{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:50:16Z","timestamp":1789563016384,"version":"build-2803163510"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"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":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Muscle wasting (MW) of burn injury (BI) remains unresolved. Microglia\u2010mediated inflammatory cytokine\/chemokine release, motor neuron loss (MNL) and MW is observed after BI but connection of the central changes to synaptic\u2010denervation and MW is unelucidated. Stimulation of microglia \u03b17acetylcholine receptors (\u03b17AChRs), a Chrna7gene\u2010product, exhibits anti\u2010inflammatory properties (decreased cytokine\/chemokines). Hypothesis tested was that exploitation of the microglia \u03b17AChR anti\u2010inflammatory properties mitigates cytokine inflammatory responses, MNL, synaptic\u2010denervation and MW of BI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Wild\u2010type or \u03b17AChR knockout (A7KO) mice received 30% body BI or Sham BI (SB) under anaesthesia with and without selective \u03b17AChR agonist, GTS\u201021. Lumbar spinal cord tissue and hindlimb muscles were harvested. Immunohistochemistry, TUNEL assay for apoptosis and\/or Nissl staining were used to examine microglia (Iba1 staining), MNL (NeuN staining) and synapse morphology (synaptophysin for nerve and \u03b1\u2010bungarotoxin for muscle \u03b17AChR). Spinal cytokine\/chemokine transcripts, inflammatory transducer\u2010protein expression and tibialis, soleus and gastrocnemius muscle weights were measured.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      BI to Wild\u2010type mice caused significant microgliosis (5.8\u2010fold increase,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and upregulated TNF\u2010\u03b1, IL\u20101\u03b2, CXCL2, MCP\u20101 transcripts, and inflammatory transducer\u2010protein (STAT3 and NF\u2010\u03baB,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) expression together with increased transcripts of iNOS (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and CD86 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) at day 14 reflective of inflammatory M1 microglia phenotype. Significant apoptosis, MNL (32.2% reduction,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), increased spinal caspase\u20103 expression (&gt;\u20091100\u2010fold,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and synaptic denervation were observed with BI. The tibialis muscle endplates (synapse) of SB had a smooth pretzel shaped appearance with good apposition of presynaptic nerve to postsynaptic muscle. In BI mice, the normal pretzel\u2010like appearance was lost, and the endplates were fragmented with less nerve to muscle apposition. Tibialis, soleus, and gastrocnemius mass were decreased 31.7% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), 23.4% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and 27.5% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) relative to SB. The A7KO mice with SB showed significant MNL loss (61.5% reduction,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), which was aggravated with BI, accompanied by significantly higher expression of STAT3 and Nf\u2010kB (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). GTS\u201021 ameliorated the spinal expression of above enumerated cytokines\/chemokines, inflammatory transducer\u2010proteins (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) together with mitigated MNL (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), synaptic denervation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and decreased MW of tibialis (25%), gastrocnemius (15%) and soleus (20%) relative to untreated wild type BI mice (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). GTS\u201021 beneficial effects were absent in the A7KO mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Microglia\u2010mediated inflammatory responses play pivotal role in MNL as decrease of inflammatory responses improved MNL; \u03b17AChR stimulation also mitigated synaptic denervation and MW changes of BI. \u03b17AChRs have a role in spinal homeostasis even in uninjured state.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13755","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T17:54:30Z","timestamp":1741715670000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Activated Microglia Mediate the Motor Neuron\u2010, Synaptic Denervation\u2010 and Muscle Wasting\u2010Changes in Burn Injured Mice"],"prefix":"10.1002","volume":"16","author":[{"given":"Jingyuan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospital for Children and Harvard Medical School  Boston Massachusetts USA"},{"name":"Department of Anesthesiology The First Affiliated Hospital, Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Kitagawa","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospital for Children and Harvard Medical School  Boston Massachusetts USA"},{"name":"Division of Anesthesiology and Critical Care Medicine, Department of Surgery  Tottori Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospital for Children and Harvard Medical School  Boston Massachusetts USA"},{"name":"Sichuan Cancer Hospital &amp; Institute, Sichuan Cancer Center, School of Medicine University of Electronic Science and Technology of China  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haobo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospital for Children and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William\u00a0R.","family":"Kem","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zerong","family":"You","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospital for Children and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Yasuhara","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospital for Children and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.\u00a0A.\u00a0Jeevendra","family":"Martyn","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospital for Children and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"issue":"10","key":"e_1_2_9_2_1","first-page":"1078","article-title":"Burn: Epidemiology, Evaluation, Organisation of Care","volume":"68","author":"Ravat F.","year":"2018","journal-title":"La Revue du Praticien"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/jbcr\/iry035"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0000000000001723"},{"issue":"3","key":"e_1_2_9_5_1","first-page":"450","article-title":"Fatigue Following Burn Injury: A Burn Model System National Database Study","volume":"39","author":"Simko L. C.","year":"2018","journal-title":"Journal of Burn Care & Research"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/BCR.0000000000000308"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000517"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/0884533614533129"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-0145-5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1988.65.4.1745"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880160403"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.5535\/arm.21133"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay9592"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bja.2022.07.055"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000005274"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000001300"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2016.02.006"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.742065"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-093019-110159"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00488"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0242-x"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0023-4"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022516-034406"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00015.2008"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-4328(00)00211-4"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2017.10.021"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e31825d628c"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.891220"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22158058"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-04-568691"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.11.4106-4114.2000"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0b013e328331e8fa"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2015.153"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.01.013"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6075-11.2013"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00427-6"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3253"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2016.01.008"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-021-02492-9"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.13755","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.13755","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.13755","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T04:13:41Z","timestamp":1771215221000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.13755"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,4]]},"references-count":38,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1002\/jcsm.13755"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.13755","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,4]]},"assertion":[{"value":"2024-08-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13755"}}