How Gut Microbe Symbiosis Helps Squirrels Keep Their Muscles During Hibernation

Squirrels prepare for their winter by gorging on food at the end of the summer. They need to store a lot of fat in order to be able to use it all winter.

The ground squirrel enters a state called torpor. Their metabolism drops to as low as 1 percent of summer levels and their body temperature plummets to close to freezing. The animal needs a lot of energy to stay alive.

That long fast means there is no new input of the body's tissues and organs. This is a problem for muscles.

Long periods of bed rest can lead to muscle wasting in people. There is little muscle wasting in animals that are in the middle of the night. Despite being inactive for six to nine months, they still retain their muscle mass and performance, which helps ensure a successful breeding season come spring.

Hibernators pull this off. It has been a real head-scratcher for biologists for decades. Our research team looked into the question of how the animals might be getting help from the microbes in their guts.

A nitrogen-recycling system

We knew from previous research that a hibernator's gastrointestinal system undergoes dramatic changes during the summer and winter.

The animals who are fast all winter are not the only ones. We found out that winter fast changes the gut microbiome.

We wondered if gut microbes could play a role in the process of hibernation. Is there a way to keep muscles and other tissues working when animals are not eating?

A clever trick in ruminant animals, such as cattle, that helps them survive during times when the diet is low or the need for high levels of proteins is high, was previously identified by biologists.

The urea nitrogen salvage process allows the animal to get rid of nitrogen that would otherwise end up in urine. The urea is retained in the body and used to make the building blocks of the proteins.

This operation is dependent on the breakdown of urea molecule to release nitrogen. The chemical breakdown of urea requires urease, which animals do not produce. How does a cow get that nitrogen out of urea?

It turns out that certain organisms in the guts of animals can do that. They make the urease enzyme and use it to split urea molecule into urea and ammonia molecule. Microbes use ammonia to make newProtein.

The ruminant digestive system has quirks that allow it to benefit from this process. It was not clear if the urea nitrogen could make its way into the animals' bodies.

We were challenged to demonstrate urea nitrogen recycling in hibernators and show that it was helpful to them longer.

Our experimental game plan

Experiments were designed using the 13-lined ground squirrel.

We injected the urea molecule into the squirrel's bloodstream and replaced the two nitrogen atoms with a heavier form of nitrogen that occurs only in tiny amounts in the body.

We were able to follow the heavier nitrogen atoms as the injected urea moved from the blood into the gut, and then as the urease broke down into its component parts.

We knew that urea was the main source of nitrogen and that the gut microbes had to get it back into the animals.

To confirm that the microbes were doing the nitrogen recycling, we compared squirrels that had normal gut microbiomes to squirrels that didn't.

Some animals were treated with antibiotics in the summer, early winter, and late winter to reduce their gut microbes.

We found evidence of urea nitrogen salvage at each step of the process we tested in squirrels. Squirrels with low microbiomes had less urea nitrogen salvaged.

The process was dependent on the gut microbes being able to break down urea and liberate its nitrogen in the hibernators' guts. The most urea nitrogen was found in the muscles and the liver during the late winter.

The ground squirrel contributes to this remarkable symbiosis.

Their gut cells increase production of urea transporters. The urea is shepherded from the blood into the gut by the microbes that contain urease.

This helps the animal by making it easier to get to the gut.

We found out that it wasn't just squirrels who benefited from the process. During the long winter fast, urea nitrogen is an important building block for both parties and the microbes were using it to build their own proteins.

Could this kind of symbiosis help humans?

There are potential clinical applications for this example of hibernator-microbe symbiosis.

Undernourishment, which affects millions of people globally, leads to a decline in muscle mass and compromises health.

People are more susceptible to injury due to sarcopenia, which is muscle wasting that is a natural part of aging. A detailed understanding of how the hibernator nitrogen salvage system is most effective when the risk of tissue loss and muscle wasting is greatest could lead to new therapies.

In human spaceflight, crew members experience high rates of muscle atrophy because of a microgravity-caused suppression of muscle protein synthesis.

The extensive exercise regime that astronauts undertake is insufficient. The process we have observed in hibernators is similar to the one we have seen in a countermeasure.

These applications are a long way from being delivered. In the 1990s, studies showed that humans can recycle small amounts of urea nitrogen with the help of their gut microbes. The necessary machinery is in place, it just needs to be adjusted.

Hannah V. Carey and Matthew Regan are both professors at the University of Wisconsin-Madison.

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