On the way to a pill for "physical education on the couch"
Geneticists have replaced exercise with a drug
Denis Strigun, Naked Science
A group of scientists from the USA, Switzerland and Australia, using the PPARδ receptor agonist, endurobol, managed to trace the molecular mechanism of artificial increase in physical endurance.
An important condition for the growth of physical endurance is overcoming the "marathon wall" – the threshold of carbohydrate depletion due to the retention of glycogen in the muscles and liver. At the molecular level, this is due to an increase in the capacity of mitochondria and the conversion of glycolytic (fast) muscle fibers into oxidative (slow) ones through the AMPK-PGC1a signaling pathway, as well as the oxidation of fatty acids. Since both processes are supposed to increase productivity and reduce the body's dependence on glucose, their stimulation is considered as a way to support athletes. However, the mechanism of such metabolic changes and their relationship with endurance have not been sufficiently studied.
In 2015, American scientists Weiwei Fan and Ronald M. Evans It was found that delta receptors activated by peroxisomal proliferators (PPARδ) can act as a key regulator of fatty acid oxidation in muscles. Overexpression of this type of receptors stimulated the oxidation of fatty acids and the formation of oxidative fibers in genetically modified mice, which increased their endurance, insulin sensitivity and resistance to obesity. Similar results were shown by the compound GW1516 (GW), or endurobol, but in this case the endurance of wild animals increased only under the condition of physical exercise.
GW is an agonist of PPARδ, the development of which stopped in the early 2000s. Tests on rats have shown that the drug has a high carcinogenicity. Subsequently, metabolites of the substance were found in samples of a number of professional athletes.
In a new paper (Fan et al., PPARδ Promotes Running Endurance by Preserving Glucose) published in the journal Cell Metabolism, the authors included GW in the diet of individuals leading a sedentary lifestyle for a longer time (eight weeks instead of four). After that, the animals were placed on a treadmill and carbohydrate depletion was assessed by blood glucose levels. According to the analysis, the drug increased the physical endurance of the experimental group by more than half: by the time glucose dropped to 70 milligrams per deciliter, they could run for up to 270 minutes versus 160 minutes in the control group. To find out the molecular mechanism of such changes, scientists analyzed the expression of genes in the muscles of mice. This made it possible to identify 975 genes whose activity changed after processing.
The proposed mechanism of metabolic changes regulated by PPARδ after exercise (top) or through ligands (bottom). Glucose is indicated in yellow, fatty acids are indicated in green. A drawing from an article in Cell Metabolism.
Approximately half (457 units) of the genes were targeted for PPARδ and were associated with fat burning (their expression increased) or the destruction of carbohydrates (their expression decreased). According to the team, this indicates that the PPARδ pathway appears to prevent carbohydrate depletion in favor of adipose tissue by trapping glucose, which is needed by the brain, in the body. Thus, fat burning is not so much a stimulant of endurance as a compensatory mechanism. It is noteworthy that the muscles of mice treated with the drug did not have specific physiological changes characteristic of loads: the growth of blood vessels and additional mitochondria.
"Physical exercise activates PPARδ, but our work shows that you can do the same without mechanical impact. In other words, it is possible to increase endurance to a comparable level without physical exertion," Weiwei Feng said (in a press release from the Salk Institute "Exercise-in-a-pill" boosts athletic endurance by 70 percent – VM). He added that pharmaceutical companies were interested in the discovery: the identified mechanism can form the basis of drugs for patients with type 2 diabetes and those suffering from obesity.
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10.05.2017