Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy

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

doi:10.1016/j.omtn.2023.02.003

Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy

Mol Ther Nucleic Acids. 2023 Feb 4:31:527-540. doi: 10.1016/j.omtn.2023.02.003. eCollection 2023 Mar 14.

Authors

Qi Liu^{1

2}, Weilin Yuan^{1

2}, Yuwei Yan^{1

2}, Bing Jin^{1

2}, Mengke You³, Tianqi Liu^{1

3}, Mingchun Gao¹, Jin Li^{1

2}, Priyanka Gokulnath⁴, Gururaja Vulugundam⁵, Guoping Li⁴, Bin Xu^{1

2

3}, Junjie Xiao^{1

2}

Affiliations

¹ 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.
² 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.
³ Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China.
⁴ Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁵ Biologics Development, Sanofi, Framingham, MA 01701, USA.

Abstract

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.

Keywords: Ang II; C2C12 myotubes; Dex; MT: Non-coding RNAs; TNF-α; miR-29b; muscle atrophy; small-molecule inhibitor.