Spotlight on our recent research

We want to make sure that results from our research are communicated clearly to those with an interest in our work. To help this happen we are creating lay summaries of our main research studies, which you can find on this page. We would love to hear what you think of them so please leave comments to help us improve the future summaries.

 

New type of muscle stem cell identified

The Myology group of the University Pierre et Marie Curie in Paris has recently identified a new population of muscle stem cells. This study shows that these muscle stem cells called ‘progenitor interstitial cells’ (PICs) can be isolated from the muscles of very young mice. Once they are isolated and cultured in the laboratory, PICs are able to form new muscle. Indeed, once they are...

Using nitric oxide to sustain muscle regeneration

Adult muscle is maintained by a type of stem cell found in the muscle called a satellite cell. These satellite cells multiply and activate during normal muscle growth, and also when muscle is injured. This allows muscle to regenerate. Normally, satellite cells are able to renew themselves, but in muscular dystrophy repeated muscle damage occurs and the satellite cell supplies can run out....

Muscular dystrophy clinical trial results

Clinical trial shows combination therapy of nitric oxide delivery and an anti-inflammatory drug are safe for long-term treatment of adults with muscular dystrophy. 

Muscular dystrophies cause muscle breakdown, weakness, and can lead to paralysis and death. The only current treatment that is effective is corticosteroids, shown to increase muscle strength. However, we do not know if...

Stem cells found in blood vessels can help make muscle

Research has shown for the first time that a non-muscle type of cell can switch to help make muscle during normal growth. These cells, called pericytes, which are normally found on small blood vessels, were shown to also make both muscle fibres and muscle stem cells. Whilst it has been shown that in extreme situations pericytes can contribute to muscle repair, it was not known whether this was...

Satellite cells are vital for muscle repair and replacement

A recent scientific study has shown that a type of muscle stem cell called ‘satellite cells’ are essential for muscle fibre repair and replacement. Scientists had already identified several different types of muscle cell that can contribute to the formation of new muscle tissue. They are now investigating what exactly each of these cell types do and how they work. In this study, Ramkumar...

Basic research discovers new factor important for muscle formation

 A scientific publication from Margaret Buckingham’s research group at Institute Pasteur in Paris identified a new factor that is important for the development of skeletal muscle.

During the development of the embryo, muscles are formed from stem cells found in a structure known as the dermomyotome. These cells are specifically defined by the fact they produce a protein called Pax3...

Nitric oxide and ibuprofen treatment of mice with muscular dystrophy

A drug that releases both nitric oxide and ibuprofen improves muscle health and function in mice with muscular dystrophy

Muscle dystrophies are heritable diseases that lead to muscle breakdown, weakness, inflammation, and in severe cases, can result in paralysis and even death. Nitric oxide, normally produced in the body, can activate satellite cells that are able to replace dying...

Relief of Duchenne muscular dystrophy symptoms in mice using artificial chromosomes

Recently it’s been shown that relief of muscular dystrophy symptoms is possible using stem cells. In Duchenne muscular dystrophy the protein dystrophin normally found in muscles is absent. Scientists of the San Raffaele Scientific Institute in Milan showed that giving muscles in mice the correct 'recipe' for dystrophin (it's gene) meant that the right protein could be produced. To do this the...

An overview of stem cells which could be used to regenerate skeletal muscle.

There has been much effort by researchers to understand how skeletal muscle repairs itself and which cells are involved in this process. This article summarises a review by researchers in the group of Professor Giulio Cossu from the Stem Cell Research Institute, University of Milan from January 2010. The review discussed the different types of stem cells which could be used to repair muscles;...

Mesoangioblasts can be derived from reprogrammed cells and may be an effective future treatment for muscular dystrophies.

A recent study has shown that muscle stem cells called mesoangioblasts can be grown in the laboratory from induced pluripotent stem cells (IPS cells). Scientists think that mesoangioblasts transplants may be an effective treatment for muscular dystrophy but currently these cells have to be taken from donor who is a tissue ‘match’ for the patient, which is relatively rare. As IPS cells are...

Muscular dystrophy clinical trial results

Summary of research

Clinical trial shows combination therapy of nitric oxide delivery and an anti-inflammatory drug are safe for long-term treatment of adults with muscular dystrophy. 

Muscular dystrophies cause muscle breakdown, weakness, and can lead to paralysis and death. The only current treatment that is effective is corticosteroids, shown to increase muscle strength. However, we do not know if it is effective in the long term, and there are side effects that limit its use. A combination of an anti-inflammatory drug, ibuprofen, and a nitric oxide delivery drug, isosorbide dinitrate, have been shown in mice to improve muscle health. This study is a small-scale clinical trial to evaluate the safety of the therapy on people with muscular dystrophy. The study shows that the therapy is safe, and a larger scale clinical trial can now be conducted to determine if it is beneficial for treatment of muscular dystrophy.

What is the idea behind this study?

Muscular dystrophies are complex diseases that result from heritable defects in muscle proteins. This causes muscle fibre breakdown and weakness. In more severe cases, paralysis and death can result due to heart and breathing difficulties.

There are currently no therapies for muscular dystrophy that increase muscle strength, except for corticosteroids (prednisone/prednisolone, and deflazacort). Corticosteroids reduce muscle breakdown and increase repair of muscle tissue. Their anti-inflammatory effects reduce scar tissue formation. However, the benefits of corticosteroid therapy have only been well demonstrated in the short term. There are also side effects that limit their use, such as weight gain, changes in behaviour, and excessive hair growth.

Ibuprofen is an anti-inflammatory drug, and isosorbide dinitrate is a drug that delivers nitric oxide to muscle. Recent studies show these two drugs together are more beneficial for preserving muscle health in mice with muscular dystrophy than each drug alone, or without treatment. This combination therapy reduces muscle fibre breakdown, and increases the ability of the muscle to repair itself. Further, this therapy allows for muscle stem cell therapies to be more effective, by allowing muscle stem cells to find their way to the affected areas, and make new healthy muscle.

A first step to introducing this drug for treatment of muscular dystrophy in patients is to test its safety. This first clinical trial evaluates if there are severe side effects, and whether it is worthwhile to pursue this as a potential mode of therapy.

 

 

What did this study show?

A clinical trial was conducted on 71 patients; 35 were given the combination therapy, and 36 were untreated. All patients were at least 16 years old, and diagnosed with a form of muscular dystrophy.

