{"id":8,"title":"Cellular senescence mediates facioscapulohumeral muscular dystrophy","title_zh":"细胞衰老介导面肩肱型肌营养不良症","url":"https://pubmed.ncbi.nlm.nih.gov/42986690","doi":"10.1172/jci207716","pmid":"42986690","journal":"J Clin Invest","kind":"paper","lang":"en","published_at":"2026-11-05T00:00:00+00:00","fetched_at":"2026-11-08T03:43:49+00:00","authors":["Jung U","Wei E","Mitanoska A","Heher P","Chen K","Ahsan H","Zhang X","Tasca G","Robbins PD","LeBrasseur NK","Kyba M","Bosnakovski D"],"primary_topic":"repro-aging","topics":[{"slug":"repro-aging","score":5.0,"hits":["senescence","senescent"]}],"topic_score":5.0,"preference_score":0.0,"preference_labels":[],"llm_score":48.0,"final_score":48.0,"score_dims":{"novelty":85,"rigor":78,"impact":30,"relevance":22,"translation":20},"recommend_reason":"在FSHD领域提出了衰老为核心早期机制，并给出拉米夫定老药新用的干预证据，设计较完整；但研究对象为骨骼肌疾病，仅因DUX4为早期胚胎转录因子、以及衰老/SASP这一与生殖衰老共通的机制而与生殖医学间接相关，对ART实验室与临床决策的直接价值有限。","keywords":["细胞衰老","DUX4","面肩肱型肌营养不良症","SASP","拉米夫定","纤维脂肪祖细胞"],"selected":0,"story_id":null,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-embryo-omics","source_name":"PubMed · 胚胎/卵母细胞组学","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":null,"journal_tier":"unknown","journal_if":null,"is_mock":false,"summary_zh":"研究分析面肩肱型肌营养不良症（FSHD）患者肌肉转录组，发现衰老及衰老相关分泌表型（SASP）程序显著富集，且与DUX4活性、临床严重程度及病理改变相关；这些特征在STIR阴性肌肉中即可检出，提示存在影像学炎症出现前的“前营养不良”状态，可作为早期生物标志物。FSHD小鼠模型显示DUX4诱导的肌损伤迅速触发衰老并逐步扩展，纤维脂肪祖细胞与巨噬细胞是主要衰老群体及SASP来源。核苷类逆转录酶抑制剂拉米夫定（3TC）可显著减轻衰老、炎症与纤维化并促进肌肉再生。","summary":"Facioscapulohumeral muscular dystrophy (FSHD) is driven by aberrant expression of the early embryonic transcription factor Double Homeobox 4 (DUX4), yet the mechanisms linking low, sporadic DUX4 activity to progressive muscle degeneration remain unclear. Here, we identify cellular senescence as a central and early mechanism in FSHD pathogenesis. Analysis of patient muscle transcriptomes revealed strong enrichment of senescence and senescence-associated secretory phenotype (SASP) programs that correlated with DUX4 activity, clinical severity, and histopathological changes. Notably, these signatures were detectable even in STIR-negative muscles, defining a prodystrophic state characterized by early molecular alterations preceding overt MRI-detectable inflammation and highlighting their potential utility as early biomarkers of disease activity. Using an FSHD mouse model, we show that DUX4-induced muscle injury rapidly triggers senescence, which then progressively expands. Fibroadipogenic progenitors and macrophages emerged as the principal senescent populations and key sources of pro-inflammatory and profibrotic SASP signals. Importantly, senescence was therapeutically modifiable. Treatment with the nucleoside reverse transcriptase inhibitor lamivudine (3TC), which inhibits LINE-1 reverse transcriptase activity, significantly reduced senescence, inflammation, and fibrosis while promoting muscle regeneration. These findings identify cellular senescence as a tractable driver of FSHD and warrant senotherapeutic strategies, particularly lamivudine, for clinical intervention in FSHD.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}