The involvement of skeletal muscle stem cells in the pathology of muscular dystrophies
Date: 25 – 27 January 2019
In french by F. Relaix
Organizers: Professors Gillian Butler-Browne, Jennifer Morgan, Francesco Muntoni and Ketan Patel
Background and aims of the workshop
Muscular dystrophies are a group of inherited disorders, in which muscle bulk and strength declines. They are caused by defects in genes that either affect proteins at the membrane of the muscle fibre that hold the fibre together, or factors that are expressed inside the muscle fibre, or in the connective tissue surrounding the muscle fibres. As a result of the genetic defect, the muscle fibres break down. This activates muscle stem cells (satellite cells) that reside in a niche between the muscle fibre and the connective tissue surrounding the muscle fibre. Satellite cells proliferate and their progeny regenerate new muscle fibres. But this muscle regenerative process becomes less efficient with time and, in dystrophic muscle, fibres may be replaced by fat and scar tissue. Satellite cells in muscular dystrophies were thought to be normal, but their ability to regenerate muscle is eventually impeded by the fat and scar tissue. However there is evidence that in some muscular dystrophies, the genetic defect may directly affect the satellite cells. Our aims were to understand:
- The involvement of satellite cells in muscular dystrophies
- The fate and biology of satellite cells during ageing and in diseased muscle
- The role of satellite cells in the development of muscle pathology in different muscular dystrophies
- The evidence that defective satellite cells or muscle precursors are a primary cause of some muscular dystrophies
- The efficacy of therapeutic strategies to correct satellite cell dysfunction in muscular dystrophies
Helge Amthor (Paris, France), Carmen Birchmeier-Kohler (Berlin, Germany), Paolo Bonaldo (Padova, Italy), Carsten Bönnemann (Bethesda, USA), Gillian Butler Browne (Paris, France), Dhananjay Chaturvedi (Bangalore, India), Richard Davenport (Portsmouth, UK), Ana Ferreiro (Paris, France), Denis Furling (Paris, France), Lorenzo Giordani (Paris, France), Miranda Grounds (Perth, Australia), Heinz Jungbluth (London, UK), Pura Manoz Canoves (Barcelona and Madrid, Spain), Prasant Mishra (Dallas, USA), Jennifer Morgan (London, UK), Francesco Muntoni (London, UK), George Padberg (Nijmegen, The Netherlands), Carmen Paradas (Seville, Spain), Terry Partridge (Washington, USA), Ketan Patel (Reading, UK), Frederic Relaix (Paris, France), Markus Rüegg (Basel, Switzerland), Alison Stevenson (London, UK), Maaike Van Putten (Leiden, The Netherlands), Alasdair Wood (Monash, Australia), Peter Zammit (London, UK).
What was discussed
The development of effective therapies for the muscular dystrophies will rely on targeting the correct tissues. It was generally believed that since muscle fibres are often damaged in some diseases they must be the sole affected cells. However, recent research has made a case that the primary lesion for example in DMD may lie in the satellite cells. To understand involvement of satellite cells in different muscular dystrophies, presentations were given by experts in particular pathologies and these were discussed in detail. We considered different models to investigate the function of satellite cells in muscular dystrophies, including mouse, drosophila and zebrafish and how they can contribute to our understanding of muscular dystrophies. We also heard how the effect of the environment, including changes in components of the connective tissue surrounding muscle fibres and the metabolism of satellite cells, can affect muscle regeneration. How satellite cell function is regulated and how this may go wrong in muscular dystrophies was discussed. We considered possible reasons for why, in some muscular dystrophies, some muscles are affected and others are not. We considered whether it might be possible and useful to directly target satellite cells rather than muscle fibres to treat muscular dystrophies. We also heard the views of one patient organization and of a young man living with muscular dystrophy. The latter two evidenced the importance of support systems as well as medical care to patients in dealing with their illness but also the role needed to be played by clinicians and scientists in communicating research advances to all stakeholders to allay fears and manage expectations.
What were the outcomes and how will they benefit patients
Definitions to end possible confusion in terms of what the community understands by stem cells (a cell that can self-renew to give more stem cells and also generate a more specialised cell type), progenitors (the descendants of stem cells that cannot return to form stem cells) and differentiated muscle cells (long cells that form from muscle progenitor cells and are specialised for muscle contraction. They cannot go back to become either progenitor or stem cells).
Identification of forms of muscular dystrophies which, as a consequences of discussions held in the workshop, may have their origin in satellite cells.
We arrived at some conclusions as to why muscles in different types of muscular dystrophy have different pathological features.
Standard operating procedures for analysing zebrafish models of muscular dystrophies should be set up.
Plan to develop the fruitfly as a model system in which to investigate the contribution of the satellite cells and the muscle fibre in the pathological process of muscular dystrophies.
These will not benefit patients in the short term, though our improved understanding of the role of satellite cells and their changed environment in muscular dystrophies may lead to new ways to treat muscular dystrophies, by either targeting the satellite cells themselves, or altering their environment.
The following key deliverables were achieved:
- We developed a consensus for the role of satellite cells in the pathology in some forms of muscular dystrophies
- Key properties of satellite cells that could contribute to muscle pathology in different muscular dystrophies were highlighted
- Collaborative projects to address unanswered questions on satellite cells in different muscular dystrophies were discussed and will be set up to conduct research on forms of muscular dystrophies
What are the future activity plans?
- We will examine materials that we already have (muscle biopsies of patients with different muscular dystrophies) with new tools and antibodies, to gain insight into satellite cell involvement in the different conditions
- We will provide a new consensus for assessing the involvement of satellite cells in a particular muscular dystrophy and for determining if the primary defect in a particular muscular dystrophy is in the satellite cell
- We will use zebrafish and drosophila models to investigate the role of satellite cells
in different muscular dystrophies
Timelines for future plans and who is taking the lead
Three major research platforms will be developed:
1) Developing a community to investigate the role of satellite cells in the development of pathology of a spectrum of muscular dystrophies. Leads: Gillian Bulter-Brown, Ana Ferreiro, Francesco Muntoni, Jenny Morgan. Timelines: 2 years
2) Develop a research programme to evaluate systematically the role of satellite cells and muscle fibres for a spectrum of disease in zebrafish. Leads: Alasdair Wood. Timelines: 2 years
3) Develop a research programme to evaluate systematically the role of satellite cells and muscle fibres for a spectrum of disease in fruitflies. Leads: Dhananjay Chaturvedi. Timelines: 2 years
The group of participants of the 240th ENMC workshop on “The involvement of skeletal muscle stem cells in the pathology of muscular dystrophies” taking place in Hoofddorp from 25-27 January 2019
We acknowledge MDUK for their co-sponsorship of this workshop.
A full report will be published in Neuromuscular Disorders (pdf)