All the patients were assessed by:

  • Physical examination
  • Neurological examination
  • Muscle function
  • Heart testing (e.g. echocardiography)
  • Blood tests to monitor inflammation and muscle health

Patients were treated for 12 months, and were assessed again at 1, 3, 6, and 12 months. The information gathered was used to compare the health of the treated patients to those that were not, to see if there were safety concerns associated with the therapy.

There were no heart or lung problems and no safety concerns with blood pressure, or other specific tests of the blood. However, there was headache experienced in the first 7 to 10 days of treatment, temporary stomach pain, swelling of the lower legs, light-headedness, skin rash, and chest pain. One patient withdrew from the study due to a racing heart (increased heart rate), and two withdrew due to heart palpitations.

This clinical trial suggests that this combination therapy is suitable for a larger scale clinical trial to determine its benefit for people with muscular dystrophy.

 

What does this mean for patients?

Previous studies in the lab and in mice have shown that the combination of nitric oxide (delivered by isosorbide dinitrate) and an anti-inflammatory drug (ibuprofen) preserve muscle health in people with muscular dystrophy. Further, these benefits extend to preserving the function of the muscle to repair itself, and allow for muscle stem cell therapies to be more effective.

However, before this combination therapy can be made available to all people with muscular dystrophy, it must first pass clinical trials. This study is a small-scale clinical trial used to assess the safety of the therapy. This must be done before a larger scale clinical trial is conducted to show the therapy is beneficial for people with muscular dystrophy. Since it has now been shown the therapy is safe, the next step is to expand the trial to include a larger number of patients. The next trial will need to be more detailed to evaluate if it will be of benefit to patients. This process is underway, and may take several years before we know the answer.

 

Further information and links

The full research article from this study, in the research journal Pharmacological Research in 2012: Link to access the full article (cost): http://www.sciencedirect.com/science/article/pii/S1043661812000072

Previous studies demonstrating the effect of combined nitric oxide and ibuprofen therapy for muscular dystrophy:

Brunelli S et al. Nitric oxide release combined with nonsteroidal anti-inflammatory activity prevents muscular dystrophy pathology and enhances stem cell therapy.

Published in the Proceedings of the National Academy of Sciences USA, in 2007.

Link to access the full article (free): http://www.pnas.org/content/104/1/264.full.pdf

Sciorati C et al. Co-administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans. Published in the British Journal of Pharmacology, in 2010.

Link to access the full article (free): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938824/

Sciorati C et al. A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy. Published in 2011.

Link to access the full article (free):   http://www.ncbi.nlm.nih.gov/pubmed/21609764

Muscular Dystrophy Campaign website: http://www.muscular-dystrophy.org/

Funding from the European Community’s Seventh Framework Programme project OPTISTEM supported this scientific work and summary. You can find out more about the scientists in this programme and the work they do at:

www.optistem.org

This summary was written by Long Nyugen

An overview of stem cells which could be used to regenerate skeletal muscle.

Summary of research

There has been much effort by researchers to understand how skeletal muscle repairs itself and which cells are involved in this process. This article summarises a review by researchers in the group of Professor Giulio Cossu from the Stem Cell Research Institute, University of Milan from January 2010. The review discussed the different types of stem cells which could be used to repair muscles; as well as how therapies using these cells might work.

 

Satellite cells and skeletal muscle regeneration

There are lots of stem cells in the body, their job is to repair or renew tissues when they are damaged or worn out. These are broadly termed ‘adult or tissue stem cells’ and most tissues have their own reservoir of stem cells that are used to repair or renew that tissue. Satellite cells are thought to be the main muscle-producing stem cell in the adult body.  Scientists have worked out techniques to find the satellite cells in muscles and grow them in the laboratory.

In the 1980s, scientists showed that injecting satellite cells into a mouse with a Duchenne muscular dystrophy-like disease could start dystrophin (the protein missing in Duchenne muscular dystrophy) production.

In 1990, satellite cells were injected into the muscle fibres of a 9 year old boy with Duchenne muscular dystrophy. The results showed that the procedure was safe and that dystrophin was produced. When the procedure was repeated in 11 patients, researchers could see a positive effect in the single muscle fibres they injected, but not in the muscles as a whole.

This meant no overall improvement of mobility was observed, and that a prohibitively large number of injections would be needed to treat a whole muscle. Follow-up studies have also failed to translate the laboratory protocols using satellite cells into a feasible clinical therapy. The main problems were:

  • immune rejection of the transplanted cells
  • death of the transplanted cells
  • getting the cells to the place they are needed

One way of reducing immune rejection is to use a patient’s own cells, however this is not possible for people with Duchenne muscular dystrophy as all their cells contain the mutation in the dystrophin gene.

For other conditions this is an option, for example using a patient’s own satellite cells to treat the muscle damage associated with heart failure. In these trial treatments, patients’ satellite cells are grown in the laboratory and transplanted back into the patient. Studies have shown they can improve heart function without being rejected. However, the cells did not develop into the expected cardiomyocytes – the cells forming the beating muscle tissue in the heart – showing that controlling development of transplanted cells is not straightforward.

Further studies will aim to address the issues of rejection and controlling the cells. However the problem of the number of injections needed to get the cells to the right place will continue to be an issue for satellite cell therapy. 

Other adult stem cells and skeletal muscle regeneration

Other stem cell types have also been investigated as possible treatments for Duchenne muscular dystrophy. Of particular interest are a type of stem cell usually found in blood vessel walls – called mesoangioblasts. These cells are able to move through the blood to the muscles and can produce muscle fibres, a significant advantage over satellite cells. The cells grow well in the laboratory, outside the body, and this may be of use in proposed treatments for Duchenne muscular dystrophy which aim to repair mutations in the dystrophin gene. The cells would then be able to produce dystrophin to repair the damaged muscles – something achieved in animal models using this system.

Some blood stem cells have also shown promising results – in particular, blood stem cells which produce a protein called CD133 (called CD133+ cells). These cells can help to repair muscle tissue and restore muscle function in mice.  They may also have therapeutic potential in Duchenne muscular dystrophy. One study showed that that it was possible to correct the mutation in the dystrophin gene – these genetically corrected CD133+ cells could promote the recovery of muscles and improved muscle function in a mouse model.

Early clinical trials have suggested it is safe to transplant CD133+ cells into children with Duchenne muscular dystrophy. Studies are also planned to test the safety of mesoangioblasts as a potential stem cell therapy for Duchenne muscular dystrophy. Immune reject remains an issue if donor cells used. However there are also significant safety issues connected with using a patient’s own genetically corrected cells. Particularly with the technique used to genetically change the cells. Work in these systems is still at a very early stage but shows some promise without some of the problems associated with using satellite cells.

