title: Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion.
abstract: Dysferlin deficiency compromises the repair of injured muscle, but the underlying cellular mechanism remains elusive. To study this phenomenon, we have developed mouse and human myoblast models for dysferlinopathy. These dysferlinopathic myoblasts undergo normal differentiation but have a deficit in their ability to repair focal injury to their cell membrane. Imaging cells undergoing repair showed that dysferlin-deficit decreased the number of lysosomes present at the cell membrane, resulting in a delay and reduction in injury-triggered lysosomal exocytosis. We find repair of injured cells does not involve formation of intracellular membrane patch through lysosome-lysosome fusion; instead, individual lysosomes fuse with the injured cell membrane, releasing acid sphingomyelinase (ASM). ASM secretion was reduced in injured dysferlinopathic cells, and acute treatment with sphingomyelinase restored the repair ability of dysferlinopathic myoblasts and myofibers. Our results provide the mechanism for dysferlin-mediated repair of skeletal muscle sarcolemma and identify ASM as a potential therapy for dysferlinopathy.
authors: Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC, USA.
authors: A
authors: A
authors: Defour
authors: Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC, USA.
authors: J H
authors: JH
authors: Van der Meulen
authors: Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC, USA.
authors: R
authors: R
authors: Bhat
authors: Institut de Myologie, UM76 Université Pierre et Marie Curie, U974 INSERM, UMR7215 CNRS, GH Pitié-Salpétrière, 47 bd de l'Hôpital, Paris, France.
authors: A
authors: A
authors: Bigot
authors: School of Biological and Biochemical Sciences, University of Durham, Durham, UK.
authors: R
authors: R
authors: Bashir
authors: 1] Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC, USA [2] Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
authors: K
authors: K
authors: Nagaraju
authors: 1] Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC, USA [2] Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
authors: J K
authors: JK
authors: Jaiswal
mesh_terms: D000818:Animals; D002460:Cell Line; D049310:Distal Myopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000073939:Dysferlin; D005089:Exocytosis; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D032448:Myoblasts, Skeletal / Q000378:metabolism* / Q000473:pathology; D012508:Sarcolemma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*
chemical_list: C114839:DYSF protein, human; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D013108:Sphingomyelin Phosphodiesterase