{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:52:53Z","timestamp":1784872373440,"version":"3.55.0"},"reference-count":43,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["RF1 NS085070"],"award-info":[{"award-number":["RF1 NS085070"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS110085"],"award-info":[{"award-number":["R01 NS110085"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["U54 NS110435"],"award-info":[{"award-number":["U54 NS110435"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006827","name":"Florida Department of Health","doi-asserted-by":"publisher","award":["22A07"],"award-info":[{"award-number":["22A07"]}],"id":[{"id":"10.13039\/100006827","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG55549"],"award-info":[{"award-number":["RF1AG55549"]}],"id":[{"id":"10.13039\/100000002","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":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The study population consisted of 38 IBM patients and 22 age\u2010 and sex\u2010matched controls without a myopathy. Mean age was 62.9\u2009years (SD\u2009=\u20099) in IBM group and 59.7 (10) in controls. Bulk RNA sequencing, Meso Scale Discovery electrochemiluminescence (ECL), western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome being the most upregulated pathway on RNA sequencing, along with increased expression of NLRP3 and ASC proteins in IBM group.\n                      <jats:italic>NLRP3<\/jats:italic>\n                      RNA levels most strongly correlated with\n                      <jats:italic>TLR7<\/jats:italic>\n                      (correlation coefficient\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.91) and complement activation\u2010related genes, and inversely correlated with several mitochondria\u2010related genes among others. On muscle histopathology, there was increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibres. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction\u2014NLRP3 inflammasome activation. Herein, we showed altered mitophagy, as witnessed by the elevated levels of p\u2010S65\u2010Ubiquitin, a mitophagy marker, in muscle lysates from IBM patients compared to controls (median of 114.3 vs. 81.25 ECL units,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.005). The p\u2010S65\u2010Ubiquitin levels were most significantly elevated in IBM males compared to male controls (136 vs. 83.5 ECL units;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.013), whereas IBM females had milder nonsignificant elevation compared to female controls (97.25 vs. 69 ECL units,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.31). On muscle histopathology, p\u2010S65\u2010Ubiquitin aggregates accumulated in muscle fibres that were mostly Type 2 and devoid of cytochrome\u2010c\u2010oxidase reactivity.\n                      <jats:italic>NLRP3 RNA<\/jats:italic>\n                      levels correlated with p\u2010S65\u2010Ubiquitin levels in both sexes (males:\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.48, females:\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.54) but with loss of muscle strength, as reflected by the manual motor test score, only in males (males:\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.62, females:\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u2009\u22120.14). Lastly, we identified sex\u2010specific molecular pathways in IBM. Females had upregulation of pathways related to response to stress, which could conceivably offset some of the pathomechanisms of IBM, while males had upregulation of pathways related to cell adhesion and migration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>There is activation of the NLRP3 inflammasome in IBM, along with altered mitophagy, particularly in males, which is of potential therapeutic significance. These findings suggest sex\u2010specific mechanisms in IBM that warrant further investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13672","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T05:37:05Z","timestamp":1735191425000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["NLRP3 Inflammasome Activation and Altered Mitophagy Are Key Pathways in Inclusion Body Myositis"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6212-1236","authenticated-orcid":false,"given":"Elie","family":"Naddaf","sequence":"first","affiliation":[{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thi\u00a0Kim\u00a0Oanh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota 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