Mustard instead of doping?
Scientists at the University of California, working under the leadership of Professor Randall Johnson, in collaboration with colleagues from the University of Pennsylvania, as well as with researchers from Sweden and Germany, have found that the skin of mice is sensitive to low oxygen levels and participates in the regulation of erythropoietin synthesis – a hormone that stimulates the production of red blood cells – thus providing adaptation the organism is resistant to conditions of high altitude and low oxygen content in the air.
This unexpected discovery contradicts the traditional view that mammalian skin is not connected to the respiratory system.
The authors believe that the mechanism they identified is an ancient feature preserved by mammals in the process of evolution from lower forms of vertebrates, such as amphibians, whose skin contains ion channels similar to channels that provide oxygen diffusion in mammalian lungs.
Amphibians, especially frogs, not only breathe through their skin, but are also able to sense and react to the concentration of oxygen in the air or water in contact with their skin. However, until now, it had never occurred to anyone that mammalian skin could have similar properties.
Of course, mammals cannot breathe through their skin, however, if it turns out that the results obtained by scientists extend to humans, they will radically change approaches to the treatment of anemia and other diseases that require stimulation of the body's ability to synthesize red blood cells. This approach can also be used to improve the endurance and strength of athletes.
Currently, two methods of stimulating the production of red blood cells are officially allowed in order to increase the oxygen capacity of the blood and improve the endurance of athletes: training at high altitude above sea level and in tents with low oxygen content in the air. Blood doping (blood transfusion before competitions) and the introduction of synthetic erythropoietin are prohibited by all sports governing bodies. Perhaps in the future, the desired results can be achieved by exposing the skin of athletes to air with a low oxygen content, or by increasing skin blood flow.
For two years, scientists have been trying to figure out why certain lines of mice created for experiments using genetic engineering methods are characterized by high levels of erythropoietin in the body. In 2004, Johnson and the students working under him published the results of work on turning an ordinary laboratory mouse into a rodent with the endurance of an Olympic athlete. They achieved this by removing a gene that ensures the switching of mammalian muscles from aerobic to anaerobic metabolism in conditions of oxygen deficiency.
Most of the movements we perform are carried out aerobically – due to biochemical mechanisms that ensure complete oxidation of glucose to carbon dioxide and water. However, if the needs of the working muscles go beyond the available oxygen resources (under heavy physical exertion), the hypoxia-induced transcription factor-1 (hypoxia inducible transcription factor-1, HIF-1) is activated. This protein switches muscle cells to function in an anaerobic (oxygen-free) mode, which allows you to quickly get a large amount of energy due to incomplete oxidation of glucose, a by-product of which is lactic acid.
Knockout of the negative regulator of the HIF-1 gene led to the appearance of mice with a very small body size and red hyperemic skin. These mice had difficulty maintaining a normal body temperature, since a significant part of their blood entered the skin and cooled quickly. However, the strangest feature of these mice was an abnormally high level of erythropoietin, due to which up to 90% of the blood volume of animals was represented by erythrocytes (normally this figure is 40-50%).
The consistency of the blood of such animals resembled paste, which, accordingly, led to an increase in the size of the heart. The authors suggested that there is their signaling mechanism that ensures the participation of the skin in the regulation of erythropoietin synthesis (90% of this hormone is synthesized by the kidneys, the remaining 10% by Kupffer liver cells).
The involvement of the HIF-1 gene in this was confirmed when creating mice that do not have this gene exclusively in skin cells. In such animals, the concentration of erythropoietin did not increase even when exposed to air with 10% oxygen content on their skin - the same as on the summit of Mount Everest (at sea level, this figure is about 21%). In normal mice, such exposure significantly increased the level of erythropoietin.
The authors found that this effect is achieved by moving a large amount of blood into the skin. Placing a nitroglycerin patch on the skin of animals increased skin blood flow, which significantly increased the production of erythropoietin and, accordingly, erythrocytes.
The participation of the skin in the regulation of erythropoietin levels was confirmed by placing mice in chambers providing different concentrations of oxygen in the inhaled air and in the air surrounding the animal's body. In mice that breathed "Everest air", but with a body in a chamber with a normal oxygen content, the amount of erythropoietin in the blood, of course, increased. But in the mice of the second group, completely sitting in an atmosphere with 10% oxygen, the level of erythropoietin increased more than twice as much.
In the figure from the article by Adam T. Boutin et al. Epidermal Sensing of Oxygen Is Essential for Systemic Hypoxic Response, published in the journal Cell on 04/18/2008, is a scheme for the participation of cutaneous blood flow in the adaptation of the body to acute and chronic hypoxia.Traditionally, it was believed that all reactions to hypoxia are triggered by hypoxia-sensitive nerves and molecules contained in the blood and internal organs, but the results indicate that the skin directly reacts to changes in the oxygen content in the air by changing the strength of blood flow.
The authors also note that people with inflammatory skin diseases, such as psoriasis, often have a low level of red blood cells in the blood, which is not affected by the administration of erythropoietin. In the future, they plan to study the mechanisms of anemia associated with inflammatory skin diseases on one of the lines of genetically modified mice they created.
The results also explain the tradition practiced in some regions of Nepal, India and Pakistan, whose residents rub newborns with mustard oil, which is a weak irritant that stimulates skin blood flow. The authors tried this technique on mice and found that rubbing mustard oil really stimulates the synthesis of erythropoietin. This effect is much less pronounced than the effect of sticking a nitroglycerin patch, but its potential benefits for the body are hard to deny.
The production of erythropoietin, used to treat various diseases characterized by a decrease in the number of red blood cells, is a significant sector of the pharmacological market, therefore, the ability to control the number of red blood cells by changing the activity of the cutaneous blood flow can have significant consequences in all respects. However, the acceptability of this method for human treatment has yet to be determined.
Portal "Eternal youth" www.vechnayamolodost.ru based on the materials of ScienceDaily
22.04.2008