Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy.

Vahid M Harandi,Valérie Allamand,Bernardo Moreira Soares Oliveira,Cibely C Fontes-Oliveira,Madeleine Durbeej,Ariana Friberg

doi:10.3390/antiox9030244

Abstract

Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe neuromuscular disorder without a cure. Using transcriptome and proteome profiling as well as functional assays, we previously demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Reactive oxygen species (ROS) increase when oxygen homeostasis is not maintained and, here, we investigate whether oxidative stress indeed is involved in the pathogenesis of LAMA2-CMD. We also analyze the effects of two antioxidant molecules, N-acetyl-L-cysteine (NAC) and vitamin E, on disease progression in the dy2J/dy2J mouse model of LAMA2-CMD. We demonstrate increased ROS levels in LAMA2-CMD mouse and patient skeletal muscle. Furthermore, NAC treatment (150 mg/kg IP for 6 days/week for 3 weeks) led to muscle force loss prevention, reduced central nucleation and decreased the occurrence of apoptosis, inflammation, fibrosis and oxidative stress in LAMA2-CMD muscle. In addition, vitamin E (40 mg/kg oral gavage for 6 days/week for 2 weeks) improved morphological features and reduced inflammation and ROS levels in dy2J/dy2J skeletal muscle. We suggest that NAC and to some extent vitamin E might be potential future supportive treatments for LAMA2-CMD as they improve numerous pathological hallmarks of LAMA2-CMD.

Highlights

Congenital muscular dystrophy type 1A (LAMA2-CMD) is a severe, recessive autosomal form of muscular dystrophy
DHE is oxidized by Reactive oxygen species (ROS), forming ethidium that fluoresces when intercalated with DNA while 4HNE is a marker for lipid peroxidation and detects ROS-caused alteration of macromolecules
We observed that the brightest positive areas in dy2J /dy2J quadriceps and triceps muscles occurred in densely packed areas, most likely corresponding to infiltrating inflammatory cells as these cells produce significant amounts of ROS [26]

Summary

Introduction

Congenital muscular dystrophy type 1A (LAMA2-CMD) is a severe, recessive autosomal form of muscular dystrophy. The disease is characterized by muscle hypotonia, progressive muscle degeneration and muscle weakness. Other clinical hallmarks of LAMA2-CMD include proximal joint contractures, scoliosis and respiratory insufficiency. Patients experience a decreased quality of life and most often the disease leads to premature death. LAMA2-CMD is caused by mutations in the LAMA2 gene, encoding the laminin α2 chain of the protein laminin-211 [1]. Laminin-211 is one of the major components expressed in the skeletal muscle basement membrane [2]

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