Back A breakthrough towards the cure for Duchenne's Muscular Dystrophy reveals new targets in the fight against this rare and serious disease
A breakthrough towards the cure for Duchenne's Muscular Dystrophy reveals new targets in the fight against this rare and serious disease
A paper published this January in the Journal of Cell Biology describes the mechanism by which an increase in the microRNA production leads to the gradual deterioration of the muscle in people affected by Duchenne's Muscular Distrophy (DMD), a neuromuscular genetic disease in the myopathies and strange diseases group, which affects one in 3,300 young people and which has its origins in a dystrophin deficiency that leads to death.
The work was directed by the Cell Biology Unit led by Pura Muñoz Canoves, ICREA researcher in the Experimental and Health Sciences department (CEXS) of the UPF. All the researchers belong to the CIBERNED (Neurodegenerative Diseases Networked Biomedical Research Centre) network of excellence.
The course of Duchenne's Muscular Dystrophy involves deterioration of the muscle cells and fibrosis, a process that eventually leads the cell to accumulate collagen-rich fibres that ends the viability of the muscle and subsequently the patient's life.
This fibrosis is induced by the cytokyne TFGB, which uses a little known mechanism to produce the collagen fibres. The paper published studies the role played by a microRNA, miR-21, the production of which is stimulated by a signalling pathway in which TGFB is involved.
Production of miR-21 has been proved to have increased in those affected by the illness in both human and animal models. At a basic experimental level, it has been shown that inhibiting its production and therefore a reducing the collagen levelsprevents and even reverses fibrogenesis in the animals studied, and the opposite effect can be achieved when the murine model overexpresses production of miR-21.
Identified: two extracellular factors
Furthermore, in the same study, the team of researchers highlighted the fact that two extracellular factors are involved in the production of miR-21, modulated by TGFB: a protease called uPA that activates TGFB, and an inhibitor, PAI-1.
In short, the autors conclude that in view of the fact that direct inhibition of the TGFB factor prevents muscle fibrosis but presents adverse effects, uPA and miR-21 may be effective targets for preventing the disease or slowing its course. According to researcher Pura Muñoz Canoves, "we need to continue investigating the function of miR-21 in other cell types involved in the muscle function, such as inflammatory cells, in order to consider these substances as a potential target in future therapeutic strategies."
The research lines of the CEXS-UPF Cell Biology Unit aim to understand the molecular mechanisms underlying muscle regeneration and growth in adults. Muscle fibre regeneration and a loss of muscle mass occurs in various contexts, including cancer, cachexia, neuromuscular disorders (such as Duchenne's Muscular Distrophy, DMD) and during ageing, it is a key factor contributing to morbidity. Understanding the molecular pathways which regulate muscle repair and loss/gain of muscle mass is crucial for the treatment of muscle atrophy related to disorders. Nevertheless, very little is known about the molecular mediators in these processes, and the group has developed experimental methods to face this challenge.
Esther Ardite, Eusebio Perdiguero, Berta Vidal, Susana Gutarra, Antonio L. Serrano, i Pura Muñoz-Cánoves (2012), " PAI-1-regulated miR-21 defines a novel age-associated fibrogenic pathway in muscular dystrophy", Journal of Cell Biology, www.jcb.org/cgi/doi/10.1083/jcb.201105013.