Potential new therapeutic target to improve symptoms for Duchenne MD

In a recent article published in the scientific journal Genes and Development, Dr Bruce Spiegelman of the Dana-Farber Cancer Instituteand colleagues report on the characterisation of a protein, called PGC-1alpha. This protein appears to play an important role in the biology of muscle function and they suggest it may be a ‘target’ for further research into its potential as a treatment for Duchenne muscular dystrophy.

Contents:


What is the PCG-1alpha protein?

The protein named PCG-1alpha was originally discovered in the laboratory of Dr Spiegelman in 1998 and was found to be a ‘transcriptional coactivator’, a protein that helps to regulate the activity of specific sets of genes. It is known that PCG-1alpha activity increases the number of mitochondria in the muscle as a response to physical activity. Mitochondria are the powerhouses of a muscle cell and ensure that the muscles always have sufficient energy available to be able to carry out their functions.

But this is not the only function of PCG-1alpha. It also regulates genes which are important for the formation and operation of the ‘neuromuscular junction’, the site on the muscle cell where it makes the connection to the nerve. By ensuring that this attachment site maintains its proper functionality, PCG-1alpha activity prevents the progressive loss of muscle mass — a phenomenon described as an “anti-atrophic effect”. However, the level of this activity depends on the level of exercise the muscle is subjected to. Physical activity results in high levels of PCG-1alpha activity giving rise to greater muscle strength, but a lack of exercise results in low levels of PCG-1alpha activity causing the muscle to weaken and become atrophic.

The research — PCG-1alpha and Duchenne MD

Duchenne muscular dystrophy [link] is an inherited disease characterised by severe muscle wasting. In the general population it has an incidence of 1 in 3500 newborn boys. The disease is caused by a genetic mutation resulting in a dysfunctional muscle protein called dystrophin. The first symptoms appear between the age of 3 to 5; by the age of 11 most of the boys are wheelchair bound and the disease can limit life expectancy when individuals get into their late teens or early twenties.

Previous research has shown that the muscles of ‘mdx’ mice (an animal model for Duchenne md) share some of the features displayed in another mouse model which has low levels of PCG-1alpha. This observation led Dr Spiegelman and his team to investigate whether PCG-1alpha has an impact on the severity of the disease. They compared ‘mdx’ mice with a second group of mice specially bred to display abnormally high levels of activity due to increased levels of the PCG-1alpha protein, as well as having Duchenne md.

They subjected both groups of mice to a specially designed exercise program and then compared the two groups using performance, muscle strength and chemical tests. Their results show that the second group (Duchenne mice with abnormally high levels of PCG-1alpha activity) were less fatigued, had improved muscle strength and function and exhibited less damage to the muscle cells.

The results

Based on these findings, the researchers suggest that an increase in PCG-1alpha levels or PCG-1alpha activity might represent a new treatment approach for Duchenne muscular dystrophy, the related Becker muscular dystrophy and other neuromuscular disorders. It is, however, this research is in its early days and very difficult to make any predictions about the impact of this potential treatment approach. A lot research must be done before this technology can be brought forward for testing in a clinical context.

“These data clearly show that experimental elevation of PCG-1alpha has therapeutic promise in an animal model of Duchenne muscular dystrophy. We hope this will lead eventually to therapeutics for a terrible disease for which there is no effective treatment at the present time,” explains Dr. Spiegelman.

Further information and links

Genes and Development
The journal, 'Genes and Development' (www.genesdev.org), is subscription only so the original article is not freely available. The article itself is written in medically technical language with no summary in layman's terms.

Dana-Barber Cancer Institute
To find out more about this research institute, visit www.dana-farber.org

About Duchenne muscular dystrophy
For more information about this condition, go to our nformation pages.

Keep up to date
The Muscular Dystrophy Campaign aims to keep its members informed about any new research developments and advances. It's free to become a member (there are some charges for overseas members) and we'll keep you up to date with research, both independently funded projects and those funded by the charity. Click here to find out more about becoming a member.

We hope you found this information useful. The Muscular Dystrophy Campaign’s research department hopes to help the general public, particularly those living with muscle disease and their families, understand the implications of research into these conditions. If you have any comments about this summary, please click here to contact our research department.