Pluripotent stem cells and skeletal muscle regeneration

Pluripotent stem cells are cells which can give rise to every cell in the body. These cells are important during development where they are responsible for construction of all tissues and organs of a human body. The ability to form different tissues means these cells have good therapeutic potential – they could be used to treat a wide range of tissue damage.  There are two main types of pluripotent stem cell: embryonic stem cells and induced pluripotent stem cells.

Embryonic stem cells, as their name suggests are isolated from embryos. Several studies in the mid-1990s showed that these cells formed three dimensional structures when grown outside the body. These structures contained muscle fibres that were similar to skeletal muscle and cells similar to satellite cells.

Induced pluripotent stem cells are generated in the laboratory. Mature cells are taken from the body and grown in a cocktail of chemicals to produce cells which behave like pluripotent cells. These cells have great potential but there is little evidence yet that induced pluripotent stem cells can be directed to form satellite cells and generate muscle tissue. However it is likely that protocols will appear in the near future as induced pluripotent cells are a current focus of stem research.

There are issues with using pluripotent stem cells that are common to therapies using tissue or adult stem cells – such as immune rejection, cell survival and controlling how cells behave. As mentioned previously immune rejection could be combatted by using a patient’s own cells, in the case of Duchenne muscular dystrophy that would involve genetically correcting the cells. However pluripotent stem cells also bring a risk of uncontrolled cell growth and tumour formation.  Scientists need to be able to filter out the stem cells which still have an uncontrolled ability to grow and divide (tumour causing cells) from those which have already committed to becoming a certain subset of cells (such as satellite cells). One of the key developments required for this research to be taken forward as a clinical therapy will be the development of techniques to remove tumour-causing cells.

The authors conclude by suggesting that the evidence from current research is that mesoangioblasts and genetically corrected induced pluripotent stem cells will be the best candidates for cell therapy of muscular dystrophy.

Further information and links

The scientific summary of the original paper can be found on this link:

http://www. ncbi. nlm. nih. gov/pubmed/20051632 

The full original paper was published in the Journal of Clinical Investigation in January 2010. It can be found on this link (subscription may be required):

http://www. ncbi. nlm. nih. gov/pmc/articles/PMC2798695/

Muscular Dystrophy Campaign website: http://www.muscular-dystrophy.org/

Funding from the European Community’s Seventh Framework Programme project OPTISTEM supported this scientific work and summary. You can find out more about the scientists in this programme and the work they do at:

www.optistem.org

Basic research discovers new factor important for muscle formation

Summary of research

 A scientific publication from Margaret Buckingham’s research group at Institute Pasteur in Paris identified a new factor that is important for the development of skeletal muscle.

During the development of the embryo, muscles are formed from stem cells found in a structure known as the dermomyotome. These cells are specifically defined by the fact they produce a protein called Pax3.  Pax 3 has been shown to guide skeletal muscle formation.

In this work the authors identified a protein, called Dmrt2, and showed its gene was controlled by Pax3.  This linked it to skeletal muscle formation. They demonstrated that Dmrt2 has a role in initiating the formation of the first muscles in the embryo. This study has identified a missing piece in the already known network of factors involved in skeletal muscle development. However, more work is needed to understand if this network is active in the adult and if it is also essential in the regeneration of diseased muscles.

What is the idea behind this study?

As an embryo develops and grows it forms structures called somites.  These are found on both sides of the embryo along the spinal cord.  It is the cells in the somites which will go on to form the skeletal muscle tissue in the body and limbs. A special part of the somites (called the dermomyotome) contains the stem cells that form muscle. These cells are defined by the production of a key protein called Pax3. Pax3 is essential for ensuring that the right cells are in the right place at right time, so the embryo forms its skeletal muscle correctly. One of the ways Pax3 has been found to do this is by activating the genes for other proteins (i.e. Myf5). As such Myf5 is called a ‘target’ of Pax3. Myf5 tells the cells to enter the muscle cell programme which leads to skeletal muscle formation and therefore determines their fate.    

What did this study show?

The identification of Pax3 targets is essential to reveal how Pax3 controls the behavior of immature muscle cells and their maturation during development. For this reason, the researchers of the Buckingham group started to look for genes controlled by Pax3 at the beginning of muscle formation. They isolated the cells expressing Pax3 from the somites of mouse embryos and through genetic and molecular approaches discovered that Pax3 directly activates the gene that leads to the production of a protein called Dmrt2. Then, by a series of genetic experiments using transgenic mouse embryos, they demonstrated that Dmrt2 is also essential for the formation of skeletal muscle. In fact, the authors showed that Dmrt2 is a connecting link between Pax3 and Myf5.  So, the scientists have identified a new control pathway in which Pax3 triggers Dmrt2, which in turn triggers Myf5 to directing the stem cells into muscle cells.

What does this mean for patients?

Many muscle disorders (i.e. muscular dystrophies) are characterized by the loss of muscle tissue so the body becomes unable to replace it faster than it is wasting away. The capacity of the muscle to replace itself is called regeneration and this is a normal part of adult life (e.g. in response to exercise). Muscle regeneration is carried out by a pool of stem cells present in the adult tissue, which upon stimuli undergo a series of events that make them change into new mature muscle cells. The events occurring during this process are similar to what happens when muscle tissue is formed during the development of the embryo. For this reason, studying how muscle develops in the embryo (like this piece of research) is helpful to understand how to fix it. Put another  way, it is much easier to understand why a car does not move anymore if you know how it has been built and how the broken piece is linked to the rest.

In this study, the scientists identified a missing link in the series of complex molecular events that controls how muscles form and work. They showed that Dmrt2 intervenes in the pathway that leads to muscle during its development.

However, the function of the Pax3/Dmrt2/Myf5 pathway has not been investigated yet in adult muscles. More experiments will be needed to understand if these factors also govern the behavior of muscle stem cells in the adult. Other remaining questions are: Is Dmrt2 also important for the regeneration of diseased muscle? And can this pathway be exploited to enhance the regenerative capacity of muscle stem cells in muscular dystrophies?  These questions are all matters for future research.

Further information and links

The scientific summary of the original paper can be found on this link:

http://www.ncbi.nlm.nih.gov/pubmed/20368965

The full original paper was published in the journal PLOS Genetics in 2010. The article can be viewed on this link:

http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000897

More information about the group headed by Dr Margaret Buckingham and its research on Molecular Genetics of Development can be found on:

http://www.pasteur.fr/ip/easysite/pasteur/en/research/scientific-departments/developmental-biology/units-and-groups/molecular-genetics-of-development/home 

Muscular Dystrophy Campaign website: http://www.muscular-dystrophy.org/

Funding from the European Community’s Seventh Framework Programme project OPTISTEM supported this scientific work and summary. You can find out more about the scientists in this programme and the work they do at:

www.optistem.org

This summary was written by Chiara Mozzetta, PhD

 

Mesoangioblasts can be derived from reprogrammed cells and may be an effective future treatment for muscular dystrophies.

