EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA Destabilization
ABSTRACT 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...
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2025-08-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
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| Online Access: | https://doi.org/10.1002/jcsm.70010 |
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| author | 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 Wu Yan Zhang Dongchao Lu Tingting Yang Yongjun Zheng Jin Li |
| author_facet | 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 Wu Yan Zhang Dongchao Lu Tingting Yang Yongjun Zheng Jin Li |
| author_sort | Qian Li |
| collection | DOAJ |
| description | ABSTRACT 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 demonstrated that EIF4A3 overexpression promoted muscle atrophy and aging in myotubes (n = 6, p < 0.05), while EIF4A3 inhibition mitigated these effects (p < 0.05). In vivo phenotypic analysis indicated that overexpression of EIF4A3 in skeletal muscle promoted muscle atrophy (n = 10, p < 0.05) including reduced grip strength (−42.36%, p < 0.001), running capacity (−21.24%, p < 0.001), contraction force (−19.62%, p < 0.001), muscle weight (gastrocnemius muscle: −15.75%; p < 0.001; tibialis anterior muscle: −9.50%, p < 0.01), myofiber size (−11.59%, p < 0.001) and worsened molecular phenotypes (all p < 0.05). Knockdown of EIF4A3 protected against muscle atrophy induced by various stimuli, including denervation (n = 10, p < 0.05), immobilization (n = 10, p < 0.05) and angiotensin II (n = 6–10, p < 0.05) in mice. Mechanistically, Neural Precursor Cell Expressed, Developmentally Down‐Regulated 9 (NEDD9) mRNA was identified as a direct target of EIF4A3. EIF4A3 promoted the decay of NEDD9 mRNA and inhibited the downstream focal adhesion kinase (FAK) and PI3K‐Akt pathway, promoting muscle atrophy. Pharmacological activation of the NEDD9‐FAK pathway abolished the pro‐atrophy effects of EIF4A3. Conclusions Our findings shed significant light on the pivotal function of the EJC in muscle atrophy, revealing novel mechanisms that contribute to EJC‐related disorders. Providing a target for therapeutic interventions aimed at combating muscle atrophy. |
| format | Article |
| id | doaj-art-2b17beed8f074d9ab7cf35ded728cc41 |
| institution | Kabale University |
| issn | 2190-5991 2190-6009 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj-art-2b17beed8f074d9ab7cf35ded728cc412025-08-22T07:30:52ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092025-08-01164n/an/a10.1002/jcsm.70010EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA DestabilizationQian Li0Xiaohang Yin1Wensi Wan2Yi Zhou3Siqi Wang4Yuwei Yan5Jingying Chen6Xinyi Ren7Junli Gao8Yuying Chen9Yanan Zhang10Caiyue Cui11Emeli Chatterjee12Guoping Li13Ming Wu14Yan Zhang15Dongchao Lu16Tingting Yang17Yongjun Zheng18Jin Li19Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaCardiovascular Division of the Massachusetts General Hospital and Harvard Medical School Boston Massachusetts USACardiovascular Division of the Massachusetts General Hospital and Harvard Medical School Boston Massachusetts USADepartment of Orthopedics Shanghai Gongli Hospital Shanghai ChinaDepartment of Orthopedics Shanghai Gongli Hospital Shanghai ChinaSchool of Integrative Medicine Shanghai University of Traditional Chinese Medicine Shanghai ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaDepartment of Pain Medicine & Department of Rehabilitation Medicine Huadong Hospital Shanghai ChinaCardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine Shanghai University Nantong ChinaABSTRACT 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 demonstrated that EIF4A3 overexpression promoted muscle atrophy and aging in myotubes (n = 6, p < 0.05), while EIF4A3 inhibition mitigated these effects (p < 0.05). In vivo phenotypic analysis indicated that overexpression of EIF4A3 in skeletal muscle promoted muscle atrophy (n = 10, p < 0.05) including reduced grip strength (−42.36%, p < 0.001), running capacity (−21.24%, p < 0.001), contraction force (−19.62%, p < 0.001), muscle weight (gastrocnemius muscle: −15.75%; p < 0.001; tibialis anterior muscle: −9.50%, p < 0.01), myofiber size (−11.59%, p < 0.001) and worsened molecular phenotypes (all p < 0.05). Knockdown of EIF4A3 protected against muscle atrophy induced by various stimuli, including denervation (n = 10, p < 0.05), immobilization (n = 10, p < 0.05) and angiotensin II (n = 6–10, p < 0.05) in mice. Mechanistically, Neural Precursor Cell Expressed, Developmentally Down‐Regulated 9 (NEDD9) mRNA was identified as a direct target of EIF4A3. EIF4A3 promoted the decay of NEDD9 mRNA and inhibited the downstream focal adhesion kinase (FAK) and PI3K‐Akt pathway, promoting muscle atrophy. Pharmacological activation of the NEDD9‐FAK pathway abolished the pro‐atrophy effects of EIF4A3. Conclusions Our findings shed significant light on the pivotal function of the EJC in muscle atrophy, revealing novel mechanisms that contribute to EJC‐related disorders. Providing a target for therapeutic interventions aimed at combating muscle atrophy.https://doi.org/10.1002/jcsm.70010EIF4A3exon junction complex (EJC)FAKmuscle atrophyNEDD9 |
| spellingShingle | 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 Wu Yan Zhang Dongchao Lu Tingting Yang Yongjun Zheng Jin Li EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA Destabilization Journal of Cachexia, Sarcopenia and Muscle EIF4A3 exon junction complex (EJC) FAK muscle atrophy NEDD9 |
| title | EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA Destabilization |
| title_full | EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA Destabilization |
| title_fullStr | EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA Destabilization |
| title_full_unstemmed | EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA Destabilization |
| title_short | EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA Destabilization |
| title_sort | eif4a3 promotes muscle atrophy and aging by inhibiting the fak pathway through nedd9 mrna destabilization |
| topic | EIF4A3 exon junction complex (EJC) FAK muscle atrophy NEDD9 |
| url | https://doi.org/10.1002/jcsm.70010 |
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