Rapamycin neutralizes mitochondrial defects
Rapamycin, a drug used to prevent transplant rejection and considered capable of increasing life expectancy, has demonstrated unexpected positive effects in a mouse model of Ley syndrome, a life–incompatible hereditary mitochondrial defect.
Children with this disease, usually diagnosed in the first year of life, develop progressive brain damage, muscle weakness, loss of the ability to coordinate movements and a decrease in body weight. As a rule, they do not live to 6-7 years and die from insufficiency of respiratory muscles. The incidence of Ley syndrome is 1 case per 40,000 newborns, but there are populations where it reaches a value of 1 per 2,000 newborns. To date, this disease, caused by several different mutations, has no effective treatment.
A mouse with simulated Ley syndrome (left) shows typical signs of the disease:
hair loss and small body size compared to a normal mouse (right).
Researchers at the University of Washington, working under the guidance of Dr. Matt Kaeberlein, have demonstrated that daily administration of rapamycin significantly improves survival and suppresses the progression of the mouse model of Ley syndrome.
The median lifespan of a mouse model of Ley syndrome is 50 days. The introduction of rapamycin more than doubled this value: up to 114 days for males and 111 days for females. The maximum life expectancy in the experimental group was 269 days, which is more than 3 times higher than the corresponding indicator in the absence of treatment.
The animals showed neurological symptoms much later, inflammation and damage to brain tissues were less pronounced. Almost until the end of their lives, the mice retained the ability to breathe normally and did not press their paws to the body, which is a characteristic symptom of this and similar brain diseases in mice. Unlike the control group animals, they could balance and run on special treadmills.
At the same time, it turned out that the drug had practically no effect on the work of mitochondria, the inferiority of which was balanced by a shift in the energy metabolism of cells. Under the action of rapamycin, cells began to use amino acids and fats as the main energy sources, which excluded the accumulation of glucose breakdown products, including lactic acid. The cells of patients with Ley syndrome are characterized by high levels of these potentially toxic compounds.
The authors believe that rapamycin can also help in the treatment of not only Ley syndrome, but also other mitochondrial diseases or conditions based on mitochondrial dysfunction.
In addition to true mitochondrial diseases, usually caused by genetic mutations, a decrease in the efficiency of mitochondria is observed in many common diseases, including heart disease, cancer, as well as age-related degeneration of muscle and nervous tissue.
Rapamycin is already used in clinical practice as a means to prevent rejection of donor organs and treat rare forms of cancer, and its ability to slow aging and the development of age-related diseases is being actively studied by many research groups. The drug has serious side effects, which may limit its use for the treatment of young children. However, the authors are very optimistic and believe that even if rapamycin does not help in the treatment of Ley syndrome, the data they have obtained will allow us to develop other methods of therapy for this rare hereditary disease.
The article by S.C. Johnson et al. mTOR Inhibition Allows Mitochondrial Disease in a Mouse Model of Leigh Syndrome is published in the journal Science Express.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the University of Washington:
FDA-approved immune-modulating drug unexpectedly benefits mice with fatal mitochondrial defect.
25.11.2013