Summary of research

A recent study has shown that muscle stem cells called mesoangioblasts can be grown in the laboratory from induced pluripotent stem cells (IPS cells). Scientists think that mesoangioblasts transplants may be an effective treatment for muscular dystrophy but currently these cells have to be taken from donor who is a tissue ‘match’ for the patient, which is relatively rare. As IPS cells are grown in the lab from a patient’s own muscle cells this could potentially overcome the problem of having to find a ‘matched’ donor. In this study researchers grew mesoangioblast-like cells from patient derived IPS cells. They then genetically corrected these cells and transplanted them into mice with Limb-girdle muscular dystrophy type 2D. After the transplant mice produced some healthy muscle cells and gained muscle strength. Researchers hope that in the future this technique might be used in cell based therapies for human muscular dystrophies.

What is the idea behind this study?

Muscular dystrophies are a group of genetic muscle wasting diseases. Scientists hope that if stem cells can be delivered to patients’ muscles they could grow healthy muscle fibres and prevent further muscle wasting. Mesoangioblasts are a type of stem cell found in skeletal muscles. Scientists think they might be a good candidate for stem cell therapy because, unlike other types of muscle stem cell, they survive well and can move across blood vessel walls into muscle tissue after injection into the bloodstream.

Recently mesoangioblasts from healthy donors have been used in a clinical trial to treat Duchenne muscular dystrophy. To prevent the patients’ immune systems from attacking these donor cells they had to be taken from siblings who were a tissue ‘match’. Unfortunately matched donors are not available for every child, limiting the number who can potentially be treated.

To avoid having to use donor cells, scientists had hoped to isolate mesoangioblasts from patients and genetically correct them in the laboratory before giving then back to the same patient. Unfortunately they found patients’ muscles didn’t contain enough mesoangioblasts to be used in any potential treatment. Instead scientists in this study aimed to grow mesoangioblasts in the laboratory from induced pluripotent stem cells before genetically correcting them and looking for possible affects in mice with limb-girdle muscular dystrophy type 2D.

What did this study show?

Scientists took muscle cells from healthy individuals and limb-girdle muscular dystrophy type 2D patients and reprogrammed them to become induced pluripotent stem (IPS) cells. They then developed a process to successfully grow mesoangioblast-like cells from these IPS cells in the laboratory. These mesoangioblasts could form muscle fibres and did not form tumours when transplanted into mice.

In limb-girdle muscular dystrophy type 2D a genetic fault stops muscle cells producing a protein called α-sarcoglycan, so next researchers used a virus to genetically correct these mesoangioblast-like cells so that they produced normal α-sarcoglycan protein. When these cells were injected into dystrophic mice they moved to damaged muscles where they formed some new, healthy muscle fibres which produced α-sarcoglycan. However this process was not very efficient, perhaps because human cells were being used in a mouse.

Finally to measure how effective this type of treatment might be, scientists created mesoangioblast- like cells from healthy mouse IPS cells. When injected into dystrophic mice these were much more effective than human cells, forming many more healthy muscle fibres. After this treatment mice gained muscle strength and could exercise for longer.

What does this mean for patients?

This study has provided scientists with a method to grow mesoangioblast-like cells from induced pluripotent stem cells in the laboratory. IPS cells are ‘immortal’ so an unlimited number of these mesoangioblast-like cells could potentially be grown from a patient’s own skin cells. Genetic correction of these cells appears to be safe and somewhat effective to treat mice with limb-girdle muscular dystrophy type 2D. This is a promising avenue for the treatment of this and other muscular dystrophies in humans in the future.

However much further work is needed before these advances can be turned into new muscular dystrophy therapies. As this work was done in mice, scientists don’t know whether it will be effective in humans and further safety checks would be needed before any clinical trial could take place. Both the production of IPS cells and the process of growing mesoangioblast like cells from them are hugely inefficient. Cell based therapies will require large numbers of cells in order to target all the muscles in the body, so scientists need to improve the efficiency of the process in order produce enough of these cells to treat patients.

Further information and links

The full original paper was published in the journal Science Translational Medicine in 2012.  It can be accessed at http://stm.sciencemag.org/content/4/140/140ra89.full.pdf?sid=c445723f-a551-4846-b667-740d8d252f16

Muscular Dystrophy Campaign website: http://www.muscular-dystrophy.org/

Funding from the European Community’s Seventh Framework Programme project OPTISTEM supported this scientific work and summary. You can find out more about the scientists in this programme and the work they do at: www.optistem.org

This summary was written by Rachel Gill, BSc.

New type of muscle stem cell identified

Summary of research

The Myology group of the University Pierre et Marie Curie in Paris has recently identified a new population of muscle stem cells. This study shows that these muscle stem cells called ‘progenitor interstitial cells’ (PICs) can be isolated from the muscles of very young mice. Once they are isolated and cultured in the laboratory, PICs are able to form new muscle. Indeed, once they are reintroduced into the damaged muscles of mice, they help muscle repair as efficiently as satellite cells, the professional muscle stem cells. This work has identified a new source of stem cells in the muscle. However, whether PICs are present in adult muscles and contribute to their regeneration in muscle disease, are all questions that need further study.

What is the idea behind this study and what did this study show?

Regeneration and repair of damaged muscles relies on the activity of resident stem cells. Stem cells are a reservoir of cells that, when activated, are instructed to form new tissue. In the case of skeletal muscle, this regenerative capacity has been mainly attributed to a type of muscle stem cell, called satellite cells. These cells are found close to the muscle fibre and are considered the master muscle stem cells. Just recently, different cells other than satellite cells had been shown to be helping in muscle regeneration. However, up until now these cells had not been identified and located.

In this study, performed by the group of Dr. Sassoon, the scientists looked at the muscles of mice during the first 2-3 weeks after birth. They found a new type of muscle stem cell located between the muscle fibres, in what is called the interstitium of the muscle, so the authors called them Progenitor Interstitial Cells, or PICs. They showed that PICs are more abundant at birth and their number declines in adults, just as for satellite cells. They isolated them from the muscles of young mice and tested the cell’s behaviour in the laboratory. These experiments showed that these cells behave like satellite cells, forming new muscle fibres. Next, they tested if PICs could do this when in the mice. So, they reintroduced PICs into the muscle of mice that had been damaged and they showed that PICs are able to form new muscle tissue as efficiently as satellite cells.

