{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:03:25Z","timestamp":1784887405666,"version":"3.55.0"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sepsis\u2010induced myopathy (SIM) is a common and life\u2010threatening complication, but its underlying mechanisms remain poorly understood. PACS2, a key resident protein at mitochondria\u2010associated endoplasmic reticulum membranes (MAMs), regulates ER homeostasis under various pathological conditions. However, whether sepsis disrupts PACS2\u2010dependent MAM integrity, thereby triggering ER dysfunction and muscle wasting, remains unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We established a sepsis mouse model via cecal ligation and puncture (CLP) and assessed muscle function using compound muscle action potential (CMAP) recording and grip strength measurements. Muscle atrophy was evaluated by H&amp;E staining and Western blotting. PACS2 expression was determined by Western blotting, immunohistochemistry and qRT\u2010PCR. MAM integrity was assessed by immunofluorescence co\u2010localization of IP3R and VDAC1, and ER\u2010phagy (reticulophagy) activation was evaluated by transmission electron microscopy, Western blotting and fluorescence microscopy. To investigate the functional role of PACS2, adeno\u2010associated virus (AAV)\u2010mediated PACS2 overexpression was performed in mouse tibialis anterior muscle and gastrocnemius muscles, followed by RNA\u2010sequencing analysis. The MAPK pathway proteins p\u2010ERK, p\u2010P38 and p\u2010JNK levels were assessed by Western blotting, and the involvement of ERK\u2013MAPK signalling was tested pharmacologically via intraperitoneal injection of the ERK inhibitor SCH772984.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Septic mice developed progressive skeletal muscle atrophy (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and dysfunction (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), accompanied by 56% reduction in PACS2 expression at 96\u2009h post\u2010CLP (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), 25% decrease in MAM integrity (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and subsequent activation of FAM134B\u2010mediated ER\u2010phagy (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). AAV\u2010mediated PACS2 overexpression significantly alleviated muscle atrophy by restoring MAM integrity by 28% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), reducing FAM134B expression by 43% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and attenuating ER\u2010phagy (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). Co\u2010immunoprecipitation revealed no detectable direct protein\u2013protein interaction between PACS2 and FAM134B. Transcriptome sequencing and Western blotting analysis demonstrated that PACS2 overexpression specifically activated the ERK\u2013MAPK signalling pathway (55% increase in p\u2010ERK,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) without affecting p\u2010P38 or p\u2010JNK levels (\n                      <jats:italic>p<\/jats:italic>\n                      &gt;0.05), which suppressed FAM134B\u2010mediated ER\u2010phagy (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and ameliorated muscle atrophy (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) by inhibiting nuclear translocation of TFEB (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). Pharmacological ERK inhibition with SCH772984 abolished the protective effects of PACS2 by promoting TFEB nuclear translocation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and TFEB\u2010mediated FAM134B expression (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings demonstrate that SIM is closely associated with disrupted MAM integrity. PACS2 plays a critical role in maintaining MAM structural integrity and regulating FAM134B\u2010mediated ER\u2010phagy through the ERK\u2013MAPK\u2010TFEB signalling axis, thereby providing novel mechanistic insights and potential therapeutic targets for SIM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70308","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T04:39:41Z","timestamp":1778301581000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PACS2 Alleviates Sepsis\u2010Induced Myopathy by Activating ERK\u2013MAPK Signalling Pathway to Suppress ER\u2010Phagy"],"prefix":"10.1002","volume":"17","author":[{"given":"Xuexin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, the Fourth Affiliated Hospital Southwest Medical University  Meishan Sichuan China"},{"name":"Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou Southwest Medical University  Luzhou Sichuan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zu\u2010an","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, the Fourth Affiliated Hospital Southwest Medical University  Meishan Sichuan China"},{"name":"Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou Southwest Medical University  Luzhou Sichuan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"He","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, the Fourth Affiliated Hospital Southwest Medical University  Meishan Sichuan China"},{"name":"Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou Southwest Medical University  Luzhou Sichuan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Mu","sequence":"additional","affiliation":[{"name":"Department of 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Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobin","family":"Wang","sequence":"additional","affiliation":[{"name":"Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou Southwest Medical University  Luzhou Sichuan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0680-5139","authenticated-orcid":false,"given":"Li","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, the Fourth Affiliated Hospital Southwest Medical University  Meishan Sichuan China"},{"name":"Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou Southwest Medical University  Luzhou Sichuan Province 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