{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:33:24Z","timestamp":1787236404069,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K17422"],"award-info":[{"award-number":["JP20K17422"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP19K23839"],"award-info":[{"award-number":["JP19K23839"]}],"id":[{"id":"10.13039\/501100001691","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":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      As glucocorticoids induce muscle atrophy during the treatment course of polymyositis (PM), novel therapeutic strategy is awaited that suppresses muscle inflammation but retains muscle strength. We recently found that injured muscle fibres in PM undergo FASLG\u2010mediated necroptosis, a form of regulated cell death accompanied by release of pro\u2010inflammatory mediators, contributes to accelerate muscle inflammation and muscle weakness. Glucagon\u2010like peptide\u20101 receptor (GLP\u20101R) agonists have pleiotropic actions including anti\u2010inflammatory effects, prevention of muscle atrophy, and inhibition of cell death, in addition to anti\u2010diabetic effect. We aimed in this study to examine the role of GLP\u20101R in PM and the effect of a GLP\u20101R agonist on\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      models of PM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Muscle specimens of PM patients and a murine model of PM, C protein\u2010induced myositis (CIM), were examined for the expression of GLP\u20101R. The effect of PF1801, a GLP\u20101R agonist, on CIM was evaluated in monotherapy or in combination with prednisolone (PSL). As an\n                      <jats:italic>in vitro<\/jats:italic>\n                      model of PM, C2C12\u2010derived myotubes were treated with FASLG to induce necroptosis. The effect of PF1801 on this model was analysed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      GLP\u20101R was expressed on the inflamed muscle fibres of PM and CIM. The treatment of CIM with PF1801 in monotherapy (PF) or in combination with PSL (PF\u00a0+\u00a0PSL) suppressed CIM\u2010induced muscle weakness (grip strength, mean\u00a0\u00b1\u00a0SD (g); PF 227\u00a0\u00b1\u00a06.0 (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01), PF\u00a0+\u00a0PSL 224\u00a0\u00b1\u00a08.5 (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01), Vehicle 162\u00a0\u00b1\u00a06.0) and decrease in cross\u2010sectional area of muscle fibres (mean\u00a0\u00b1\u00a0SD (\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      ); PF 1896\u00a0\u00b1\u00a0144 (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05), PF\u00a0+\u00a0PSL 2018\u00a0\u00b1\u00a0445 (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01), Vehicle 1349\u00a0\u00b1\u00a0199) as well as the severity of histological inflammation scores (median, interquartile range; PF 0.0, 0.0\u20130.5 (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05), PF\u00a0+\u00a0PSL 0.0, 0.0\u20130.0 (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01), Vehicle 1.9, 1.3\u20133.3). PF1801 decreased the levels of inflammatory mediators such as TNF\u03b1, IL\u20106, and HMGB1 in the serum of CIM. PF1801 inhibited necroptosis of the myotubes in an AMP\u2010activated protein kinase (AMPK)\u2010dependent manner. PF1801 activated AMPK and decreased the expression of PGAM5, a mitochondrial protein, which was crucial for necroptosis of the myotubes. PF1801 promoted the degradation of PGAM5 through ubiquitin\u2010proteasome activity. Furthermore, PF1801 suppressed FASLG\u2010induced reactive oxygen species (ROS) accumulation in myotubes, also crucial for the execution of necroptosis, thorough up\u2010regulating the antioxidant molecules including\n                      <jats:italic>Nfe2l2<\/jats:italic>\n                      ,\n                      <jats:italic>Hmox1<\/jats:italic>\n                      ,\n                      <jats:italic>Gclm<\/jats:italic>\n                      , and\n                      <jats:italic>Nqo1<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>GLP\u20101R agonist could be a novel therapy for PM that recovers muscle weakness and suppresses muscle inflammation through inhi biting muscle fibre necroptosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13025","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T02:40:34Z","timestamp":1656643234000},"page":"2118-2131","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Amelioration of inflammatory myopathies by glucagon\u2010like peptide\u20101 receptor agonist via suppressing muscle fibre necroptosis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2093-3823","authenticated-orcid":false,"given":"Mari","family":"Kamiya","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU)  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumitaka","family":"Mizoguchi","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU)  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6171-2077","authenticated-orcid":false,"given":"Shinsuke","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU)  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2005.045690"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410160207"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.128834"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-052016-100247"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27875-4"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2019.105732"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12434"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00248.2012"},{"key":"e_1_2_7_10_1","article-title":"Weekly subcutaneous doses of Glymera (PB1023), a novel GLP\u20101 analogue reduces glucose exposure dose dependently","volume":"61","author":"Christiansen M","year":"2012","journal-title":"Am Diabetes Assoc 72nd Sci Sess"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-017-0078"},{"key":"e_1_2_7_12_1","first-page":"1591","article-title":"Percutaneous conchotome muscle biopsy. 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