animals | Cyclophilins | Cyclosporine | Humans | Laminin | Mice | Mice, Inbred C57BL | Mice, Inbred mdx | Mice, Knockout | Mitochondria, Muscle | Mitochondrial Swelling | Muscle, Skeletal | Muscular Dystrophy, Animal | Myocardium | Necrosis | Sarcoglycans

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Associated grants

  • Agency: NHLBI NIH HHS, Id: 5 T32 HL07382
  • Agency: NHLBI NIH HHS, Id: P01 HL069779
  • Agency: NHLBI NIH HHS, Id: P01 HL069779-06A10003
  • Agency: NHLBI NIH HHS, Id: P50 HL077101
  • Agency: NHLBI NIH HHS, Id: P50 HL077101-050004
  • Agency: NHLBI NIH HHS, Id: R01 HL060562
  • Agency: NHLBI NIH HHS, Id: R01 HL060562-11
  • Agency: NHLBI NIH HHS, Id: R01 HL062927
  • Agency: NHLBI NIH HHS, Id: R01 HL062927-10A1
  • Agency: NHLBI NIH HHS, Id: R01 HL081104
  • Agency: NHLBI NIH HHS, Id: R01 HL081104-04
  • Agency: NIAMS NIH HHS, Id: U54 AR052646
  • Agency: Howard Hughes Medical Institute, Id:

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