Tag Archives: #muscledisease

Study Clarifies Cause Of A Rare Genetic Muscle Disease (Medicine)

An international team of researchers led by the University of Bonn (Germany) has identified the cause of a rare, severe muscle disease. According to these findings, a single spontaneously occurring mutation results in the muscle cells no longer being able to correctly break down defective proteins. As a result, the cells perish. The condition causes severe heart failure in children, accompanied by skeletal and respiratory muscle damage. Those affected rarely live beyond the age of 20. The study also highlights experimental approaches for potential treatment. Whether this hope will be fulfilled, however, will only become clear in a few years. The results are published in the journal Nature Communications.

Anyone who has ever snapped a spoke on their bike or broken down with their car knows that mechanical stresses sooner or later result in damage that needs to be repaired. This also applies to the human musculature. “With each movement, structural proteins are damaged and have to be replaced,” explains adjunct professor Dr. Michael Hesse from the Institute of Physiology at the University of Bonn, who led the study together with his colleague Prof. Dr. Bernd Fleischmann.

The defective molecules are normally broken down in the cell and their components are then recycled. An important role in this complex process is played by a protein called BAG3. The results of the new study show how important this is: The researchers were able to demonstrate that a single change in the genetic blueprint of BAG3 results in a fatal disease.

“The mutation causes BAG3 to form insoluble complexes with partner proteins that grow larger and larger,” Hesse says. This brings the repair processes to a standstill – the muscles become less and less efficient. Moreover, toxic levels of proteins accumulate over time, eventually resulting in the death of the muscle cell. “The consequences are usually first seen in the heart,” Hesse says. “There, muscle is successively replaced by scar tissue. This causes the heart’s elasticity to decrease until it can barely pump blood.”

Affected individuals therefore usually require a heart transplant in childhood. Even this measure only provides temporary relief, as the disease also affects the skeletal and respiratory muscles. As a result, sufferers often die at a young age.

Very rare condition, therefore little research

The lethal mutation can arise spontaneously during embryo development. Fortunately, this is a very rare occurrence: There are probably only a few hundred affected children worldwide. However, due to its rarity, the disease has received little research attention to date. “Our study now takes us a great deal further,” stresses Bernd Fleischmann.

After experimental therapy (right), there are significantly fewer protein aggregates (marked in green) and damage in the myocardium compared with control animals (left). © Kathrin Graf-Riesen/UKB

This is because the researchers have succeeded for the first time in replicating the disease in mice and using the new animal model to identify its causes. This allows it to be researched better than before – also with regard to possible therapies. Maybe the effect of the mutation can at least be reduced. Humans have two versions of each gene, one from the mother and the other from the father. This means that even if one version of BAG3 mutates during embryo development, there is still a second gene that is intact.

Unfortunately, however, the defective BAG3 also clumps with its intact siblings. The mutation in one of the genes is therefore sufficient to stop the breakdown of the defective muscle proteins. However, if the mutated version could be eliminated, the repair should work again. It would also prevent the massive accumulation of proteins in the cell that eventually results in its death.

There are indeed methods to specifically inhibit the activity of individual genes. “We used one of them to treat the sick mice,” explains Kathrin Graf-Riesen of the Institute of Physiology, who was responsible for most of the experiments along with Dr. Kenichi Kimura and her colleague Dr. Astrid Ooms. The animals treated in this way then showed significantly fewer symptoms. Whether this approach can be transferred to humans, however, remains the subject of further research.

Participating institutions:

In addition to the Institute of Physiology I, the Institute for Cell Biology of the University of Bonn and the Clinic for Cardiac Surgery of the University Hospital Bonn were involved in the study. The partners also include Forschungszentrum Jülich, the Universities of Münster, Freiburg and Cologne, as well as Stanford University in the USA and the University of Tsukuba in Japan.

Featured image: Heart of a healthy (left) and a diseased mouse (cross sections). Connective tissue inclusions (right, red) make the diseased heart less efficient. © Kenichi Kimura/UKB


Publication: Kenichi Kimura et al: Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy. Nature Communications, https://doi.org/10.1038/s41467-021-23858-7


Provided by University of Bonn

New Research Provides Fresh Hope For Children Suffering From Rare Muscle Diseases (Medicine)

Results of an international study published today in Autophagy and led by researchers from Monash University, School of Biological Sciences, provides renewed hope for children suffering from a progressive and devastating muscle disease.

