How do some animals get through hibernation without losing a lot of muscle mass? Apparently, urea-recycling gut microbes help them, shows a study of North American ground squirrels. The nitrogen-rich degradation product, which normally ends up in the urine, is therefore increasingly released into the intestine. There, certain bacteria convert the urea into nitrogen compounds that the animals can absorb as nutrients. These protein building blocks can then curb the breakdown of muscle tissue during the inactive period. As the researchers explain, this concept could have potential for medicine and even for space travel.
It is well known that some mammals sleep through the months of barren winter. Although their metabolism is severely reduced, a basic supply of certain substances is still necessary. They are mobilized from fat, but also from muscle tissue. However, the corresponding degradation – as well as protein metabolism in general – produces the nitrogen compound ammonium, which is then further converted into urea. Because high levels of this substance are toxic to neurons, urea is normally excreted in the urine. As a result of the process, the body constantly loses usable nitrogen compounds that have to be supplied to build up proteins.
Since there is often no supply of food during hibernation, the animals should actually experience severe muscle atrophy. But surprisingly, that’s not the case: many hibernators are able to keep their muscle mass stable. There were already assumptions that this is possible through recycling processes of urea with the help of intestinal bacteria. To prove this clearly, the researchers led by Matthew Regan from the University of Wisconsin-Madison carried out experiments with thirteen-striped squirrels (Ictidomys tridecemlineatus). These small mammals, which are widespread in North America, hibernate in their underground burrows for up to seven months.
On the trail of labeled urea
For the study, the researchers injected doubly labeled urea into their test animals at various stages of hibernation. That means: In contrast to the normal substance, this version consisted of isotopes of nitrogen and carbon. These special components allowed the scientists to trace the carbon and nitrogen derived from the tagged urea through the various steps of the putative urea-nitrogen recovery process.
With their analytical methods, the researchers were able to show that the urea is released from the blood of the animals into their intestines. There it is then picked up by special bacteria that can metabolize it – which is not possible for mammals. Because only microbes form so-called ureases – enzymes that can break down the urea into usable components. The bacteria then convert these into amino acids, which they use themselves. However, a significant part is apparently also taken up by the ground squirrels in the form of usable nitrogen compounds: The researchers were finally able to detect the marked substances in the liver and muscle tissue of the animals.
Refined recycling
The principle is now clearly evident: Urea, which comes from the animal’s protein metabolism, can again be used to build up and maintain muscle mass via the function of the intestinal bacteria. Tests with squirrels, in which the researchers had impaired the natural intestinal flora by administering antibiotics, again showed the decisive role of the microbes particularly clearly: in these test animals, hardly any components of the labeled urea ended up in the muscle tissue.
The investigations also showed that the incorporation of urea nitrogen in the tissue proteins of the squirrels was most intensive in late winter. Presumably, this serves to strengthen the early awakening, the scientists explain. This is important because the strenuous mating season for thirteen-striped squirrels begins right after hibernation. “Urea-nitrogen recovery could therefore improve the overall biological fitness of the animals,” says Regan.
Potential for medicine and aerospace
In addition to the biological significance, the possible use of the findings for humans is also an important topic for the scientist. As he explains, the animal concept could have potential for medicine and space travel. Muscle atrophy is an important health problem in older people, but it also occurs with prolonged inactivity and when staying in space. “The mechanisms that mammals like the thirteen-striped squirrel have naturally evolved to maintain protein balance in their own nitrogen-limited situations may provide strategies for maximizing the health of other nitrogen-limited creatures — including humans,” says Regan. Specifically, according to him, a probiotic pill would be conceivable that people could take to promote an intestinal microbiome that can ensure an optimized supply of nitrogen compounds beyond nutrition.
As for spaceflight, Regan says, “Since we already know which muscle proteins are suppressed during spaceflight, we can now compare those proteins to those that are boosted by urea-nitrogen reclamation during hibernation,” Regan says. Potential to increase the astronauts’ muscle protein synthesis may become apparent, the argument goes. In conclusion, however, the scientist emphasizes: “All these applications appear theoretically possible, but are still a long way from being implemented, and a lot of work is still required to transfer this mechanism safely and effectively to humans,” Regan points out.
Source: University of Montreal, University of Wisconsin-Madison, professional article: Science, doi: 10.1126/science.abh2950