{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:20:07Z","timestamp":1787746807717,"version":"build-2784847793"},"reference-count":63,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G086823N"],"award-info":[{"award-number":["G086823N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["12Z8622N"],"award-info":[{"award-number":["12Z8622N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["11PRA24N"],"award-info":[{"award-number":["11PRA24N"]}],"id":[{"id":"10.13039\/501100003130","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":[[2026,8]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Skeletal muscle atrophy in amyotrophic lateral sclerosis (ALS) drives loss of muscle strength, function and quality of life in ALS patients. The endocannabinoid system (ECS) regulates muscle homeostasis via regenerative and metabolic processes, and although ECS alterations have been reported in ALS neural tissues, ECS remodelling within ALS skeletal muscle has never been studied. This study investigated temporal and muscle type\u2013specific ECS changes in ALS.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Female hSOD1\n G93A<\/jats:sup>\n transgenic mice and nontransgenic littermates were studied at presymptomatic and symptomatic ages (56\u2013138\u2009days of age;\n n<\/jats:italic>\n \u2009=\u20097\u20138\/group). Endocannabinoids,\n N<\/jats:italic>\n \u2010acyl\u2010ethanolamine congeners and inflammatory lipid mediators were quantified using targeted LC\u2013MS\/MS in the tibialis anterior (TA) and soleus (SOL) muscles. ECS\u2010related enzymes and receptors were assessed by immunoblotting and integrated with transcriptomic analyses of skeletal muscle biopsies from ALS patients (\n n<\/jats:italic>\n \u2009=\u20095\/group; ~63\u2009years). To evaluate therapeutic relevance, ALS mice were treated with the fatty acid amide hydrolase (FAAH) inhibitor URB937 or vehicle (\n n<\/jats:italic>\n \u2009=\u200910\u201311\/group), and survival, body weight, welfare and motor function were assessed longitudinally.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n ALS caused severe atrophy in the predominantly fast\u2010twitch TA muscle (\u221276.5%;\n p<\/jats:italic>\n \u2009<\u20090.01), while the slow\u2010twitch soleus was largely preserved (\u221214.4%;\n p<\/jats:italic>\n \u2009<\u20090.01). Accordingly, the lipid perturbation due to ALS was more pronounced in the TA, reflected by extensive alterations in unsaturated fatty acids, hydroxy\u2010 and epoxy\u2010fatty acids (TA: 63% and SOL: 22% of lipid mediators different between ALS vs. NTG) and marked ECS remodelling, including elevated anandamide (+37.3%;\n p<\/jats:italic>\n \u2009=\u20090.03) and multiple\n N<\/jats:italic>\n \u2010acyl\u2010ethanolamine congeners (+76\u2013102%;\n p<\/jats:italic>\n \u2009<\u20090.05), reduced 2\u2010arachidonoylglycerol (\u221228%;\n p<\/jats:italic>\n \u2009=\u20090.06), increased CB1 receptor expression (+93%;\n p<\/jats:italic>\n \u2009<\u20090.01) and dynamic, age\u2010dependent regulation of FAAH (presymptomatic: \u221268%;\n p<\/jats:italic>\n \u2009=\u20090.04, symptomatic: +21%;\n p<\/jats:italic>\n \u2009=\u20090.02). In contrast, the SOL showed modest or opposite changes, consistent with its relative resistance to atrophy. Notably, ECS remodelling in the TA was already evident at presymptomatic age (e.g., CB1: +76%;\n p<\/jats:italic>\n \u2009=\u20090.01) and the same ECS enzymes were affected in human ALS skeletal muscle transcriptomes (e.g., twofold decrease in FAAH;\n p<\/jats:italic>\n FDR<\/jats:sub>\n \u2009=\u20090.010). Despite evidence for a therapeutic potential, chronic peripheral FAAH inhibition with URB937 did not improve weight loss, motor functions and survival of ALS mice (all\n p<\/jats:italic>\n \u2009>\u20090.05).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Muscle type\u2013specific endocannabinoid system remodelling in ALS precedes overt neurological decline and might relate to degenerative features such as metabolic disturbance and inflammation. Although peripheral FAAH inhibition alone was insufficient to modify disease outcomes, these findings identify the endocannabinoid system as an integral component of ALS muscle pathology and support skeletal muscle lipid signalling as a potentially relevant early target for adjunctive therapeutic strategies.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70357","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T23:36:23Z","timestamp":1785886583000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early and Divergent Lipid Mediator Remodelling in Fast Versus Slow Skeletal Muscles of Female hSOD1\n G93A<\/sup>\n Mice"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5734-3993","authenticated-orcid":false,"given":"Sebastiaan","family":"Dalle","sequence":"first","affiliation":[{"name":"Exercise and Muscle Physiology Research Group, Department of Movement Sciences University of Leuven Leuven Belgium"},{"name":"MOVANT Research Group, Department of Rehabilitation Sciences and Physiotherapy University of Antwerp Wilrijk Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaat","family":"Vanderbeke","sequence":"additional","affiliation":[{"name":"Exercise and Muscle Physiology Research Group, Department of Movement Sciences University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8788-2936","authenticated-orcid":false,"given":"Thibaut","family":"Burg","sequence":"additional","affiliation":[{"name":"Leuven Brain Institute, Department of Neurosciences University of Leuven Leuven Belgium"},{"name":"Laboratory of Neurobiology, VIB Center for Neuroscience Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5565-2941","authenticated-orcid":false,"given":"Moniek","family":"Schouten","sequence":"additional","affiliation":[{"name":"Exercise and Muscle Physiology Research Group, Department of Movement Sciences University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8177-7712","authenticated-orcid":false,"given":"Wout","family":"Lauriks","sequence":"additional","affiliation":[{"name":"Exercise and Muscle Physiology Research Group, Department of Movement Sciences University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Hersmus","sequence":"additional","affiliation":[{"name":"Leuven Brain Institute, Department of Neurosciences University of Leuven Leuven Belgium"},{"name":"Laboratory