{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:01:17Z","timestamp":1791579677065,"version":"4.3.4"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T00:00:00Z","timestamp":1645488000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001632","name":"Ulster University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001632","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006510","name":"Association pour la Recherche sur la Scl\u00e9rose Lat\u00e9rale Amyotrophique et autres Maladies du Motoneurone","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006510","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013013","name":"Target ALS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The cause of the motor neuron (MN) death that drives terminal pathology in amyotrophic lateral sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards MNs, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Because MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle\u2010secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Sporadic ALS patients were confirmed to be ALS according to El Escorial criteria and were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS\u2010R score. Muscle biopsies of either mildly affected deltoids of ALS patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a027) or deltoids of aged\u2010matched healthy subjects (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a030) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RT\u2010qPCR, and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human\u2010derived iPSC MNs and on healthy human myotubes, with untreated cells used as controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>An accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy\u2010derived denervation\u2010na\u00efve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome\u2010like vesicles and disruption of RNA\u2010processing. Compared with vesicles from healthy control myotubes, when administered to healthy MNs the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA\u2010processing proteins. The RNA\u2010processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient MNs was abolished by anti\u2010CD63 immuno\u2010blocking of vesicle uptake.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ALS muscle vesicles are shown to be toxic to MNs, which establishes the skeletal muscle as a potential source of vesicle\u2010mediated toxicity in ALS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.12945","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T23:03:05Z","timestamp":1645570985000},"page":"1385-1402","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Muscle cells of sporadic amyotrophic lateral sclerosis patients secrete neurotoxic vesicles"],"prefix":"10.1002","volume":"13","author":[{"given":"Laura","family":"Le Gall","sequence":"first","affiliation":[{"name":"Northern Ireland Center for Stratified Medicine Biomedical Sciences Research Institute  Londonderry UK"},{"name":"Sorbonne Universit\u00e9, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Association Institut de Myologie, Centre de Recherche en Myologie  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Duddy","sequence":"additional","affiliation":[{"name":"Northern Ireland Center for Stratified Medicine Biomedical Sciences Research Institute  Londonderry UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecile","family":"Martinat","sequence":"additional","affiliation":[{"name":"I\u2010Stem, INSERM\/UEVE UMR 861, I\u2010STEM, AFM  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Mariot","sequence":"additional","affiliation":[{"name":"NIHR Biomedical Research Centre University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust  London 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