Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model

• Type of Material: Article
• Authors: Jing Deng, Central South University; Xin-Xin Guan, Central South University; Ying-Bao Zhu, Central South University; Hai-Tao Deng, Central South University; Guang-Xu Li, Central South University; Yi-Chen Guo, Central South University; Peng Jin, Emory University; Ran-Hui Duan, Central South University; Wen Huang, Central South University
• Language: English
• Date: 2022-03-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/jpm12030385
• Title of Journal or Parent Work: JOURNAL OF PERSONALIZED MEDICINE
• Volume: 12
• Issue: 3
• Grant/Funding Information: This work was supported by the National Natural Science Foundation of China (81571253, 81771385, 82071273 and 82101958), the Hunan Science and Technology major project of Birth Defect Cooperative Control (2019SK1010), the Hunan Provincial Natural Science Foundation (2016JJ3135), and the Changsha Municipal Natural Science Foundation (kq2007073).
• Keywords: General & Internal Medicine; HEART; chemical screen; TGF-BETA-1; CUG; myotonic dystrophy type 2; CTG REPEAT; Life Sciences & Biomedicine; REPEAT EXPANSION; EXPRESSION; Science & Technology; REVEALS; Medicine, General & Internal; REGENERATION; Health Care Sciences & Services; Drosophila; DYSFUNCTION; TGF-beta pathway; ZNF9
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Expanded non‐coding RNA repeats of CCUG are the underlying genetic causes for myotonic dystrophy type 2 (DM2). There is an urgent need for effective medications and potential drug targets that may alleviate the progression of the disease. In this study, 3140 small‐molecule drugs from FDA‐approved libraries were screened through lethality and locomotion phenotypes using a DM2 Drosophila model expressing 720 CCTG repeats in the muscle. We identified ten effective drugs that improved survival and locomotor activity of DM2 flies, including four that share the same predicted targets in the TGF‐β pathway. The pathway comprises two major branches, the Activin and BMP pathways, which play critical and complex roles in skeletal development, maintenance of homeostasis, and regeneration. The Drosophila model recapitulates pathological features of muscle degeneration in DM2, displaying shortened lifespan, a decline in climbing ability, and progressive muscle degeneration. Increased levels of p‐smad3 in response to activin signaling were observed in DM2 flies. Decreased levels of activin signaling using additional specific inhibitors or genetic method ameliorated climbing defects, crushed thoraxes, structure, and organization of muscle fibers. Our results demonstrate that a decrease in activin signaling is sufficient to rescue muscle degeneration and is, therefore, a potential therapeutic target for DM2.