EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA Destabilization

作者：Qian Li, Xiaohang Yin, Wensi Wan, Yi Zhou, Siqi Wang, Yuwei Yan, Jingying Chen, Xinyi Ren, Junli Gao, Yuying Chen, Yanan Zhang, Caiyue Cui, Emeli Chatterjee, Guoping Li, Ming‐Fang Wu, Yan Zhang, Dongchao Lu, Tingting Yang, Yongjun Zheng, Jin Li · 发表于：Journal of Cachexia Sarcopenia and Muscle · 年份：2025 · DOI：10.1002/jcsm.70010 · 被引用次数：6 · 研究领域：Muscle Physiology and Disorders、Amyotrophic Lateral Sclerosis Research、RNA Research and Splicing

BACKGROUND: Muscle atrophy has a poor prognosis, caused by various factors. Identifying a shared treatment target could address an unmet clinical need. The exon junction complex (EJC), a protein complex assembly that binds to RNA, facilitates post-transcriptional regulation by participating in mRNA splicing, mRNA export, translation and nonsense-mediated mRNA decay. This study aims to investigate the role of the EJC in muscle atrophy. METHODS: Single-cell transcriptome analysis and western blot were employed to analyse EJC expression in muscle atrophy. Overexpression of EJC helicase EIF4A3, as well as counteracting endogenous EIF4A3, was manipulated using lentiviral and adeno-associated virus 8 (AAV8) at both in vitro and in vivo levels. Imaging, RT-qPCR and immunoblot were utilized to identify phenotypes associated with muscle atrophy and aging. RNA-seq, RIP-seq, RT-qPCR and RIP-PCR were conducted to determine the targets of EIF4A3. A pharmacological approach that activates the downstream pathways in EIF4A3 knockdown muscle was employed to elucidate the molecular mechanisms of EIF4A3 in muscle atrophy. RESULTS: The core RNA helicase of the EJC, EIF4A3, showed increased expression in atrophied muscles and aging human muscle (+150.43%, n = 5 in young and aged human, age: 26.20 ± 6.760 vs. 73.60 ± 5.030, p < 0.001) and aged mice muscle (+74.54% in male, +61.28% in female: n = 6 in young and aged mice in male/female, age: 3 months vs. 20 months, p < 0.001). In vitro studies demo...