Msi2 enhances muscle dysfunction in a myotonic dystrophy type 1 mouse model

Autores de IIS La Fe

• 

  Teresa Sevilla Mantecón

  Autor

• Ariadna Bargiela Schonbrunn

  Autor

Participantes ajenos a IIS La Fe

• Sabater-Arcis, M
• Moreno, N
• Alonso, MP
• Artero, R

Grupos

• Patología Neuromuscular y Ataxias

Abstract

Background: Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the 3' untranslated region of the DM1 protein kinase gene. Characteristic degenerative muscle symptoms include myotonia, atrophy, and weakness. We previously proposed an Musashi homolog 2 (MSI2)>miR-7>autophagy axis whereby MSI2 overexpression repressed miR-7 biogenesis that subsequently de-repressed muscle catabolism through excessive autophagy. Because the DM1 HSA(LR) mouse model expressing expanded CUG repeats shows weak muscle-wasting phenotypes, we hypothesized that MSI2 overexpression was sufficient to promote muscle dysfunction in vivo. Methods: By means of recombinant AAV murine MSI2 was overexpressed in neonates HSA(LR) mice skeletal muscle to induce DM1-like phenotypes. Results: Sustained overexpression of the murine MSI2 protein in HSA(LR) neonates induced autophagic flux and expression of critical autophagy proteins, increased central nuclei and reduced myofibers area, and weakened muscle strength. Importantly, these changes were independent of MBNL1, MBNL2, and Celf1 protein levels, which remained unchanged upon Msi2 overexpression. Conclusions: Globally, molecular, histological, and functional data from these experiments in the HSA(LR) mouse model confirms the pathological role of MSI2 expression levels as an atrophy-associated component that impacts the characteristic muscle dysfunction symptoms in DM1 patients.

© 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords

• Msi2; Myotonic dystrophy; Muscle atrophy; Adeno-associated virus