New Mouse Model Opens Window into Duchenne Muscular Dystrophy Pathogenesis Interview with:

Dr Addolorata Pisconti Ph.D. Department of Biochemistry Institute of Integrative Biology University of Liverpool Liverpool United Kingdom

Dr. Addolorata Pisconti

Dr Addolorata Pisconti Ph.D.
Department of Biochemistry
Institute of Integrative Biology
University of Liverpool
Liverpool United Kingdom What is the background for this study?

Dr. Pisconti: Duchenne muscular dystrophy (DMD) is a genetic disorder caused by lack of the cytoskeletal protein dystrophin which, under normal conditions, protects the muscle fibres during the stress of contraction. In the absence of dystrophin, muscle fibres are more fragile and are easily damaged leading to progressive loss of muscle mass and strength, loss of ambulation, difficulties breathing, cardiomyopathy and eventually premature death. There is no cure for DMD.

In Duchenne muscular dystrophy the resident muscle stem cells are impaired and therefore regeneration of damaged muscle fibres is also impaired. Some of the mechanisms leading to impaired muscle stem cell function have been hypothesised, however this remains to date an elusive topic. Chronic inflammation and fibrosis are a hallmark of dystrophic muscle but how they affect muscle stem cells and their regenerative potential remains largely unknown. What are the main findings?

Dr. Pisconti: We hypothesised that changes in the muscle extracellular environment brought about by muscle fibre damage, inflammation and fibrosis directly impair muscle stem cell regenerative potential. To test our hypothesis we have used a mouse model of Duchenne muscular dystrophy and we developed a proteomics method to determine how the muscle extracellular environment changes in response to dystrophin loss. In this way we have identified the regulation of serine protease activity as a key function altered in dystrophic muscle. We have then focused on neutrophil elastase and discovered that this serine protease accumulates in dystrophic muscle as the disease progresses and regenerative capacity is lost. We then went on to demonstrate that elastase activity dramatically affects muscle stem cell proliferation, survival and differentiation. What should readers take away from your report?

Dr. Pisconti: The bottom line of our study is that neutrophil-mediated inflammation plays a key role in the pathogenesis of muscular dystrophy. We also show that the dystrophy-associated changes in the extracellular environment, such as an increase in elastase activity, can dramatically affect muscle stem cell regenerative potential and identify neutrophil elastase as a potential novel target for the treatment ofDuchenne muscular dystrophy. What recommendations do you have for future research as a result of this study?

Dr. Pisconti: The next step would be to test whether neutrophil elastase activity can be inhibited and whether such inhibition would ameliorate muscle pathology in dystrophic mice. Moreover, it will be interesting to further investigate the molecular mechanisms that mediate the effect of elastase on muscle stem cells. Thank you for your contribution to the community.


N. Arecco, C. J. Clarke, F. K. Jones, D. M. Simpson, D. Mason, R. J. Beynon, A. Pisconti. Elastase levels and activity are increased in dystrophic muscle and impair myoblast cell survival, proliferation and differentiation. Scientific Reports, 2016; 6: 24708 DOI:10.1038/srep24708

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