Not only against viruses
The drug against hepatitis and HIV improved the condition of mice with muscular dystrophy
RNF Press Service
The antiviral drug alisporivir can normalize the state of the "power stations" of cells — mitochondria — in Duchenne myodystrophy. Russian scientists came to this conclusion after conducting an experiment on mouse models. The drug was originally used to treat patients with hepatitis C and HIV infection, but it turned out that it is also able to improve calcium metabolism in mitochondria - it can also have a beneficial effect on the condition of patients suffering from muscle pathologies. The results of the work supported by a grant from the Russian Science Foundation (RNF) are published in the International Journal of Molecular Sciences and Biomedicines (Dubinin et al., Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis).
Duchenne myodystrophy affects one in 3500-5000 newborn boys and one in 50,000 girls. This disease is caused by mutations of the dystrophin protein gene located on the X chromosome - since it is the only one in men, the stronger sex in this situation turned out to be more vulnerable. Dystrophin connects the cytoskeleton of a muscle cell with the surrounding tissue — this is the only way the muscle can work normally. In patients with Duchenne myodystrophy, it is completely or almost completely absent. The muscles gradually weaken, and by adolescence the child becomes severely disabled, confined to a wheelchair and a breathing apparatus. Sooner or later, pathology also affects the heart. At the same time, patients most often die from respiratory failure at the age of 20-25 years.
"At the moment, the most common treatment option for this pathology is the use of glucocorticoids, in particular prednisone and deflazacort, which help to suppress inflammatory processes in the muscles. But such therapy is often accompanied by significant side effects, as well as disruption of the genes involved in muscle regeneration, which leads to chronic myopathy. There are drugs that really improve the condition of patients and almost restore muscle function, but they are not registered in Russia and are also very expensive: only an annual course of treatment will cost 53 million rubles!", — says Konstantin Belosludtsev, one of the authors of the articles, Doctor of Biological Sciences, professor of the Department of Biochemistry, Cell Biology and Microbiology of Mari State University (Yoshkar-Ola).
Biologists from Mari State University (Yoshkar-Ola) and the Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences (Pushchino) evaluated an alternative therapy option and tested it on ten mice with a "broken" dystrophin protein gene. The drug alisporivir, which has an antiviral effect against HIV and hepatitis C (preclinical studies on SARS-COV-2 are also underway), affects the mitochondria ("energy stations") of muscle cells. Mitochondria also serve as a storage for excess calcium ions: when muscles contract, the latter work in the cytoplasm of the cell, and at rest they return to the "energy stations". However, Duchenne myodystrophy changes their mode of operation: special protein pores in the membranes are no longer able to hold calcium inside the mitochondria, and the organelle itself is disturbed by respiration and energy generation, and it stops functioning normally. As a result, an excess of calcium ions in the cytoplasm of muscle cells triggers the processes of degradation and necrosis, and without respiration, muscle fibers do not receive the necessary energy. Alisporivir specifically suppresses the formation of pores in the mitochondrial membrane, so that these organelles continue to maintain normal levels of calcium in the muscle fiber and function normally.
For a month, the authors conducted experiments on four groups of mice: animals with myodystrophy without treatment and on daily injections of the drug, healthy without therapy and with it. It turned out that the administration of the drug to sick rodents reduced the intensity of the inflammatory process by one and a half to two times. Inflammation occurs due to the fact that with Duchenne myodystrophy, the muscles not only weaken, but also die, which causes the immune system to react. According to scientists, the result suggests that the destruction of muscles has slowed down. In addition, the treatment brought the condition of mitochondria and the structure of muscle cells closer to normal, the exchange of calcium in the "power stations" also normalized.
It is important that scientists have observed an improvement in muscle strength and endurance of animals. Sick mice receiving injections of alisporivir were able to hang on a horizontal string, clinging to it with their front paws, longer than their relatives without treatment.
"In the short term, this approach can be really useful. Nevertheless, we noted that alisporivir somewhat suppresses the formation of new mitochondria in muscle fibers, which is important for muscle growth, and also modifies the heart rate. So in the long run, such treatment may not be too right. But we already have suggestions on how to eliminate these negative effects — in the future we want to check it. If our hypothesis is correct, then we can say that an effective method of supportive therapy of patients with Duchenne myodystrophy has been found, which does not have significant side effects, unlike existing approaches. I hope that one day this development will help improve the quality of life of such patients," sums up Mikhail Dubinin, head of the project under the RNF grant, Candidate of Biological Sciences, Associate Professor of the Department of Biochemistry, Cell Biology and Microbiology of Mari State University (Yoshkar-Ola).
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