of Neurobiology, VIB Center for Neuroscience Leuven Belgium"},{"name":"Department of Neurology University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0104-4067","authenticated-orcid":false,"given":"Ludo","family":"Van Den Bosch","sequence":"additional","affiliation":[{"name":"Leuven Brain Institute, Department of Neurosciences University of Leuven Leuven Belgium"},{"name":"Laboratory of Neurobiology, VIB Center for Neuroscience Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6022-1097","authenticated-orcid":false,"given":"Katrien","family":"Koppo","sequence":"additional","affiliation":[{"name":"Exercise and Muscle Physiology Research Group, Department of Movement Sciences University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000200109"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.04.006"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010025\u201000876\u20103"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035\u2010022\u201000322\u20100"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv439"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmr.2025.100070"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2025.101342"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.16400"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27096"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2012.0313"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1155\/2024\/1228194"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.09221.001"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201700835R"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.11.018"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glaf189\/8242768"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201006267\u20101"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2024.123296"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2024.167179"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0303\u20107207(02)00361\u20101"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/JCP.30034"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201801145R"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201023224\u20107"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2632"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.13166"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05\u20104743fje"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2011.06.005"},{"key":"e_1_2_10_28_1","unstructured":"K.Stassburg B.Molloy C.Mallet et\u00a0al. \u201cTargeted Lipidomics of Oxylipins (Oxygenated Fatty Acids) \u201d (2015)."},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.204450"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1388\u201020.2020"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201017389\u20109"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12855"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010024\u201074669\u2010x"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201018140\u20101"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10974\u2010020\u201009584\u20105"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0032632"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082112"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00831"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2016.06.003"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad202"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12496"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/admt.202101216"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/S41598\u2010021\u201097859\u20103"},{"key":"e_1_2_10_44_1","doi-asserted-by":"crossref","unstructured":"D.Ito M.Iida Y.Iguchi et\u00a0al. \u201cDysregulated Expanded Endocannabinoid System as Therapeutic Targets of Amyotrophic Lateral Sclerosis \u201d (2024). doi:https:\/\/doi.org\/10.1101\/2024.01.12.575341.","DOI":"10.1101\/2024.01.12.575341"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010018\u20100959\u20102"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0041880"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.11.006"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035\u2010023\u201000377\u20107"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddmod.2018.10.001"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.681868"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201070510\u20103"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.31083\/FBL28260"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010019\u20100498\u20109"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.63.8.1139"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1080\/14660820410021311"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102228"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571\u2010026\u201001674\u20101"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00529.2023"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252211909"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755\u20105949.2012.00358.x"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00720.2015.\u2010Bedrid"},{"key":"e_1_2_10_62_1","doi-asserted-by":"crossref","unstructured":"T. I.Lima P.\u2010P.Laurila M.Wohlwend et\u00a0al. \u201cInhibiting De Novo Ceramide Synthesis Restores Mitochondrial and Protein Homeostasis in Muscle Aging \u201d (2023).","DOI":"10.1126\/scitranslmed.ade6509"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574\u2010020\u20100320\u20105"},{"key":"e_1_2_10_64_1","doi-asserted-by":"crossref","unstructured":"P.\u2010P.Laurila P.Luan M.Wohlwend et\u00a0al. \u201cInhibition of Sphingolipid De Novo Synthesis Counteracts Muscular Dystrophy \u201d8 no.4(2022):eabh4423.","DOI":"10.1126\/sciadv.abh4423"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70357","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.70357","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70357","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T11:31:32Z","timestamp":1787743892000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.70357"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":63,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/jcsm.70357"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.70357","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2026-03-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70357"}}