文献类型： 外文期刊

作者： Wei, Chengjie ¹ ; Wang, Dandan ¹ ; Ma, Yitian ¹ ; Wang, Shengnan ¹ ; Pan, Dengke ³ ; Ma, Yuehui ¹ ; Jiang, Lin ¹ ;

作者机构： 1.Chinese Acad Agr Sci CAAS, Inst Anim Sci, Lab Anim Poultry Genet Breeding & Reprod, Minist Agr, Beijing, Peoples R China

2.Chinese Acad Agr Sci CAAS, Inst Anim Sci, Natl Germplasm Ctr Domest Anim Resources, Minist Sci & Technol Peoples Republ China, Beijing, Peoples R China

3.Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Inst Organ Transplantat, Chengdu, Peoples R China

关键词： ageing; dexamethasone; Dkk3; skeletal muscle atrophy; ZBED6

期刊名称：JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE （ 影响因子：9.1； 五年影响因子：10.8 ）

ISSN： 2190-5991

年卷期： 2025 年 16 卷 3 期

页码：

收录情况： SCI

摘要： Background Effective treatments for skeletal muscle atrophy, a debilitating condition linked to ageing and glucocorticoid therapy, remain lacking. Zinc finger BED-type containing 6 (ZBED6), a transcriptional repressor, enhances muscle growth and protects against sepsis-induced atrophy, but its role in ageing- and dexamethasone (Dex)-induced muscle atrophy remains unknown. This study investigated the protective role of ZBED6 knockout (KO) against muscle atrophy through the Dkk3-Fbxo32 pathway. Methods The muscle mass, ratio and myofibrillar morphology of 5-day-old (wild-type (WT): KO, n = 5:3), 5-month-old (n = 8:9) and 8-month-old (n = 3:3) ZBED6-KO pigs and 18-month-old mice (n = 3:3) were analysed. A model of Dex-induced muscle atrophy was established using 3-month-old mice (n = 6:6) via intraperitoneal injections (15 mg/kg/day for 10 days). C2C12 myotubes were treated with 100 mu M Dex for 24 h. Muscle morphology was analysed through H&E and immunofluorescence staining. Gene expression was assessed through RNA-seq, qRT-PCR and western blotting. The downstream targets were identified through ChIP-seq using anti-ZBED6 antibodies and RNA-seq analysis of the gastrocnemius muscle from ZBED6-KO and WT pigs. Dkk3 was overexpressed by injecting AAV9-myo2A-Dkk3 (2 x 10(11)) into the tibialis anterior muscle of 3-month-old ZBED6-KO mice (n = 4), which were harvested 1 month postinjection. ZBED6-KO C2C12 cells were generated via CRISPR/Cas9 and treated with Dex to assess the effects on myotube diameter and gene expression. Results The muscle mass and muscle-to-carcass ratio in ZBED6-KO pigs increased by 27% and 12%, respectively (p < 0.05), while the Dkk3-Fbxo32 pathway was suppressed by 50% (p < 0.01). ChIP-seq/RNA-seq identified Dkk3 as the most significant ZBED6 target (log2FC = -3.38, p < 0.01). The myofibrillar cross-sectional areas (CSAs) increased twofold in aged ZBED6-KO mice, while fibrosis and the Dkk3-Fbxo32 pathway were suppressed by 76% and 50%, respectively (all p < 0.01). Dkk3 overexpression reduced the tibialis anterior muscle weight and CSA in ZBED6-KO mice by 31% and 61%, respectively (p < 0.01). Dex reduced the CSA in WT mice (45%, p < 0.01), but ZBED6-KO mice resisted atrophy (CSA similar to untreated WT). ZBED6-KO increased myotube diameter by twofold (p < 0.01) and inhibited the activation of the Dkk3-Fbxo32 pathway (p < 0.01). Conversely, Zbed6 overexpression reduced the CSA and myotube diameter by 32% and 64%, respectively (p < 0.01) and rescued by Dkk3 silencing (50% recovery, p < 0.01). Conclusions ZBED6 depletion mitigates ageing- and Dex-induced muscle atrophy via the Dkk3-Fbxo32 axis, highlighting its therapeutic potential.