The key mechanism of skeletal muscle atrophy
The main culprit of the development of muscular atrophy has been established
Nanonewsnet based on materials from University of Iowa Carver College of Medicine: Researchers identify key culprit causing muscle atrophyWe all get sick, get injured and... just get old.
And we gloomily watch our muscles weaken. Skeletal muscle atrophy – whether as a result of injury, illness or senile withering – is almost as natural a condition for a person as breathing. However, despite the "habitual" nature of this phenomenon, scientists know little about its molecular mechanisms. Will science be able to stop this process or at least slow it down?
It is known that proteins are responsible for the atrophy of skeletal muscles, but there are thousands of different proteins in the body, and, consequently, thousands of suspects in this crime come to the attention of scientists. Distinguishing the key players from the extras is not an easy task.
Scientists at the University of Iowa have made significant progress in this area of research.
They were able to identify a protein – Gadd45a – and found that it regulates 40 percent of the activity of genes associated with the development of skeletal muscle atrophy.
In addition, they learned that Gadd45a does its diabolical work inside the nucleus of muscle cells, arranging such a "bazaar" when reprogramming hundreds of genes that the nucleus even changes its shape.
(The upper picture shows a myocyte with a normal nucleus, the lower one shows what this Gadd–VM did to it).
Photo: Adams lab, University of Iowa.
"We now understand the key molecular mechanism of skeletal muscle atrophy," says Christopher Adams, associate professor of internal Medicine and author of an article published in The Journal of Biological Chemistry (Stress–induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy).
The scientist believes that the discoveries just made by his group will help to find methods of treating this condition, and now it is clear that we need to start by reducing the level of Gadd45a expression.
It is known from already published works that with malnutrition, nerve damage or inactivity in skeletal muscle cells, ATF4 protein synthesis increases. This protein, in turn, initiates muscle atrophy by activating many genes. But the details of these processes eluded the researchers. It remained unclear, for example, whether all genes are equally important or some of them play more important roles.
To get answers to these questions, Adams and his colleagues conducted a series of experiments aimed at identifying the most important target genes of the ATF4 protein. Experiments have shown that activation of the Gadd45a gene by this protein leads to muscle atrophy. Further tests, however, showed that Gadd45a does not need this "benefactor" protein, that is, by causing atrophy, it can act independently of the ATF4 signaling pathway.
Scientists have learned that Gadd45a has a negative effect on muscles, acting simultaneously from two flanks: it commands muscle cells to synthesize fewer proteins (necessary for tissue maintenance) and stimulates the degradation of protein molecules already existing in muscle fibers. The result of both processes is muscle atrophy.
Being under stress, the nuclei of muscle cells change their shape, turning from cigar-shaped formations into swollen bubbles with enlarged nucleoli. The introduction of Gadd45a into a muscle cell changes the shape of its nucleus in the same way as if the cell was under stress.
"To sum up, this means that Gadd45a gets into the nuclei of muscle cells, and this completely changes them – so much so that these changes become visible," concludes Professor Adams. "It's turning genes on, it's turning genes off. The cell has already been changed."
Gadd45a protein alters the expression of approximately 600 genes associated with muscle atrophy, increasing the number of matrix RNAs, which are responsible for either the destruction of muscle proteins or the suppression of the growth of new ones. According to the article, in general, about 40 percent of all mRNAs in the human body are involved in the processes of muscle atrophy.
According to Adams, "Gadd45a is like a central switchboard." If it is blocked, it is possible, presumably, to significantly stop muscle atrophy.
The scientists set out to find out how to block Gadd45a and find other signaling pathways involved in this process.
Portal "Eternal youth" http://vechnayamolodost.ru21.08.2012