ZFIN ID: ZDB-PUB-210303-8
hnRNP L is essential for myogenic differentiation and modulates myotonic dystrophy pathologies
Alexander, M.S., Hightower, R.M., Reid, A.L., Bennett, A.H., Iyer, L., Slonim, D.K., Saha, M., Kawahara, G., Kunkel, L.M., Kopin, A.S., Gupta, V.A., Kang, P.B., Draper, I.
Date: 2021
Source: Muscle & nerve   63(6): 928-940 (Journal)
Registered Authors: Alexander, Matthew, Gupta, Vandana A, Hightower, Rylie, Kunkel, Louis M., Reid, Andrea
Keywords: MBNL, ascochlorin, hnRNP L, myotonic dystrophy, smooth
MeSH Terms:
  • Adult
  • Animals
  • Cell Line
  • Heterogeneous-Nuclear Ribonucleoproteins/genetics
  • Heterogeneous-Nuclear Ribonucleoproteins/metabolism*
  • Humans
  • Male
  • Middle Aged
  • Muscle Development/genetics*
  • Myoblasts/metabolism*
  • Myoblasts/pathology
  • Myotonic Dystrophy/genetics*
  • Myotonic Dystrophy/metabolism
  • Myotonic Dystrophy/pathology
  • Zebrafish
PubMed: 33651408 Full text @ Muscle Nerve
ABSTRACT
RNA binding proteins (RBPs) play an important role in skeletal muscle development and disease by regulating RNA splicing. In myotonic dystrophy type 1 (DM1), the RBP MBNL1 (Muscleblind-like) is sequestered by toxic CUG repeats, leading to mis-splicing of MBNL1 targets. Mounting evidence from the literature has implicated other factors in the pathogenesis of DM1. Here we sought to evaluate the functional role of hnRNP L in normal and DM1 muscle cells. We sought to test if modulation of hnRNP L expression affected DM1 splicing targets and myogenic outcomes.
Co-immunoprecipitation assays using hnRNPL and MBNL1 expression constructs and expression profiling in normal and DM1 muscle cell lines were performed. Zebrafish morpholinos targeting hnrnpl and hnrnpl2 were injected into one-cell zebrafish for developmental and muscle analysis. Ascochlorin administration to DM1 myoblasts was performed and expression of the CUG repeats, DM1 splicing biomarkers, and hnRNP L expression levels were evaluated.
Using DM1 patient myoblast cell lines we observed the formation of abnormal hnRNP L nuclear foci within and outside the expanded CUG repeats, further suggesting a role for this factor in DM1 pathology. We showed that the antiviral and antitumorigenic isoprenoid compound ascochlorin increased MBNL1 and hnRNP L expression levels. Drug treatment of DM1 muscle cells with ascochlorin partially rescued mis-splicing of established early biomarkers of DM1 and improved the defective myotube formation displayed by DM1 muscle cells.
Together, these studies reveal that hnRNP L modulated DM1 pathologies, and is a potential therapeutic target. This article is protected by copyright. All rights reserved.
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