{"doi":"10.1093/gerona/glaf231","title":"Sex-specific phosphoproteome responses to calorie restriction and insulin in skeletal muscle from older rats","abstract":"Calorie restriction (CR; calorie intake reduced by ∼20%-40% below ad libitum, AL, intake) potentiates skeletal muscle insulin sensitivity during old age by incompletely understood mechanisms. We aimed to identify CR-induced changes in muscle insulin signaling that may explain this enhanced sensitivity. We examined how CR (65% of AL intake for 8-weeks) alters muscle insulin action and signaling in aged rats (24-month old) of both sexes. We assessed insulin-stimulated glucose uptake (ISGU) in muscle together with deep phosphoproteomic profiling. CR enhanced ISGU in both sexes, with higher ISGU in females regardless of diet. We identified 590 diet-responsive phosphosites, indicating extensive CR-induced remodelling of muscle phosphorylation, particularly within structural and contractile pathways. Strikingly, 70% of these sites were sex-specific. Numerous insulin-responsive sites were identified (193 in females; 107 in males) with 60 overlapping sites. The magnitude of the insulin-effects among all significantly regulated sites correlated between sexes. S1443 phosphorylation on EH domain-binding protein 1-like protein-1 (Ehbp1l1; a potential regulator of Rab proteins that control GLUT4 glucose transporter trafficking) was insulin-responsive in both sexes but only associated to ISGU in females. Personalized phosphoproteomic analysis also identified insulin-responsive sites on Leiomodin-1 (Lmod1) that correlated with ISGU across individuals. Both Lmod1 and Ehbp1l1 have strong genetic association with glycemic traits in humans, reinforcing their translational relevance. This study revealed sex-dependent and sex-independent phosphosignaling mechanisms that associate with muscle insulin responsiveness as well as hundreds of sex-specific, CR-responsive phosphosites. These findings provide a rich resource for future research on CR and insulin sensitivity.","journal":"The Journals of Gerontology Series A","year":2025,"id":527225,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"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":463045,"name":"Søren Madsen","orcid":"0000-0002-1585-7862","position":1,"is_corresponding":false},{"id":1323310,"name":"Elise J. Needham","orcid":"0000-0001-6326-9048","position":2,"is_corresponding":false},{"id":1368008,"name":"Sean J. Humphrey","orcid":"0000-0002-2666-9744","position":3,"is_corresponding":false},{"id":226456,"name":"Amy Zheng","orcid":"0009-0004-4051-2796","position":4,"is_corresponding":false},{"id":541065,"name":"Edward B. Arias","orcid":"0000-0001-7316-4397","position":5,"is_corresponding":false},{"id":688730,"name":"Jacqueline Stöckli","orcid":null,"position":6,"is_corresponding":false},{"id":1403894,"name":"Harry B. Cutler","orcid":"0000-0002-2074-8599","position":7,"is_corresponding":false},{"id":688076,"name":"David E. James","orcid":"0000-0001-5946-5257","position":8,"is_corresponding":false},{"id":541066,"name":"Gregory D. Cartee","orcid":"0000-0001-5311-1722","position":9,"is_corresponding":false},{"id":1089770,"name":"Haiyan Wang","orcid":"0000-0002-0237-4319","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T02:50:39.280101Z","pmid":"41105193","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":[]}