Stephen Greenspan and Laura Zah were devastated when they learned their son Alexander had a rare genetic mutation, which causes a deadly neuromuscular disease with no known treatment or cure.

Metformin rescues muscle function in BAG3 myofibrillar myopathy models. ©Taylor & Francis

But the results of an international study published today in Autophagy and led by researchers from Monash University, School of Biological Sciences, provides renewed hope for children suffering from the progressive and devastating muscle disease. Known as myofibrillar myopathies, these rare genetic diseases lead to progressive muscle wasting, affecting muscle function and causing weakness.

Using the tiny zebrafish, Associate Professor Robert Bryson-Richardson from the School of Biological Sciences and his team of researchers were able to show that a defect in protein quality control contributes to the symptoms of the diseases.

“We tested 75 drugs that promote the removal of damaged proteins in our zebrafish model and identified nine that were effective” explained first author Dr Avnika Ruparelia, who completed her student and post-doctoral training in the team working on the disease. “Importantly two of these are already approved for human use in other conditions.”

“We found that one of the drugs, metformin, which is normally used to treat diabetes, removed the accumulating damaged protein in the fish, prevented muscle disintegration and restored their swimming ability,” said Associate Professor Bryson-Richardson, who led the study.

The most severe form of the myofibrillar myopathy, caused by a mutation in the gene BAG3, starts to affect children between 6 and 8 years of age. The disease is usually fatal before the age of 25 due to respiratory or cardiac failure.

In the case of Alexander (who was born in 2003) clinicians were able to draw on the study’s information to prescribe metformin – which is so far proving positive.

“Initially, we were devastated by our son’s diagnosis. Alexander has a rare mutation that causes a deadly neuromuscular disease. No treatment or cure was known. In desperation we formed the charitable organization, Alexander’s Way, to promote and sponsor research into this disease. Upon learning of our awful problem, A/Prof Bryson-Richardson was compassionate, and found a way to share with us his pre-publication results about the disease and metformin. The research conducted by Robert Bryson-Richardson and Avnika Ruparelia has given us hope, and we thank them deeply for their work and compassion,” said Alexander’s father, Stephen.

“This is a wonderful outcome, as initially we thought that because of the rarity of the mutation, it was unlikely that there would ever be a treatment or therapeutic intervention available,” said Alexander’s mother, Laura Zah. “Compared to previous case studies, the progression of our son’s disease has been slower, likely due to metformin. Another boy, Marco, who is affected by this disease also takes metformin, and is presently judged by his mother to be stable. Metformin may have given us more time with our boys and more time to work for a cure.”

Associate Professor Bryson-Richardson said the repurposing of existing drugs provided a very rapid route to clinical use, as there was already existing safety data for the drug. This is especially important for these rare diseases as the patient numbers are low, meaning it might not be possible to do clinical trials with novel drugs.

“We have identified metformin as a strong candidate to treat BAG3 myofibrillar myopathy, and also myofibrillar myopathy due to mutations in other genes (we showed similar defects in protein quality control in three other forms) and in cardiomyopathy due to mutations in BAG3,” he said.

“Given that metformin is taken by millions of people for diabetes and known to be very safe this makes clinical translation highly feasible, and in fact many patients are now taking it.”

Stephen and Laura Zah are the founders of the charitable organisation Alexander’s Way Research Fund which they established to promote and sponsor research into myofibrillar myopathies.

“The research conducted by Monash scientists has given us hope, and we thank them deeply for their compassion – they have given us time,” said Laura Zah.

References: Avnika A. Ruparelia , Emily A. McKaige, Caitlin Williams, Keith E. Schulze, Margit Fuchs , Viola Oorschot, Emmanuelle Lacene , Mirella Meregalli , Clara Lee , Rita J. Serrano , Emily C. Baxter , Keyne Monro , Yvan Torrente , Georg Ramm, Tanya Stojkovic , Josée N. Lavoie & Robert J. Bryson-Richardson, “Metformin rescues muscle function in BAG3 myofibrillar myopathy models”, Journal Autophagy, doi: https://doi.org/10.1080/15548627.2020.1833500 link: https://www.tandfonline.com/doi/full/10.1080/15548627.2020.1833500

Provided by Taylor And Francis Group