Mitochondrial damage is thought to be one of the mechanisms leading to muscle cell death in muscular dystrophy. Drugs were used by the researchers to block this mitochondrial damage either in a small number of patients or mouse models of muscular dystrophy.
This treatment strategy of targeting mitochondria does not aim to fix the mutated gene or replace the protein which is the root cause of the muscle weakness. Instead, it attempts to block one of the effects that this lack of a particular protein has on muscle cells, therefore reducing symptoms.
One of the research papers was published by researchers in the US, lead by Professor Jeffery Molkentin. They targeted the mitochondria in the mouse models of limb girdle muscular dystrophy 2F, congenital muscular dystrophy 1A (CMD) and Duchenne muscular dystrophy 1. These mice were treated with a drug called Debio-025 which blocked mitochondrial damage with promising improvements in symptoms. In another article by Professor Paolo Bernardi’s group in Italy, cyclosporin A was used to block mitochondrial damage in five people with collagen VI myopathies (Ullrich congenital muscular dystrophy or Bethlem myopathy) 2. The muscle cells examined under the microscope after treatment appeared to be healthier.
- What did the new research in the USA show?
- What about the research in Italy?
- What do the results of the study mean for people with muscular dystrophy?
- Background Information- What are mitochondria and how are they involved in muscular dystrophy?
- Further information and links:
What did the new research in the USA show?
Mitochondria are the batteries of cells, providing them with energy. Damage to the mitochondria can trigger the death of the whole cell. This mitochondrial damage involves the protein cyclophilin D and blocking the action of this protein can prevent the mitochondrial damage and subsequent cell death (you can read more background about this process at the end of this article).
Professor Jeffery Molkentin’s group of researchers used the mouse models of limb girdle muscular dystrophy 2F, congenital muscular dystrophy 1A and Duchenne muscular dystrophy. In all three models it was shown that the mitochondria was swollen and damaged. Two different strategies were used to block cyclophilin D. Initially, the three mouse model strains were bred so that they also lacked the gene coding for cyclophilin D. In other experiments a drug called Debio-025 was used to block cyclophilin D. In all cases, the mitochondria were less swollen when cyclophilin D was absent or inhibited. The muscles of these mice also had less degeneration and inflammation, looked healthier under the microscope and were stronger. The mice also had better heart function. In the mouse model of congenital muscular dystrophy 1A, which had severe symptoms, a longer lifespan was noticed. It is important to note that the muscle dysfunction was reduced but not completely prevented.
What about the research in Italy?
The Italian researchers used a drug called cyclosporin A to treat individuals with mutations in collagen VI- four with Ullrich congenital muscular dystrophy and one with Bethlem myopathy. Cyclosporin A is a drug which was originally developed to prevent immune rejection of organs after transplant, but it has also been found to protect mitochondria from damage. Due to the strong suppression of the immune system with this drug there is an increased vulnerability to serious infections, so the participants in this study were only treated for one month. This was not long enough to see an improvement in muscle symptoms. However, muscle biopsies were taken before and after treatment and their muscle cells showed less mitochondrial dysfunction, less cell death and increased muscle fibre regeneration after treatment.
Due to the risk of infections, the authors acknowledged that cyclosporin A is not a viable treatment option for long term therapy but used the drug to prove the principle that inhibiting mitochondrial damage could be a potential treatment strategy for these neuromuscular conditions. More specific drugs such as Debio-025, which seems to have a similar effect on mitochondria, could be a viable alternative to cyclosporin A.
What do the results of the study mean for people with muscular dystrophy?
The studies in mice concentrated on models of limb girdle muscular dystrophy 2F, congenital muscular dystrophy 1A and Duchenne muscular dystrophy. The Italian group on the other hand, looked at patients with Ullrich congenital muscular dystrophy and Bethlem myopathy. The full range of neuromuscular conditions that could potentially be treated with drugs which block mitochondrial damage is yet to be discovered.
Of particular interest in the U.S. study was the use of the drug Debio-025. This drug is not yet available but has recently completed phase IIa clinical trials in Switzerland for the treatment of hepatitis C (find out more at DebioPharm Group). For this purpose the drug was shown to be safe and effective in 90 patients. This drug therefore presents an exciting treatment possibility for muscular dystrophy.
These studies have been carried out in mouse models or on a very small number of patients. The extent to which mitochondria are involved in muscle disease is not yet fully understood. Therefore, further studies on a large number of patients, to determine the extent of mitochondrial involvement in neuromuscular conditions are required to determine the potential of this treatment strategy. We also don’t yet know if the drug Debio-025 will be as effective on humans as in mice, or if the drug is safe for long term use.
Treatment with a drug such as Debio-025 might not provide a cure for muscular dystrophy, but if successful, will add another string to our bow of treatment options. Experts believe that in the future a combination of treatments, perhaps including the one discussed here, might be the answer to successfully treating neuromuscular conditions 3.
Background information – what are mitochondria and how are they involved in muscular dystrophy?
Mitochondria are the powerhouses of the cell. They take in nutrients and turn them into energy for the cell. Muscles cells need a lot of energy, so they have many mitochondria. If mitochondria are damaged they release signals that lead to the death of the cell.
The thin membrane that covers each muscle fibre is called the sarcolemma and it is very important for muscle structure and function. Many forms of muscular dystrophy are caused by mutations in proteins which are thought to stabilise and protect the sarcolemma. Without these stabilising proteins, the sarcolemma is damaged and becomes leaky, allowing too much calcium to enter the muscle fibre. The calcium then enters the mitochondria, which swell up and rupture, causing the muscle cell to degenerate. An important protein involved in allowing calcium into the mitochondria and causing damage is the protein cyclophilin D.
Further information and links
Find out more about the neuromuscular conditions.
The research paper about Professor Jeffery Molkentin’s (Ohio, USA) study using mouse models can found at the Nature Medicine Journal. The paper is called “Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy”.
The research paper by Professor Paolo Bernadi’s group in Italy called “Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies” can be found at the Proceedings of the National Academy of Sciences.
The papers were published in the journals ‘Nature Medicine’ and ‘Proceedings of the National Academy of Sciences’ (PNAS) which are available by subscription only, so the original articles are not freely available. The articles are written in technical language with no summary in layman’s terms.
Commentary about the article can also be read in the journal Gene Therapy
The Muscular Dystrophy Campaign funds research on the involvement of mitochondria in Bethlem myopathy and Ullrich congenital muscular dystrophy.
1. Millay, D.P., et al. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nat Med 14, 442-447 (2008).
2. Merlini, L., et al. Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in
patients with collagen VI myopathies. Proc Natl Acad Sci U S A 105, 5225-5229 (2008).
3. Wells, D.J. Treatments for muscular dystrophy: increased treatment options for Duchenne and related muscular dystropies. Gene Ther 15, 1077-1078 (2008).