ZFIN ID: ZDB-PUB-190704-4
Selective serotonin reuptake inhibitors ameliorate MEGF10 myopathy
Saha, M., Rizzo, S.A., Ramanathan, M., Hightower, R.M., Santostefano, K.E., Terada, N., Finkel, R.S., Berg, J.S., Chahin, N., Pacak, C.A., Wagner, R.E., Alexander, M.S., Draper, I., Kang, P.B.
Date: 2019
Source: Human molecular genetics   28: 2365-2377 (Journal)
Registered Authors: Alexander, Matthew, Hightower, Rylie
Keywords: none
MeSH Terms:
  • Animals
  • Cell Line
  • Cell Movement
  • Cell Proliferation
  • Citalopram/pharmacology
  • Citalopram/therapeutic use
  • Drosophila/drug effects
  • Drosophila/genetics
  • Drug Evaluation, Preclinical
  • Humans
  • Membrane Proteins/genetics*
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal/metabolism
  • Muscular Diseases/drug therapy*
  • Muscular Diseases/genetics
  • Mutation
  • Myoblasts/drug effects*
  • Myoblasts/metabolism
  • Receptor, Notch1/metabolism
  • Serotonin Uptake Inhibitors/pharmacology
  • Serotonin Uptake Inhibitors/therapeutic use*
  • Sertraline/pharmacology
  • Sertraline/therapeutic use*
  • Signal Transduction
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed: 31267131 Full text @ Hum. Mol. Genet.
MEGF10 myopathy is a rare inherited muscle disease that is named after the causative gene, MEGF10. The classic phenotype, early onset myopathy, areflexia, respiratory distress and dysphagia, is severe and immediately life-threatening. There are no disease-modifying therapies. We performed a small molecule screen and follow-up studies to seek a novel therapy. A primary in vitro drug screen assessed cellular proliferation patterns in Megf10-deficient myoblasts. Secondary evaluations were performed on primary screen hits using myoblasts derived from Megf10-/- mice, induced pluripotent stem cell-derived myoblasts from MEGF10 myopathy patients, mutant Drosophila that are deficient in the homologue of MEGF10 (Drpr) and megf10 mutant zebrafish. The screen yielded two promising candidates that are both selective serotonin reuptake inhibitors (SSRIs), sertraline and escitalopram. In depth follow-up analyses demonstrated that sertraline was highly effective in alleviating abnormalities across multiple models of the disease including mouse myoblast, human myoblast, Drosophila and zebrafish models. Sertraline also restored deficiencies of Notch1 in disease models. We conclude that SSRIs show promise as potential therapeutic compounds for MEGF10 myopathy, especially sertraline. The mechanism of action may involve the Notch pathway.