Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion.

MedStar author(s):
Citation: Cell Death & Disease. 5:e1306, 2014.PMID: 24967968Institution: MedStar Washington Hospital CenterDepartment: Emergency MedicineForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov't | Research Support, U.S. Gov't, Non-P.H.S.Subject headings: *Membrane Proteins/me [Metabolism] | *Muscle Proteins/me [Metabolism] | *Myoblasts, Skeletal/me [Metabolism] | *Sarcolemma/me [Metabolism] | *Sphingomyelin Phosphodiesterase/se [Secretion] | Animals | Cell Line | Distal Myopathies/ge [Genetics] | Distal Myopathies/me [Metabolism] | Distal Myopathies/pa [Pathology] | Distal Myopathies/th [Therapy] | Exocytosis | Humans | Membrane Proteins/ge [Genetics] | Mice | Muscle Proteins/ge [Genetics] | Muscular Atrophy/ge [Genetics] | Muscular Atrophy/me [Metabolism] | Muscular Atrophy/pa [Pathology] | Muscular Atrophy/th [Therapy] | Myoblasts, Skeletal/pa [Pathology] | Sarcolemma/ge [Genetics] | Sarcolemma/pa [Pathology]Year: 2014Name of journal: Cell death & diseaseAbstract: 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.All authors: Bashir R, Bhat R, Bigot A, Defour A, Jaiswal JK, Nagaraju K, Van der Meulen JHFiscal year: FY2015Digital Object Identifier: Date added to catalog: 2015-03-17
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Journal Article MedStar Authors Catalog Article 24967968 Available 24967968

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.

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