{"doi":"10.1016/j.celrep.2024.114149","title":"Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner","abstract":"Loss of muscle mass is a feature of chronic illness and aging. Here, we report that skeletal muscle-specific thrombospondin-1 transgenic mice (Thbs1 Tg) have profound muscle atrophy with age-dependent decreases in exercise capacity and premature lethality. Mechanistically, Thbs1 activates transforming growth factor β (TGFβ)-Smad2/3 signaling, which also induces activating transcription factor 4 (ATF4) expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to facilitate muscle atrophy. Indeed, myofiber-specific inhibition of TGFβ-receptor signaling represses the induction of ATF4, normalizes ALP and UPS, and partially restores muscle mass in Thbs1 Tg mice. Similarly, myofiber-specific deletion of Smad2 and Smad3 or the Atf4 gene antagonizes Thbs1-induced muscle atrophy. More importantly, Thbs1 −/− mice show significantly reduced levels of denervation- and caloric restriction-mediated muscle atrophy, along with blunted TGFβ-Smad3-ATF4 signaling. Thus, Thbs1-mediated TGFβ-Smad3-ATF4 signaling in skeletal muscle regulates tissue rarefaction, suggesting a target for atrophy-based muscle diseases and sarcopenia with aging.","journal":"Cell Reports","year":2024,"id":419465,"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":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9625,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1209400,"name":"Tobias G Schips","orcid":null,"position":1,"is_corresponding":false},{"id":303255,"name":"Rachel A Minerath","orcid":null,"position":2,"is_corresponding":false},{"id":864629,"name":"Jiuzhou Huo","orcid":"0000-0003-3242-568X","position":3,"is_corresponding":false},{"id":1209401,"name":"Naga Swathi Sree Kavuri","orcid":null,"position":4,"is_corresponding":false},{"id":274726,"name":"Vikram Prasad","orcid":"0000-0002-8852-3986","position":5,"is_corresponding":false},{"id":1209402,"name":"Suh-Chin Lin","orcid":null,"position":6,"is_corresponding":false},{"id":289833,"name":"Michael J. Bround","orcid":"0000-0003-3238-5489","position":7,"is_corresponding":false},{"id":625536,"name":"Michelle A. Sargent","orcid":"0000-0002-8069-1686","position":8,"is_corresponding":false},{"id":1209403,"name":"Christopher M Adams","orcid":null,"position":9,"is_corresponding":false},{"id":289834,"name":"Jeffery D. Molkentin","orcid":"0000-0002-3558-6529","position":10,"is_corresponding":false},{"id":625535,"name":"Davy Vanhoutte","orcid":"0000-0002-8147-6953","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T01:57:14.586331Z","pmid":"38678560","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":[]}