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

Maria Sabater-Arcis; Nerea Moreno; Teresa Sevilla; Manuel Perez Alonso; Ariadna Bargiela; Ruben Artero

doi:10.1016/j.bj.2023.100667

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

Biomed J. 2023 Oct 3:100667. doi: 10.1016/j.bj.2023.100667. Online ahead of print.

Authors

Maria Sabater-Arcis¹, Nerea Moreno², Teresa Sevilla³, Manuel Perez Alonso⁴, Ariadna Bargiela⁵, Ruben Artero⁶

Affiliations

¹ Human Translational Genomics Group, University Institute for Biotechnology and Biomedicine (BIOTECMED), Dr. Moliner 50, Burjasot, Valencia, 46100, Spain; INCLIVA Biomedical Research Institute, Avda. Menéndez Pelayo 4, Valencia, 46010, Spain. Electronic address: maria.sabater@uv.es.
² Human Translational Genomics Group, University Institute for Biotechnology and Biomedicine (BIOTECMED), Dr. Moliner 50, Burjasot, Valencia, 46100, Spain; INCLIVA Biomedical Research Institute, Avda. Menéndez Pelayo 4, Valencia, 46010, Spain. Electronic address: Nerea.moreno@uv.es.
³ Neuromuscular and Ataxias Research Group, Health Research Institute Hospital La Fe (IIS La Fe). Av. de Fernando Abril Martorell, 106, 46026 Valencia, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER); U763, CB06/05/0091, Valencia, Spain; Department of Medicine, University of Valencia. Av. Blasco Ibañez 15, Valencia, 46010, Spain. Electronic address: sevilla_ter@gva.es.
⁴ Human Translational Genomics Group, University Institute for Biotechnology and Biomedicine (BIOTECMED), Dr. Moliner 50, Burjasot, Valencia, 46100, Spain; INCLIVA Biomedical Research Institute, Avda. Menéndez Pelayo 4, Valencia, 46010, Spain. Electronic address: manuel.perez@uv.es.
⁵ Neuromuscular and Ataxias Research Group, Health Research Institute Hospital La Fe (IIS La Fe). Av. de Fernando Abril Martorell, 106, 46026 Valencia, Spain. Electronic address: ariadna_bargiela@iislafe.es.
⁶ Human Translational Genomics Group, University Institute for Biotechnology and Biomedicine (BIOTECMED), Dr. Moliner 50, Burjasot, Valencia, 46100, Spain; INCLIVA Biomedical Research Institute, Avda. Menéndez Pelayo 4, Valencia, 46010, Spain. Electronic address: ruben.artero@uv.es.

PMID: 37797921
DOI: 10.1016/j.bj.2023.100667

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 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.

Keywords: HSA(LR); Msi2; adeno-associated virus; muscle atrophy; myotonic dystrophy.