Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy.
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.
Millay
Douglas P
DP
Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
Sargent
Michelle A
MA
Osinska
Hanna
H
Baines
Christopher P
CP
Barton
Elisabeth R
ER
Vuagniaux
Grégoire
G
Sweeney
H Lee
HL
Robbins
Jeffrey
J
Molkentin
Jeffery D
JD
D000818:Animals; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D007797:Laminin / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000473:pathology; D008933:Mitochondrial Swelling / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics
D000081406:Peptidyl-Prolyl Isomerase F; D007797:Laminin; C000631446:PPIF protein, mouse; D049031:Sarcoglycans; C102645:laminin alpha 2; D016572:Cyclosporine; D021983:Cyclophilins; C499715:alisporivir