Having had a short break over the summer, we’re delighted to let you know that our internal ‘Research in Progress’ seminar series has returned for members of the WCMR team and colleagues! Since hosting our first virtual meeting in March 2020, these meetings continue to be a great way to keep in touch and hear about exciting research updates.
Last week we heard from two members of the John Walton Muscular Dystrophy Research Centre, Professor Jordi Diaz Manera and Esther Fernández-Simón. Please see their research summaries below:
Role of PDGF-AA in the fibrotic development process in Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a disease characterized by fibrosis, which involves deposition of extracellular matrix (ECM) proteins that impair tissue function. Activated fibroblast are responsible for the production of ECM due to activation of fibrogenic cytokines such as transforming growth factor β1 (TGF-β1) and platelet-derived growth factor (PDGF). Although the effect of TGF-β1 on fibroblast has been widely studied, the effect of PDGF-AA is not well known yet, but it appears as if PDGF-AA promotes the fibrotic response in DMD patients. We studied the proteomic profile in human fibroblasts obtained from DMD patients and treated with PDGF-AA. We observed that RhoA pathway was increased after treatment with PDGF-AA which resulted in increased activation of fibroblasts in vitro. We found that inhibiting that pathway in vitro reduced the activation of fibroblasts by decreasing its proliferation, migration and collagen release.
New genetic-phenotypic correlation in sarcoglycanopathies
Sarcoglycanopathies are a group of limb girdle muscular dystrophies produced by mutations in one of the four sarcoglycan genes: alfa, beta, delta or gamma-sarcoglycans. Although it is well known that onset of symptoms is in the first decade of life and progression is quick and severe in most of the cases , there are also adult cases with milder forms described. It is not really known what are the factors explaining these differences in clinical progression. We collected genetic, clinical and muscle pathology data of 430 patients affected of a sarcoglycanopathy. We identified that age of onset before 10 years old and remaining protein lower than 30% were independent risk factors associated to a earlier onset and quicker progression. In contrast patients started symptoms after 18 years old and with a remaining protein expresion higher than 30% had a late onset and milder progression. These results demonstrate that there are two main phenotypes associated to mutations in these genes with different progression, which is extremely relevant for patient expectations and the design of clinical trials.