{"doi":"10.1101/2025.05.28.655862","title":"Convergent Skeletal Muscle Cytokine Responses to TFEB Overexpression and Voluntary Wheel Running Reflect Sex-Based Variability in Exercise Adaptations","abstract":"Endurance exercise (running) promotes skeletal muscle remodeling through metabolic and inflammatory signaling cascades. However, the extent to which these responses are sex-dependent remains unclear. Here, we profiled cytokine responses in quadriceps muscle lysates from sedentary, voluntary wheel-running (VWR; 5 weeks), and muscle-specific TFEB-overexpressing (cTFEB;HSACre) male and female mice. Cytokine analysis revealed 40 differentially expressed factors associated with exercise and/or TFEB overexpression, many displaying sex-dimorphic expression patterns. In males, VWR induced significant increases in interleukins (e.g., IL-1α, IL-1β, IL-2, IL-5, IL-17) and chemokines (e.g., MCP-1, CCL5, CXCL9), as well as cytokines involved in TNF signaling (e.g., TNFα, sTNFR1/2, Fas ligand). TFEB overexpression in sedentary males recapitulated many of these cytokine elevations. In contrast, female runner muscle showed limited cytokine activation, with significant changes restricted to IL-3, IL-3Rb, IL-13, and CXCL16. Both sexes exhibited a reduction in IL-4 and an increase in IGFBP-5 with running. Several additional male-specific cytokine profiling responses, including increases in IFNγ, SCF, TPO, VCAM1A, and leptin, further underscored the sex-specificity of exercise-related inflammatory adaptations. These findings demonstrate that skeletal muscle cytokine responses to endurance-like stimuli are profoundly influenced by sex and suggest that male muscle exhibits a broader and/or later remodeling profile than female muscle. Our data also implicate skeletal muscle TFEB-overexpression as a partial molecular mediator of the cytokine shifts observed with exercise, particularly in males, and highlights their potential use as a new prioritization platform for exercise-associated phenotypes.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":567088,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9476,"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":569974,"name":"Allison Birnbaum","orcid":"0000-0002-8904-3917","position":1,"is_corresponding":false},{"id":985551,"name":"Ian Matthews","orcid":"0000-0002-1537-1096","position":2,"is_corresponding":false},{"id":780211,"name":"Constanza J. Cortés","orcid":"0000-0002-6033-7428","position":3,"is_corresponding":false},{"id":985553,"name":"Dalton C. Patterson","orcid":"0000-0002-0208-7301","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:56:44.340853Z","pmid":"40502167","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":[]}