Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy
Muscle atrophy is debilitating and can be induced by several stressors. Unfortunately, there are no effective pharmacological treatment until now. MicroRNA (miR)-29b is an important target that we identified to be commonly involved in multiple types of muscle atrophy. Although sequence-specific inhi...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123000239 |
| _version_ | 1797895564246908928 |
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| author | Qi Liu Weilin Yuan Yuwei Yan Bing Jin Mengke You Tianqi Liu Mingchun Gao Jin Li Priyanka Gokulnath Gururaja Vulugundam Guoping Li Bin Xu Junjie Xiao |
| author_facet | Qi Liu Weilin Yuan Yuwei Yan Bing Jin Mengke You Tianqi Liu Mingchun Gao Jin Li Priyanka Gokulnath Gururaja Vulugundam Guoping Li Bin Xu Junjie Xiao |
| author_sort | Qi Liu |
| collection | DOAJ |
| description | Muscle atrophy is debilitating and can be induced by several stressors. Unfortunately, there are no effective pharmacological treatment until now. MicroRNA (miR)-29b is an important target that we identified to be commonly involved in multiple types of muscle atrophy. Although sequence-specific inhibition of miR-29b has been developed, in this study, we report a novel small-molecule miR-29b inhibitor that targets miR-29b hairpin precursor (pre-miR-29b) (Targapremir-29b-066 [TGP-29b-066]) considering both its three-dimensional structure and the thermodynamics of interaction between pre-miR-29b and the small molecule. This novel small-molecule inhibitor has been demonstrated to attenuate muscle atrophy induced by angiotensin II (Ang II), dexamethasone (Dex), and tumor necrosis factor α (TNF-α) in C2C12 myotubes, as evidenced by increase in the diameter of myotube and decrease in the expression of Atrogin-1 and MuRF-1. Moreover, it can also attenuate Ang II-induced muscle atrophy in mice, as evidenced by a similar increase in the diameter of myotube, reduced Atrogin-1 and MuRF-1 expression, AKT-FOXO3A-mTOR signaling activation, and decreased apoptosis and autophagy. In summary, we experimentally identified and demonstrated a novel small-molecule inhibitor of miR-29b that could act as a potential therapeutic agent for muscle atrophy. |
| first_indexed | 2024-04-10T07:27:51Z |
| format | Article |
| id | doaj.art-a39ffc5d6fae4664a83b62f8080937ce |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-10T07:27:51Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-a39ffc5d6fae4664a83b62f8080937ce2023-02-24T04:30:37ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-03-0131527540Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophyQi Liu0Weilin Yuan1Yuwei Yan2Bing Jin3Mengke You4Tianqi Liu5Mingchun Gao6Jin Li7Priyanka Gokulnath8Gururaja Vulugundam9Guoping Li10Bin Xu11Junjie Xiao12Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, ChinaInstitute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, ChinaInstitute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, ChinaInstitute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, ChinaDepartment of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, ChinaInstitute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, ChinaInstitute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, ChinaInstitute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, ChinaCardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USABiologics Development, Sanofi, Framingham, MA 01701, USACardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USAInstitute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China; Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China; Corresponding author Bin Xu, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China; Corresponding author Junjie Xiao, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.Muscle atrophy is debilitating and can be induced by several stressors. Unfortunately, there are no effective pharmacological treatment until now. MicroRNA (miR)-29b is an important target that we identified to be commonly involved in multiple types of muscle atrophy. Although sequence-specific inhibition of miR-29b has been developed, in this study, we report a novel small-molecule miR-29b inhibitor that targets miR-29b hairpin precursor (pre-miR-29b) (Targapremir-29b-066 [TGP-29b-066]) considering both its three-dimensional structure and the thermodynamics of interaction between pre-miR-29b and the small molecule. This novel small-molecule inhibitor has been demonstrated to attenuate muscle atrophy induced by angiotensin II (Ang II), dexamethasone (Dex), and tumor necrosis factor α (TNF-α) in C2C12 myotubes, as evidenced by increase in the diameter of myotube and decrease in the expression of Atrogin-1 and MuRF-1. Moreover, it can also attenuate Ang II-induced muscle atrophy in mice, as evidenced by a similar increase in the diameter of myotube, reduced Atrogin-1 and MuRF-1 expression, AKT-FOXO3A-mTOR signaling activation, and decreased apoptosis and autophagy. In summary, we experimentally identified and demonstrated a novel small-molecule inhibitor of miR-29b that could act as a potential therapeutic agent for muscle atrophy.http://www.sciencedirect.com/science/article/pii/S2162253123000239MT: Non-coding RNAsmiR-29bmuscle atrophyAng IIDexTNF-α |
| spellingShingle | Qi Liu Weilin Yuan Yuwei Yan Bing Jin Mengke You Tianqi Liu Mingchun Gao Jin Li Priyanka Gokulnath Gururaja Vulugundam Guoping Li Bin Xu Junjie Xiao Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy Molecular Therapy: Nucleic Acids MT: Non-coding RNAs miR-29b muscle atrophy Ang II Dex TNF-α |
| title | Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy |
| title_full | Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy |
| title_fullStr | Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy |
| title_full_unstemmed | Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy |
| title_short | Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy |
| title_sort | identification of a novel small molecule inhibitor of mir 29b attenuates muscle atrophy |
| topic | MT: Non-coding RNAs miR-29b muscle atrophy Ang II Dex TNF-α |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123000239 |
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