How to become healthy, strong and hardy?
Swiss researchers from the Federal Polytechnic School of Lausanne and the University of Lausanne, working together with specialists from the Salk Institute, California, came to the conclusion that if it were not for the action of a natural inhibitor, our muscles could be much stronger than they really are. By acting on the NCoR1 protein (Nuclear Receptor Corepressor), they managed to modulate the transcription of a number of genes in such a way that the resulting mouse line boasts muscles twice as strong as those of ordinary individuals.
The transcription process underlying the synthesis of proteins according to the "instructions" encoded in the DNA of the organism is modulated by so-called cofactors that stimulate it (coactivators) or inhibit it (corepressors). Cofactors react to changes in the concentration of certain hormones, which, in turn, is a reflection of the state of the body.
In parallel experiments on mice and nematodes, an international group of scientists working under the leadership of Professor Johan Auwerx managed to inhibit the activity of the NCoR1 corepressor in muscle cells. Under normal conditions, this protein receptor, found in the cells of various tissues of the body, suppresses the growth of muscle tissue.
The resulting effect was more than impressive. The development of muscle tissue in mice without this natural inhibitor occurred much more efficiently than in normal animals. The individuals of the resulting line were real "marathon runners", capable of running distances at high speed, almost twice the distances subject to ordinary mice, before the first signs of fatigue appeared. In addition, they tolerated the cold much better.
Unlike other experiments on the creation of "supermys", the approach used in this work did not change the mechanism of energy utilization, but modified the process of formation of muscle tissue during the growth of the body. Microscopic analysis showed that, compared with the muscles of normal mice, the muscle fibers of transgenic animals are thicker, the muscles themselves are more massive, and their constituent cells contain more mitochondria – organelles that break down nutrients with the release of energy.
Similar results were observed in parallel experiments on nematodes. Based on this, the researchers concluded that the approach they developed is applicable to a wide range of living organisms.
As part of the second study conducted by scientists from the same institutions, the group of Professor Jerrold M. Olefsky created a line of mice that did not have the NCoR protein in adipose tissue cells.
NCoR is the main corepressor of the transcription factor gamma receptor activated by peroxisome proliferators or PPAR-gamma, a protein common in the body that regulates fatty acid storage and glucose metabolism. However, judging by the results obtained by Professor Olefsky's group and Professor Overks' group that created "marathon mice", the functions of this protein are much more versatile than previously thought.
Despite the obesity caused by genetic factors and predisposition to diabetes, mice without the NCoR receptor in adipose tissue cells showed good glucose tolerance. Moreover, their liver cells, as well as muscle and adipose tissues, were characterized by increased sensitivity to insulin, and for the body as a whole – low levels of systemic inflammation. Resistance to insulin, a hormone that regulates the metabolism of carbohydrates and fats, and chronic inflammation are the main signs of diabetes.
According to Professor Olefsky, apparently, NCoR stimulates the inactivation of PPAR-gamma by phosphorylation (addition of a phosphate group). Interestingly, the removal of NCoR only from adipocytes and, accordingly, the preservation of the activity of the PPAR-gamma receptor exclusively in these cells provided a persistent increase in insulin sensitivity in all tissues of the body.
An extremely important fact is that during both studies, the researchers did not register any negative side effects associated with the inactivation of NCoR in muscle and adipose tissue cells. They are currently studying potential drugs that could reduce the activity of NCoR without the use of genetic engineering methods.
The data obtained are a great achievement on the way to understanding the work of the fundamental mechanisms underlying the functioning of living organisms. From a practical point of view, they can help in the development of treatments for diseases such as diabetes, obesity, as well as age-related or genetic diseases caused by atrophy of muscle tissue. However, Professor Overks notes that if the mechanism identified by his group extends to a person, it can attract increased attention from athletes. Therefore, organizations involved in doping control will have to monitor for the detection of unauthorized use of such therapies.
Articles by Hiroyasu Yamamoto et al. NCoR1 Is a Conserved Physiological Modulator of Muscle Mass and Oxidative Function and Pingping Li et al. Adipocyte NCoR Knockout Decreases PPARy Phosphorylation and Enhances PPARy Activity and Insulin Sensitivity are published in the journal Cell.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Ecole Polytechnique Federale de Lausanne:
Better muscles thanks to a genetic knock-out and New therapeutic avenues for obesity and diabetes.
14.11.2011