 

What does this mean for patients?

In muscle diseases such as Duchenne muscular dystrophy the muscles weaken and start to waste away. The muscle is lost because the body cannot adequately regenerate and/or repair itself during the progression of the disease. Therefore, promoting the regeneration potential of muscle stem cells would be one way to prevent muscle loss.

Up to now satellite cells were considered the main type of cells involved in skeletal muscle regeneration. However, in muscle affected by muscle disease and in aged muscles, satellite cells are eventually exhausted and show a limited regenerative potential. The identification of a new muscle stem cell type represents a new possibility for therapeutic approaches. These cells could be exploited to regenerate diseased or aged muscles. Moreover, the fact that PICs can be easily isolated and grown in the laboratory makes them possible candidates for cell-therapy. In fact, it may be possible to increase the numbers of   PICs in the laboratory and then reintroduce them to repopulate damaged muscles.

Nevertheless, before this becomes real and applicable to patients a lot of further work needs to be done. For example, the role of PICs in adult muscle has yet to be investigated. The number of PICs declines after birth and their contribution in adult skeletal muscle regeneration is still unknown. Moreover, PICs have only up to now been identified in mice. Whether these cells are also present in human muscles and whether they could also be isolated from humans is a topic for further study.

 

Further information and links

This scientific work and summary were supported by funding from the European Community’s Seventh Framework Programme project OPTISTEM.

 

Nitric oxide and ibuprofen treatment of mice with muscular dystrophy

Summary of research

A drug that releases both nitric oxide and ibuprofen improves muscle health and function in mice with muscular dystrophy

Muscle dystrophies are heritable diseases that lead to muscle breakdown, weakness, inflammation, and in severe cases, can result in paralysis and even death. Nitric oxide, normally produced in the body, can activate satellite cells that are able to replace dying fibres with new healthy fibres. However, nitric oxide is not as active as it should be in patients with muscular dystrophy. This study tests NCX 320, a new drug that can release both nitric oxide and ibuprofen (an anti-inflammatory drug). Mice with muscular dystrophy are treated with NCX 320, and are observed to have reduced muscle breakdown, reduced inflammation, and preserved activity of satellite cells for maintaining healthy muscle. This holds promise for chronic treatment of people with muscular dystrophy.

What is the idea behind this study?

Muscle dystrophies are heritable diseases that result from defects in muscle proteins. These defects cause progressive muscle damage, and in the most severe cases, can lead to paralysis and death, due to heart and/or breathing difficulties.

Nitric oxide is a compound that is made by the body, and normally functions to activate cells surrounding muscle fibres, called satellite cells. Satellite cells have the ability to make new muscle fibres to repair muscle damage from normal daily activity. However, nitric oxide is found to be misplaced and thus not active in people with muscular dystrophy. As a result, the satellite cells become exhausted, and eventually lose their ability to make new muscle fibres. This leads to breakdown of muscle fibres, and inflammation. The deteriorating muscle becomes replaced with scar tissue. Eventually, symptoms worsen leading to muscle weakness and muscle breakdown.

To counteract these effects, previous studies have shown that a drug capable of releasing nitric oxide within the muscle tissue can reduce muscle breakdown. Administration of an anti-inflammatory drug, such as ibuprofen, reduces inflammation. Together, the two drugs are known to preserve the activity of satellite cells to make new muscle fibres that restore the health of the muscle.

This study is to test a new drug, called NCX 320 that can simultaneously release both nitric oxide, and ibuprofen, in mice with muscular dystrophy. The effect of the drug in reducing muscle breakdown, inflammation, and improving satellite cell activity can be evaluated.

What did this study show?

The effects of NCX 320 were tested in the lab, and then in mice. The lab work showed that NCX 320 inhibits two of the main inflammatory pathways (COX-1 and COX-2). NCX 320 also releases nitric oxide, to cause vasodilation (which is the relaxation of arteries and capillaries to allow more blood flow).

Mice that have been genetically engineered to have muscular dystrophy very similar to humans were treated orally with NCX 320 for 8 months. During treatment, blood levels of nitric oxide and ibuprofen were found to be appropriate.

After 8 weeks, muscle function was tested using a running wheel and a treadmill. This revealed the mice treated with NCX 320 performed significantly better than the untreated mice. Further, NCX 320 resulted in a reduction of signs in the blood for both muscle damage and inflammation to an extent greater than when the mice were treated with ibuprofen alone, or with no treatment. 

Moreover, analysis of the muscle revealed that in mice treated with NCX 320, there are more healthy muscle fibres. Also, the activity of satellite cells in replacing damaged muscle fibres with healthy fibres was preserved in mice treated with NCX 320. 

What does this mean for patients?

Current therapy for muscular dystrophy is based on steroid treatment (corticosteroids such as prednisone/prednisolone or deflazacort) that is mainly only able to delay the progression of the disease. There are currently many approaches scientists and clinicians are considering, but most are either not yet experimentally tested or are not broadly effective on most patients.

NCX 320, a drug that releases both nitric oxide and ibuprofen, holds a lot of promise for treatment of people with muscular dystrophy. This is because it is well known that nitric oxide helps improve muscle function and health. Further, ibuprofen is known to reduce inflammation, and is well tolerated in patients who require long-term treatment.

This study demonstrates that the combination of nitric oxide and ibuprofen through administration of the drug NCX 320 significantly improves muscle health in mice with muscular dystrophy. However, to know how helpful this will be in humans, clinical studies must be performed. However, the reason NCX 320 holds promise is that both the individual compounds nitric oxide and ibuprofen have been shown to be broadly helpful in many different people. Ibuprofen is already widely used as an anti-inflammatory by people for headaches and pain.

A large clinical randomized control trial on NCX 320 for treatment of muscular dystrophy must be performed before it is approved for treatment. This may take several years, but will provide more convincing evidence to support whether the drug will be helpful, and whether it will be safe.

Further information and links

The full original paper was published in the Journal of Pharmacological Research in 2011. Link to access the full article (free): http://www.ncbi.nlm.nih.gov/pubmed/21609764

Previous studies demonstrating the effect of combined nitric oxide and ibuprofen therapy for muscular dystrophy:

Brunelli S et al. Nitric oxide release combined with nonsteroidal anti-inflammatory activity prevents muscular dystrophy pathology and enhances stem cell therapy.

