Therapeutic effects of exon skipping and losartan on skeletal muscle of mdx mice

Abstract

Various attempts have been made to find treatments for Duchenne muscular dystrophy (DMD) patients. Exon skipping is one of the promising technologies for DMD treatment by restoring dystropin protein, which is one of the muscle components. It is well known that losartan, an angiotensin II type1 receptor blocker, promotes muscle regeneration and differentiation by lowering the level of transforming growth factor-beta1 signaling. In this study, we illustrated the combined effects of exon skipping and losartan on skeletal muscle of mdx mice. We supplied mdx mice with losartan for 2 weeks before exon skipping treatment. The losartan with the exon skipping group showed less expression of myf5 than the losartan treated group. Also the losartan with exon skipping group recovered normal muscle architecture, in contrast to the losartan group which still showed many central nuclei. However, the exon skipping efficiency and the restoration of dystrophin protein were lower in the losartan with exon skipping group compared to the exon skipping group. We reveal that losartan promotes muscle regeneration and shortens the time taken to restore normal muscle structure when combined with exon skipping. However, combined treatment of exon skipping and losartan decreases the restoration of dystrophin protein meaning decrease of exon skipping efficiency.

Combined Therapies for Duchenne Muscular Dystrophy to Optimize Treatment Efficacy

“…Losartan treatment has been shown to increase the efficiency of myoblast cell therapy (Fakhfakh et al, 2012 ) and Adipose-Derived Stem Cell therapy (Lee et al, 2015 ). However, a study by Lee et al ( 2014 ) showed that although combined therapy with Losartan and exon skipping was beneficial in terms of muscle regeneration, the efficiency of exon skipping was lower in Losartan treated mice due to decreased in vivo morpholino penetration. In this study, Losartan was added prior to morpholino treatment, it would be interesting to see what happens when losartan treatment is started after the exon skipping treatment.…”

BMP4 inhibits myogenic differentiation of bone marrow–derived mesenchymal stromal cells in mdx mice

“…Duchenne muscular dystrophy (DMD) is an Xlinked inherited muscular disorder characterized by the absence of dystrophin [1]. Without dystrophin, the muscles undergo repetitive degeneration and regeneration cycles leading to muscle fibrosis and weakness [2]. Various attempts have been made to overcome DMD, including steroid treatment [3,4], gene therapy [5,6] and stem cell therapy [7].…”