{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T20:03:18Z","timestamp":1763928198613,"version":"3.45.0"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Duchenne Muscular Dystrophy (DMD) features immune\u2010muscle crosstalk, where muscle fibre degeneration enhances pro\u2010inflammatory macrophage infiltration, worsening inflammation and impairing regeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the impact of immunoproteasome (IP) inhibition on the gut\u2010muscle axis in mdx mice, a well\u2010established model of DMD. We employed microbiota perturbation models, including broad\u2010spectrum antibiotic treatment (ABX) and faecal microbiota transplantation (FMT) from IP\u2010inhibited mdx mice. IP inhibition effects were assessed by analysing gut microbiota composition, intestinal inflammation, muscle integrity and associated metabolic and inflammatory pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      IP inhibitor ONX\u20100914 significantly impacted the intestinal inflammatory microenvironment and gut microbiota of mdx mice. ONX\u20100914 treatment increased gastrointestinal transit (increased wet\/dry faecal weights,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0486 and\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0112, respectively) and partially restored intestinal barrier integrity (reduced FITC\u2010dextran leakage,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0449). JAM\u2010A was significantly upregulated (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). Colonic CD206+ M2 macrophages increased, while CD68\u2009+\u2009M1 cells partially decreased. ONX\u20100914 downregulated IP isoforms in macrophages (PSMB8:\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0022; PSMB9:\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0186) as well as FOXO\u20101 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0380) and TNF\u2010\u03b1 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0487). Antibiotic\u2010induced microbiota depletion abrogated these effects. Metagenomic analysis revealed significant differences in microbiota composition between C57Bl controls and mdx mice (PERMANOVA\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), with ONX\u20100914 inducing enrichment of stachyose degradation pathways. Metabolomic analysis showed enrichment of bacterial metabolites, fatty acid and sugar metabolism pathways, with increased glutathione, galactose, glycerol, glyceraldehyde and TCA cycle intermediates. ONX\u20100914 improved mitochondrial activity in skeletal muscle, as increased expression of ETC complexes (mdx vs. mdx+ONX: Complex II,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0338; Complex IV,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0023) and TCA enzymes (mdx vs. FTMmdx+ONX: IDH\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0258; FH\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0366). This led to a shift towards oxidative muscle fibres and improved muscle morphology (increased fibre size,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001 mdx vs. mdx+ONX and mdx vs. FTMmdx+ONX). Muscle performance was enhanced with reduced CPK levels (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0015 mdx vs. mdx+ONX) and fibrosis (decreased TGF\u03b2: mdx vs. mdx+ONX,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0248; mdx vs. FTMmdx+ONX,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0279). ONX\u20100914 reduced CD68+ (mdx vs. mdx+ONX,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0024; mdx vs. FTMmdx+ONX,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and increased CD206+ (mdx vs. FTMmdx+ONX:\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0083) macrophages in muscle, downregulated inflammatory genes (mdx vs. mdx+ONX:\n                      <jats:italic>ccl2 p<\/jats:italic>\n                      \u2009=\u20090.0327,\n                      <jats:italic>vcam\u20101p<\/jats:italic>\n                      \u2009=\u20090.0378) and reduced pro\u2010inflammatory proteins (MCP1, mdx vs. mdx+ONX,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0442). Inflammatory cytokines and endothelial vessel density in ONX\u20100914 treated mdx were restored to wild type mice. These data demonstrate that ONX\u20100914 enhances muscle function through microbiota\u2010dependent mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study advances the understanding of the role of dysbiosis in DMD disease and identifies IP inhibition as a potential therapeutic strategy to modulate the dystrophic gut\u2013muscle axis, offering new perspectives for microbiota\u2010targeted therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70054","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T06:09:46Z","timestamp":1759385386000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunoproteasome Inhibition Positively Impacts the Gut\u2010Muscle Axis in Duchenne Muscular Dystrophy"],"prefix":"10.1002","volume":"16","author":[{"given":"Andrea","family":"Farini","sequence":"first","affiliation":[{"name":"Neurology Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Strati","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences University of Milano\u2010Bicocca  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Molinaro","sequence":"additional","affiliation":[{"name":"Neurology Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debora","family":"Mostosi","sequence":"additional","affiliation":[{"name":"Stem Cell Laboratory, Dino Ferrari Center, Department of Pathophysiology and Transplantation University of Milan  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Saccone","sequence":"additional","affiliation":[{"name":"Neurology Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luana","family":"Tripodi","sequence":"additional","affiliation":[{"name":"Stem Cell Laboratory, Dino Ferrari Center, Department of Pathophysiology and Transplantation University of Milan  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacopo","family":"Troisi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana University of Salerno  Baronissi Italy"},{"name":"Theoreo Srl Spinoff Company of the University of Salerno  Montecorvino Pugliano Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annamaria","family":"Landolfi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana University of Salerno  Baronissi Italy"},{"name":"Theoreo Srl Spinoff Company of the University of Salerno  Montecorvino Pugliano Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Amoroso","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences University of Milano\u2010Bicocca  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Cassani","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnologies and Translational Medicine Universit\u00e0 Degli Studi di Milano  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aitor","family":"Blanco\u2010M\u00edguez","sequence":"additional","affiliation":[{"name":"PreBiomics S.r.l.  Trento Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Leonetti","sequence":"additional","affiliation":[{"name":"Stem Cell Laboratory, Dino Ferrari Center, Department of Pathophysiology and Transplantation University of Milan  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Bazzani","sequence":"additional","affiliation":[{"name":"PreBiomics S.r.l.  Trento Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mattia","family":"Bolzan","sequence":"additional","affiliation":[{"name":"PreBiomics S.r.l.  Trento Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Fortunato","sequence":"additional","affiliation":[{"name":"Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT) University of Milan  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavio","family":"Caprioli","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Unit of Gastroenterology and Endoscopy Universit\u00e0 Degli Studi di Milano, Fondazione IRCCS Ca' Granda, Ospedale Policlinico di Milano  Milano Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Facciotti","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences University of Milano\u2010Bicocca  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2705-3984","authenticated-orcid":false,"given":"Yvan","family":"Torrente","sequence":"additional","affiliation":[{"name":"Neurology Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico  Milan Italy"},{"name":"Stem Cell Laboratory, Dino Ferrari Center, Department of Pathophysiology and Transplantation University of Milan  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.81.4.1189"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-015-0041-y"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2004.06.008"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.04.006"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/21675511.2015.1010966"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0163779"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.13968"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay0240"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0332-7"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.011"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2604"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1019378108"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202216244"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202216225"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sigtrans.2017.23"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/1178638820980490"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan5662"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01063-4"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2018.10.010"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2016.162"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-05416-1"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1891-0"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/689492"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms7080271"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph17207618"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.01.001"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232314657"},{"issue":"1","key":"e_1_2_10_29_1","first-page":"478","article-title":"Colonic Proteome Signature in Immunoproteasome\u2010Deficient Stressed Mice and Its Relevance for Irritable Bowel Syndrome","volume":"18","author":"Goichon A.","year":"2019","journal-title":"Journal of Proteome Research"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom11070989"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-11054-2"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2015.08.015"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2007.05.015"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy404"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-017-0257-2"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-018-0154-1"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302821"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19041057"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.02.005"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201445427"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70054","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T20:00:13Z","timestamp":1763928013000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.70054"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":40,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/jcsm.70054"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.70054","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"type":"print","value":"2190-5991"},{"type":"electronic","value":"2190-6009"}],"subject":[],"published":{"date-parts":[[2025,10]]},"assertion":[{"value":"2023-11-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70054"}}