{"doi":"10.1002/jcsm.13755","title":"Activated Microglia Mediate the Motor Neuron‐, Synaptic Denervation‐ and Muscle Wasting‐Changes in Burn Injured Mice","abstract":"BACKGROUND: Muscle wasting (MW) of burn injury (BI) remains unresolved. Microglia-mediated inflammatory cytokine/chemokine release, motor neuron loss (MNL) and MW is observed after BI but connection of the central changes to synaptic-denervation and MW is unelucidated. Stimulation of microglia α7acetylcholine receptors (α7AChRs), a Chrna7gene-product, exhibits anti-inflammatory properties (decreased cytokine/chemokines). Hypothesis tested was that exploitation of the microglia α7AChR anti-inflammatory properties mitigates cytokine inflammatory responses, MNL, synaptic-denervation and MW of BI. METHODS: Wild-type or α7AChR knockout (A7KO) mice received 30% body BI or Sham BI (SB) under anaesthesia with and without selective α7AChR agonist, GTS-21. 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 α-bungarotoxin for muscle α7AChR). Spinal cytokine/chemokine transcripts, inflammatory transducer-protein expression and tibialis, soleus and gastrocnemius muscle weights were measured. RESULTS: BI to Wild-type mice caused significant microgliosis (5.8-fold increase, p < 0.001) and upregulated TNF-α, IL-1β, CXCL2, MCP-1 transcripts, and inflammatory transducer-protein (STAT3 and NF-κB, p < 0.01) expression together with increased transcripts of iNOS (p < 0.01) and CD86 (p < 0.01) at day 14 reflective of inflammatory M1 microglia phenotype. Significant apoptosis, MNL (32.2% reduction, p < 0.05), increased spinal caspase-3 expression (> 1100-fold, p < 0.05) 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-like appearance was lost, and the endplates were fragmented with less nerve to muscle apposition. Tibialis, soleus, and gastrocnemius mass were decreased 31.7% (p < 0.01), 23.4% (p < 0.01) and 27.5% (p < 0.01) relative to SB. The A7KO mice with SB showed significant MNL loss (61.5% reduction, p < 0.05), which was aggravated with BI, accompanied by significantly higher expression of STAT3 and Nf-kB (p < 0.05). GTS-21 ameliorated the spinal expression of above enumerated cytokines/chemokines, inflammatory transducer-proteins (p < 0.05) together with mitigated MNL (p < 0.05), synaptic denervation (p < 0.05) and decreased MW of tibialis (25%), gastrocnemius (15%) and soleus (20%) relative to untreated wild type BI mice (p < 0.01). GTS-21 beneficial effects were absent in the A7KO mice. CONCLUSIONS: Microglia-mediated inflammatory responses play pivotal role in MNL as decrease of inflammatory responses improved MNL; α7AChR stimulation also mitigated synaptic denervation and MW changes of BI. α7AChRs have a role in spinal homeostasis even in uninjured state.","journal":"Journal of Cachexia Sarcopenia and Muscle","year":2025,"id":528030,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1045238,"name":"Yoshinori Kitagawa","orcid":"0000-0002-3275-3336","position":1,"is_corresponding":false},{"id":1394867,"name":"Fei Xie","orcid":"0000-0002-7218-5222","position":2,"is_corresponding":false},{"id":294910,"name":"Haobo Li","orcid":"0000-0002-5660-7835","position":3,"is_corresponding":false},{"id":779422,"name":"William R. Kem","orcid":"0000-0001-8492-3969","position":4,"is_corresponding":false},{"id":870442,"name":"Zerong You","orcid":null,"position":5,"is_corresponding":false},{"id":1222401,"name":"Shingo Yasuhara","orcid":null,"position":6,"is_corresponding":false},{"id":1107554,"name":"J. A. Jeevendra Martyn","orcid":"0000-0001-9618-4526","position":7,"is_corresponding":false},{"id":537846,"name":"Jingyuan Chen","orcid":"0000-0001-8691-883X","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:50:44.062153Z","pmid":"40035088","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}