Some bears have a brilliant strategy for getting through winter: staying in bed.
Not all bears hibernate, of course, and even those who do may technically be in a state called torpor, not true hibernation. Nonetheless, a bear's long winter nap can spare her from life-threatening cold and hunger until the weather warms up.
Bears fatten up before winter arrives, then reduce their heart rate and metabolism during hibernation, letting them sleep through the worst of winter without needing to worry about food. But since hibernation can involve barely moving for months, how do bears avoid muscle atrophy during such a sedentary period?
That's what a team of researchers sought to learn with a new study on hibernating grizzly bears, published in the journal Scientific Reports. Aside from shedding light on bears themselves, this research could also benefit our species, the researchers say, by helping us limit the muscle weakness that often occurs when people are bedridden or otherwise immobilized for stretches of time.
"Muscle atrophy is a real human problem that occurs in many circumstances. We are still not very good at preventing it," says lead author Douaa Mugahid, a postdoctoral researcher at Harvard Medical School, in a statement. "For me, the beauty of our work was to learn how nature has perfected a way to maintain muscle functions under the difficult conditions of hibernation. If we can better understand these strategies, we will be able to develop novel and non-intuitive methods to better prevent and treat muscle atrophy in patients."
Hazards of hibernation
While curling up to sleep all winter may sound nice, a protracted slumber like this would wreak havoc with the human body, Mugahid and her co-authors point out. A person would probably suffer blood clots and psychological effects, they note, along with significant loss of muscle strength due to disuse, similar to what we experience after having a limb in a cast or having to stay in bed for extended periods.
Grizzly bears, however, seem to handle hibernation pretty well. They may be a little sluggish and hungry when they wake up in the spring, but that's about it. In hopes of understanding why, Mugahid and her colleagues studied muscle samples taken from grizzly bears during hibernation as well as more active times of year.
"By combining cutting-edge sequencing techniques with mass spectrometry, we wanted to determine which genes and proteins are upregulated or shut down both during and between the times of hibernation," says Michael Gotthardt, head of the Neuromuscular and Cardiovascular Cell Biology group at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin.
Bear in mind
The experiments revealed proteins that "strongly influence" a bear's amino acid metabolism during hibernation, the researchers report, resulting in higher levels of certain non-essential amino acids (NEAAs) within a bear's muscle cells. The team also compared their findings from bears with data from humans, mice and nematodes.
"In experiments with isolated muscle cells of humans and mice that exhibit muscle atrophy, cell growth could also be stimulated by NEAAs," Gotthardt says. That said, however, earlier clinical studies have shown "that the administration of amino acids in the form of pills or powders is not enough to prevent muscle atrophy in elderly or bedridden people," he adds.
This suggests it's important for the muscle to produce these amino acids itself, he explains, since just ingesting them might not deliver them where they're needed. So, rather than trying to mimic a bear's muscle-protecting technique in the form of pills, a better therapy for humans might involve trying to induce human muscle tissue to make NEAAs on its own. First, though, we need to know how to activate the right metabolic pathways in patients at risk for muscle atrophy.
To figure out which signaling pathways must be activated within the muscle, the researchers compared the activity of genes in grizzly bears with those of humans and mice. The human data came from elderly or bedridden patients, they report, while the mouse data came from mice experiencing muscle atrophy, caused by a plaster cast that reduced movement.
"We wanted to find out which genes are regulated differently between animals that hibernate and those that do not," Gotthardt says.
They found lots of genes matching that description, however, so they needed another plan to narrow down the list of candidates for muscle-atrophy therapy. They conducted more experiments, this time with tiny animals called nematodes. In nematodes, Gotthardt explains, "individual genes can be deactivated relatively easily and one can quickly see what effects this has on muscle growth."
Thanks to those nematodes, the researchers identified several intriguing genes that they now hope to study further. Those genes include Pdk4 and Serpinf1, which are involved in the metabolism of glucose and amino acids, as well as the gene Rora, which helps our bodies develop circadian rhythms.
This is a promising discovery, but as Gotthardt points out, we still need to fully grasp how this works before we can test it in humans. "We will now examine the effects of deactivating these genes," he says. "After all, they are only suitable as therapeutic targets if there are either limited side effects or none at all."