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

Defour, A.; van der Meulen, J.H.; Bhat, R.; Bigot, A.; Bashir, R.; Nagaraju, K.; Jaiswal, J.K.

doi:10.1038/cddis.2014.272

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

Defour, A.; van der Meulen, J.H.; Bhat, R.; Bigot, A.; Bashir, R.; Nagaraju, K.; Jaiswal, J.K.

Authors

A. Defour

J.H. van der Meulen

R. Bhat

A. Bigot

R. Bashir

K. Nagaraju

J.K. Jaiswal

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.

Citation

Defour, A., van der Meulen, J., Bhat, R., Bigot, A., Bashir, R., Nagaraju, K., & Jaiswal, J. (2014). Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion. Cell Death and Disease, 5(6), https://doi.org/10.1038/cddis.2014.272

Journal Article Type	Article
Acceptance Date	May 20, 2014
Publication Date	Jun 26, 2014
Deposit Date	Dec 18, 2014
Publicly Available Date	Apr 13, 2015
Journal	Cell Death and Disease
Publisher	Springer Nature [academic journals on nature.com]
Peer Reviewed	Peer Reviewed
Volume	5
Issue	6
DOI	https://doi.org/10.1038/cddis.2014.272

Files

Published Journal Article (3.5 Mb)
PDF

Publisher Licence URL
http://creativecommons.org/licenses/by-nc-nd/4.0/

Copyright Statement
Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/.