Published in the Proceedings of the National Academy of Sciences USA, in 2007.

Link to access the full article (free): http://www.pnas.org/content/104/1/264.full.pdf

Sciorati C et al. Co-administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans. Published in the British Journal of Pharmacology, in 2010.

Link to access the full article (free): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938824/ 

Muscular Dystrophy Campaign website: http://www.muscular-dystrophy.org/

Funding from the European Community’s Seventh Framework Programme project OPTISTEM supported this scientific work and summary. You can find out more about the scientists in this programme and the work they do at:

www.optistem.org

This summary was written by Long Nyugen

Relief of Duchenne muscular dystrophy symptoms in mice using artificial chromosomes

Summary of research

Recently it’s been shown that relief of muscular dystrophy symptoms is possible using stem cells. In Duchenne muscular dystrophy the protein dystrophin normally found in muscles is absent. Scientists of the San Raffaele Scientific Institute in Milan showed that giving muscles in mice the correct 'recipe' for dystrophin (it's gene) meant that the right protein could be produced. To do this the dystrophin gene was first put into human artificial chromosomes, man-made tools to carry the information and deliver it to muscles. These artificial chromosomes were then put into a specific type of stem cell. These stem cells, known as ‘mesoangioblasts’ were able to successfully integrate into the affected muscles. Interestingly they also became part of the muscles satellite cell pool, which is its factory of new cell production. Increasing the amount of dystrophin in muscles resulted in improvements in muscle function, and some relief of the symptoms. Testing by the scientists showed that these effects continued for 8 months afterwards. 

What is the idea behind this study?

There is currently no effective treatment for muscular dystrophy. The disease is caused by changes in the gene responsible for producing dystrophin meaning dystrophin is absent. This leads to symptoms of muscle weakness and progressive muscle loss. A technique to give patients the correct dystrophin gene and therefore protein is not a new idea. Dystrophin is an essential structural protein in muscle. The dystrophin gene itself is large, and a recurring problem is the difficulty transporting such a large piece of DNA to cells. The idea in this study to use an artificial chromosome is a new one, which exploits the ability of artificial chromosomes to carry more information. Prior to this, artificial chromosomes hadn’t been used in this context; however they’re desirable as they don’t interfere with the persons own DNA.

This research group had already shown that the entire dystrophin gene and other necessary elements could be fitted into the artificial chromosome. Here they then looked to see if the HAC slotted into mesoangioblasts, could be used to improve muscle function in mice. These mice were genetically modified to contain no functional dystrophin. This is the animal model most similar to DMD known as the ‘mdx mouse model’. Mesoangioblasts themselves were a good candidate for use, as previous work had shown their ability to differentiate into various cell types including those implicated in DMD: skeletal muscle cells.

What did this study show?

Mesoangioblasts were first obtained from the mice themselves. The artificial chromosome with the dystrophin gene was then slotted in as well as other key genetic ‘checkpoint’ information; for example a protein which fluoresces upon UV light, meaning scientists could see the cells and where they were. Cells then underwent a selection process whereby only the successfully ‘corrected’ ones were reintroduced to the mice.

Three injections into major muscle groups was carried out after exercise and every 3 weeks. The Fluorescence was used to check that the stem cells were actually producing new cells. A technique for protein detection was used to look at how much dystrophin protein was present in the mdx mice compared to normal unmodified mice (with functional dystrophin). Mdx mice produced 25% the amount of dystrophin which equated to enhanced muscle function. Treated mice could run for 50-80% longer than untreated mdx mice. In addition there were fewer damaged muscle cells. Positive effects were seen when corrected mesoangioblasts were transplanted into another mouse model with a more severe form of dystrophy.

What does this mean for patients?

Scientists also looked to see what happened when mesoangioblasts were injected into arteries rather than muscles. It was found that they were able to cross blood vessel walls and contribute to the relief of muscular dystrophy symptoms. They also contributed to the muscle’s satellite cell pool. Both these additional findings help to reinforce the suitability of mesoangioblasts for use in gene therapy.

It is credible to say that using artificial chromosome mesoangioblasts to administer the correct gene has a basis for therapeutic use in the future.

The technique has been shown to be fairly robust; however, it is only at an early preclinical stage. The effects seen in mice may not be the same in humans. The therapeutic dystrophin protein produced from the gene also needs to be tested, as it may provoke an immune response in patients.

The team is currently carrying out further work to develop mesoangioblasts from patients, which are in early phase human trials. 

Currently a technique known as exon skipping has shown positive effects in patients, but it would not work on a quarter of the genetic mutations associated with DMD. If this artificial chromosome stem cell technique can be refined and if further requirements are met, it may form the basis of a treatment for patients in the years to come.

Further information and links

The full original paper was published in the journal Science Translational Medicine in 2011.  It can be accessed at http://stm.sciencemag.org/content/3/96/96ra78.full?sid=815fc603-2ccf-4e89-863f-5c83a521f214

Muscular Dystrophy Campaign website: http://www.muscular-dystrophy.org/

Funding from the European Community’s Seventh Framework Programme project OPTISTEM supported this scientific work and summary. You can find out more about the scientists in this programme and the work they do at:

www.optistem.org

This summary was written by Amy Johnson.

Satellite cells are vital for muscle repair and replacement

Summary of research

A recent scientific study has shown that a type of muscle stem cell called ‘satellite cells’ are essential for muscle fibre repair and replacement. Scientists had already identified several different types of muscle cell that can contribute to the formation of new muscle tissue. They are now investigating what exactly each of these cell types do and how they work. In this study, Ramkumar Sambasivan and colleagues at the Pasteur Institute in Paris discovered that when satellite cells were destroyed in mice, other types of cells were unable to repair muscle damage. This study tells us more about how different cell types work together to grow new muscle. It is hoped this knowledge can be used in the future to develop treatments for muscle wasting diseases including muscular dystrophy.

 

What is the idea behind this study?

Muscles of people with Duchenne muscular dystrophy can’t produce the muscle protein dystrophin, making them fragile and easily damaged.  Their muscles can’t fully repair this damage leading to a loss of muscle tissue. In skeletal muscle there are various types of cells which are involved repairing muscle after injury, including a type called ‘satellite cells’. Scientists believe satellite cells are a type of muscle stem cell. They can form the many other muscle cell types that make up a working muscle, but can also copy themselves to ensure a reserve supply of satellite cells.

Satellite cells produce myoblasts which in turn fuse to produce new muscle fibres that comprise the contractile unit for skeletal muscle function. Distinguishing the satellite cells and their daughters which have a more restricted ability to self-renew themselves is currently challenging.

For the first time in this study scientists found a way to look at the contribution of different types of cells by destroying only satellite cells in the leg muscle of mice.  By removing satellite cells and looking at the impact this has on muscle repair scientists can build a picture of how exactly these different cells contribute to the process of muscle regeneration.

 

What did this study show?

Working with mice, scientists genetically altered a gene, called Pax7, which is unique to satellite cells. This caused satellite cells to die when a chemical called diphtheria toxin was injected into the muscle.

First the scientists treated muscles only with diphtheria toxin and looked at them under the microscope. The muscle looked normal confirming that diphtheria toxin only killed satellite cells and didn’t affect other muscle cells appreciably. Scientists also found that after diphtheria toxin injection the amount of muscle tissue decreased somewhat over time, but the that the effects on differentiated muscle cells was not significant in the short term.

Next they looked at the effect of damaging the muscles in the mice which no longer had any satellite cells. They did this by either injecting a chemical known to destroy muscle tissue or by making the mice exercise. In both cases the muscle did not repair itself despite the fact that other types of repair cells were still present. This suggests that satellite cells play a vital role in muscle regeneration.

Finally, to show that the effect observed was specific to satellite cells, the researchers transplanted only the satellite cells from normal mice into mice with no satellite cells. The mice regained the ability to repair their muscles after injury and their muscle mass increased, proving that satellite cells are needed for muscle regeneration to take place. 

 

What does this mean for patients?

This study has significantly added to the picture scientists have of how muscle regeneration works and the importance of satellite cells to that process.

An important outcome of this study is that for the first time scientists have been able to selectively destroy only a particular type of muscle cell. Now that they know how to do this it provides a useful experimental model which can be used to study the role of other cell types in muscle regeneration. For example, this model could be used to study the possibility of transplanting different types of muscle stem cells to treat Duchenne muscular dystrophy.

Scientists hope that understanding how healthy muscle repairs itself will help them to understand why this repair process fails in the muscles of Duchenne muscular dystrophy patients.  Then they can explore how to restart the repair process to reverse muscle wastage.

However, there is still much work to be done before these discoveries in the lab can be translated into potential treatments.  This study was carried out using mice and it is not known whether these results will also apply to humans. Also, further work is needed to investigate the role that the other types of repair cells play in muscles. Researchers need to understand how these other cells work with satellite cells to repair muscles and how this process is controlled.

 

Further information and links

The full original paper was published in the journal Development in 2011.  It can be accessed at http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=21828093

Muscular Dystrophy Campaign website: http://www.muscular-dystrophy.org/

Funding from the European Community’s Seventh Framework Programme project OPTISTEM supported this scientific work and summary. You can find out more about the scientists in this programme and the work they do at:

www.optistem.org

 

By Rachel Gill

Stem cells found in blood vessels can help make muscle

Summary of research

Research has shown for the first time that a non-muscle type of cell can switch to help make muscle during normal growth. These cells, called pericytes, which are normally found on small blood vessels, were shown to also make both muscle fibres and muscle stem cells. Whilst it has been shown that in extreme situations pericytes can contribute to muscle repair, it was not known whether this was also part of natural muscle growth.  This finding is important because it means that normally, there is a signal which ‘tells’ the pericytes to make muscle. We don’t yet know what this signal is but, once we do, it could be used to help repair damaged muscle after injury or disease.

What is the idea behind this study? 

When muscles are damaged after injury or in disorders such as muscular dystrophy, specialised muscle stem cells or ‘satellite cells’ repair them by making new muscle. This process is called ‘regeneration’.  It has recently been shown that during extreme regeneration in muscle, other stem cells have the potential to contribute to muscle repair. It is thought that this could be when the satellite cells are overwhelmed and cannot make enough muscle. One of the other stem cells shown to repair extensively damaged muscle is pericytes.

A pericyte is a type of stem cell which sits wrapped around small blood vessels called capillaries. Capillaries with connected pericytes are found throughout long fibres of muscle tissue providing nutrients and oxygen, and allowing the muscle to function normally. This results in many pericytes being found next to satellite cells inside a muscle. 

There are currently no cures for muscular disorders, and a major hope for the future is stem cell therapies. This would involve giving the individual healthy stem cells, which would repair the damaged muscle both immediately, and when future damage occurred.

Although it seems that pericyte cells could have great potential in future therapies, it was not known whether their apparent muscle-making ability was only seen after major injuries, or if it naturally occurred. The idea of this study was to determine whether or not pericytes contribute to normal muscle growth.

What did this study show?

In this study, the scientists from San Raffaele Scientific Institute, Milan followed a subset of pericytes producing a protein called Alkaline phosphatase (AP) in mice.  To see these cells easily, they marked the AP-producing cells. Straight after marking, these cells were only found around the blood vessels. This proved that they were marking cells which weren’t originally found in the muscle tissue.

To see whether the AP producing pericytes helped to make muscle during growth, they marked the AP-producing pericytes of young mice and waited until adulthood. They saw that over time muscle fibres and satellite cells also became marked. This meant that the marked pericytes were able to change the type of cells they were to become muscle and muscle-specific stem cells. When they did the same experiment in fully grown mice, hardly any muscle became marked, which showed that during maintenance the pericytes weren’t required. They also noticed that when muscles were regenerating, after injury or in a model of Duchenne muscular dystrophy, the number of marked muscle fibres increased.

The researchers tested the muscle-making potential of the switched pericytes by culturing them in a laboratory. They saw that 30% of cells spontaneously made muscle, and that they behaved as normal satellite cells.

These experiments show that there is a balance. During normal maintenance, the satellite cells alone repair damaged muscle. However, when lots of muscle is required – during growth and major repair – AP-producing pericytes help satellite cells to make extra muscle.

What does this mean for patients?

Transplanting healthy muscle-making stem cells in the clinic has great potential, but there are several hurdles to overcome. The current issue with the main muscle stem cell – satellite cells – is how to put them into a patients muscle. If they are injected into the bloodstream, they do not efficiently travel to affected muscles. Therefore satellite cells need to be injected into each affected muscle, which is not very efficient. The benefit of using pericytes is that being a blood vessel-associated cell, they can be injected into the blood and find damaged muscle.  In fact, human clinical trials in Italy have already started where they are injecting healthy mesoangioblasts, the in vitro expanded cell population derived from pericytes into boys with Duchenne muscular dystrophy (DMD). However, this is at the stage where they are testing the safety of this, and it will be several years until this is completed.

The knowledge from this paper that pericytes normally contribute to muscle growth and the satellite cell population is very important, especially as it showed for the first time that AP-producing pericytes in growing mice switched cell-type to become satellite cells. It is not known what ‘told’ the cells to switch, but finding this out would be valuable for future clinical applications. This is because once we know what this signal is, scientists could use it to maximise the muscle-making potential of pericytes. An example of this would be in muscular dystrophy, where the individual’s satellite cells do not function correctly, so cannot repair damaged muscle. Healthy pericytes could be given the signal to become satellite cells before being injected. Once they travel to the damaged muscles, as well as repairing them, they could provide a new population of satellite cells to repair future damage. This would increase the efficiency of the therapy, providing that it is safe.

Further information and links

The full original paper was published in the journal Nature Communications in 2011. The article can be viewed on this link:

http://www.nature.com/ncomms/journal/v2/n10/full/ncomms1508.html

Muscular Dystrophy Campaign website: http://www.muscular-dystrophy.org/

Funding from the European Community’s Seventh Framework Programme project OPTISTEM supported this scientific work and summary. You can find out more about the scientists in this programme and the work they do at:

www.optistem.org

This summary was written by Louise Moyle.

Using nitric oxide to sustain muscle regeneration

Summary of research

Adult muscle is maintained by a type of stem cell found in the muscle called a satellite cell. These satellite cells multiply and activate during normal muscle growth, and also when muscle is injured. This allows muscle to regenerate. Normally, satellite cells are able to renew themselves, but in muscular dystrophy repeated muscle damage occurs and the satellite cell supplies can run out. Recent research led by Emilio Clementi (from E Medea Scientific Institute and University of Milan in Italy) has shown that nitric oxide, a key molecule involved in cell signalling, can help maintain this supply of satellite cells. Nitric oxide stimulates an increase in satellite cell numbers. It also increases the number of satellite cells with certain features that show they can renew themselves. This research is important for developing muscular dystrophy therapies, and shows that a nitric oxide drug called molsidomine may be a successful future treatment. 

What is the idea behind this study?

 

Muscular dystrophy involves muscle weakness and loss of muscle tissue, getting worse over time. Muscle fibres are repeatedly injured, and this reduces the muscle’s ability to repair and regenerate itself. Normally, the body uses a muscle stem cell called a satellite cell to repair muscle fibres. This happens during normal muscle growth or after injury. When needed, the satellite cells multiply, become active, and change into healthy replacement muscle cells. After this, some go back to an inactive form to renew themselves as a reserve supply for future regeneration. However, with repeated damage in muscular dystrophy, this supply runs out over time.

Previous research shows that several substances control whether satellite cells can renew themselves. However, this knowledge has not led to any developments in increasing satellite cell renewal to treat muscular dystrophy.

It is known that production of nitric oxide (a cell signalling molecule controlling the way muscle is arranged and how it works) is altered in muscular dystrophies. Research has shown that restoring nitric oxide signalling improves muscle function and limits damage, but it is unknown how it affects satellite cells. Therefore, the researchers behind this study investigated how nitric oxide maintains the satellite cell reserve supply, and if it could be used in muscular dystrophy therapy.

When satellite cells are inactive, they can be identified because they possess certain proteins. An important one is Pax7, which sustains the reserve supply of satellite cells and stops them changing into muscle cells. Equally, there are different proteins that identify activated satellite cells. One of these is Myf5, and it reduces Pax7 levels. Therefore, when you test the reserve supply of satellite cells (inactive cells) you find that they do have Pax7, but don’t have Myf5. This is described as Pax7+/Myf5-. To study the effect of nitric oxide on satellite cell renewal and the available reserve supply, levels of these proteins were tested.  

What did this study show

Firstly, the scientists compared the effects of a chemical called SIN-1 that increased levels of nitric oxide in muscle with one called L-NAME that decreased levels. This was carried out in normal muscles extracted from mice. They found that SIN-1 increased the number of inactive Pax7+/Myf5- satellite cells (cells that do have Pax7, but don’t have Myf5). L-NAME decreased the number of inactive Pax7+/Myf5- satellite cells. Therefore, increasing levels of nitric oxide increases the number of satellite cells in the reserve supply (inactive Pax7+/Myf5- cells) for muscle regeneration.

Next, they looked at the effect of nitric oxide on muscle that had been repeatedly damaged, as occurs in muscular dystrophy. The nitric oxide drug molsidomine was compared with L-NAME, and these were given to mice before muscle damage occurred. Molsidomine increased the number of Pax7+/Myf5- satellite cells, delaying the reduction of the satellite cell supply and sustaining muscle regeneration.

The researchers also found that SIN-1 stimulates multiplication of satellite cells. Their research showed two possible pathways for this, involving different signalling molecules:

  • Cyclic guanosine monophosphate pathway – nitric oxide increases the number of activated satellite cells.
  • Wnt noncanonical pathway – nitric oxide increases the number of inactive (reserve supply) satellite cells, dependent on a protein called Vangl2.

Finally, when examining the effect of nitric oxide on muscular dystrophy symptoms, they found that molsidomine increased the number of Pax7+/Myf5- satellite cells in a mouse model. Also, these mice had more regenerating muscle fibres, less signs of muscle fibre cell death, and better muscle function.

What does this mean for patients?

There is not yet an effective drug treatment for muscular dystrophy, and current therapies have severe side effects. Recent developments in research with stem cells and exon skipping are promising, but expensive. Drug treatments could be cheaper and help a wide range of people. In this case, the effect of the drug would be to support and enhance the body’s own ability to heal itself.

Nitric oxide drugs such as molsidomine could become important in the treatment of muscular dystrophy, either on their own or in conjunction with other therapies. This study showed that nitric oxide controls the number of satellite cells in muscles, and whether they renew themselves. Therefore, it could prevent the reserve supply of satellite cells from running out in conditions with severe muscle damage, like muscular dystrophy.

However, while these researchers showed two potential pathways for the effect of nitric oxide on satellite cell multiplication, there may be others that have not been discovered. The precise effects of nitric oxide on satellite cells are not yet fully understood.

While these results are encouraging, this study was carried out in mice and effects in humans may be different. It will take time for any developments to come through into medical treatment.  

Further information and links

The full original paper was published in the journal Stem Cells in 2012.  It can be accessed at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378700/

Muscular Dystrophy Campaign website: http://www.muscular-dystrophy.org/

This scientific work and summary were supported by funding from the European Community’s Seventh Framework Programme project OPTISTEM. You can find out more about the scientists in this programme and the work they do at www.optistem.org

This summary was written by Heather Kennedy