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by Scott Schrage, University of Nebraska-Lincoln
SEPTEMBER 4, 2019
For millennia, the massive Tibetan mastiff has laid literal claim to the label “top dog.”
The fierce breed, which boasts a lionesque mane and can reach 150 pounds, has long protected Himalayan flocks of sheep from Tibetan wolves and other predators lurking upward of 15,000 feet above sea level—heights no other canine can survive.
Prior research suggests the Tibetan mastiff took an evolutionary shortcut by breeding with the Tibetan wolf, which had already adapted to the altitude by evolving more efficient hemoglobin: the protein that snares oxygen in the bloodstream and distributes it to organs.
The University of Nebraska–Lincoln’s Jay Storz, Tony Signore and colleagues have now determined that sleeping with the enemy granted the Tibetan mastiff a hemoglobin architecture that catches and releases oxygen about 50 percent more efficiently than in other dog breeds. Signore reached the conclusion after testing the Tibetan mastiff hemoglobin against that of multiple domestic breeds, including Storz’s own half-Great Pyrenees, half-Irish wolfhound.
“At altitude, the problem is taking in oxygen, because there’s just less of it,” said Signore, a postdoctoral researcher working in Storz’s lab. “If you think of hemoglobin like an oxygen magnet, this magnet’s just stronger.”
The Nebraska researchers, who collaborated with colleagues at Qinghai University in China, already knew that the Tibetan mastiff’s hemoglobin included changes in two amino acids—slight modifications to the structure of the protein—that are present in the Tibetan wolf but absent in all other dog breeds.
By engineering and then testing hemoglobins that contained both amino acid mutations vs. just one or the other, the team discovered that both mutations are crucial to the adaptive change in hemoglobin performance. When either mutation was absent, the hemoglobin performed no differently than that of other dog breeds.
“There had been no direct evidence documenting that, yes, these two unique mutations have some beneficial physiological effect that is likely to be adaptive at high altitude,” said Storz, professor of biological sciences and author of a recent book on hemoglobin. “What we’ve discovered is one of the reasons why the Tibetan mastiff is so different from other dogs. And that’s because it’s borrowed a few things from Tibetan wolves.”
Those two amino acid mutations originate from a gene segment that the Tibetan wolf passed to the mastiff via cross-breeding. But the new study also suggests that the gene segment itself came from an inactive gene—a so-called pseudo-gene—that lay dormant in the wolf subspecies for probably thousands of years. At some point, the pseudo-gene segment harboring the two mutations was copied and pasted into the corresponding segment of a similar but active gene, which then reformatted the Tibetan wolf’s hemoglobin.
Because those mutations came from an inactive gene—one with no physiological effects on the wolf—they weren’t initially subject to the pressures of natural selection. In this instance, though, the mutations just so happened to improve the oxygen-binding capacity of hemoglobin, raising the Tibetan wolf’s survival odds. That encouraged the passage of the gene segment through subsequent generations of the wolf and, eventually, to the Tibetan mastiff.
“They wouldn’t have conferred any benefit under normal circumstances,” Storz said. “It was just (that) this conversion event occurred in an environmental context where the increase in hemoglobin-oxygen affinity would have been beneficial. So mutations that otherwise would have been either neutral or even detrimental actually had a positive fitness effect.”
Storz said there are few other documented cases where an initially inconsequential or adverse mutation ultimately benefited an organism as its environment changed. And most such cases have involved experimental studies on micro-organisms in the lab.
“This is a nice example of the effect involving vertebrate animals and the natural environment,” he said.
More information: Anthony V Signore et al. Adaptive Changes in Hemoglobin Function in High-Altitude Tibetan Canids Were Derived via Gene Conversion and Introgression, Molecular Biology and Evolution (2019). DOI: 10.1093/molbev/msz097
Journal information: Molecular Biology and Evolution
https://www.youtube.com/watch?v=9DdJhNlM7ao
NEWS RELEASE 30-DEC-2019
Learning from the bears
MAX DELBRÜCK CENTER FOR MOLECULAR MEDICINE IN THE HELMHOLTZ ASSOCIATIONhttps://eurekalert.org/pub_releases/2019-12/mdcf-lft123019.php
Grizzly bears spend many months in hibernation, but their muscles do not suffer from the lack of movement. In the journal “Scientific Reports”, a team led by Michael Gotthardt reports on how they manage to do this. The grizzly bears’ strategy could help prevent muscle atrophy in humans as well.
A grizzly bear only knows three seasons during the year. Its time of activity starts between March and May. Around September the bear begins to eat large quantities of food. And sometime between November and January, it falls into hibernation. From a physiological point of view, this is the strangest time of all. The bear’s metabolism and heart rate drop rapidly. It excretes neither urine nor feces. The amount of nitrogen in the blood increases drastically and the bear becomes resistant to the hormone insulin.
A person could hardly survive this four-month phase in a healthy state. Afterwards, he or she would most likely have to cope with thromboses or psychological changes. Above all, the muscles would suffer from this prolonged period of disuse. Anyone who has ever had an arm or leg in a cast for a few weeks or has had to lie in bed for a long time due to an illness has probably experienced this.
A little sluggish, but otherwise fine
Not so the grizzly bear. In the spring, the bear wakes up from hibernation, perhaps still a bit sluggish at first, but otherwise well. Many scientists have long been interested in the bear’s strategies for adapting to its three seasons.
A team led by Professor Michael Gotthardt, head of the Neuromuscular and Cardiovascular Cell Biology group at the Max Delbrueck Center for Molecular Medicine (MDC) in Berlin, has now investigated how the bear’s muscles manage to survive hibernation virtually unharmed. The scientists from Berlin, Greifswald and the United States were particularly interested in the question of which genes in the bear’s muscle cells are transcribed and converted into proteins, and what effect this has on the cells.
Understanding and copying the tricks of nature
“Muscle atrophy is a real human problem that occurs in many circumstances. We are still not very good at preventing it,” says the lead author of the study, Dr. Douaa Mugahid, once a member of Gotthardt’s research group and now a postdoctoral researcher in the laboratory of Professor Marc Kirschner of the Department of Systems Biology at Harvard Medical School in Boston.
“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,” says Mugahid. “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.”
Gene sequencing and mass spectrometry
To understand the bears’ tricks, the team led by Mugahid and Gotthardt examined muscle samples from grizzly bears both during and between the times of hibernation, which they had received from Washington State University. “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,” explains Gotthardt.
“This task proved to be tricky – because neither the full genome nor the proteome, i.e., the totality of all proteins of the grizzly bear, were known,” says the MDC scientist. In a further step, he and his team compared the findings with observations of humans, mice and nematode worms.
Non-essential amino acids allowed muscle cells to grow
As the researchers reported in the journal “Scientific Reports”, they found proteins in their experiments that strongly influence a bear’s amino acid metabolism during hibernation. As a result, its muscle cells contain higher amounts of certain non-essential amino acids (NEAAs).
“In experiments with isolated muscle cells of humans and mice that exhibit muscle atrophy, cell growth could also be stimulated by NEAAs,” says Gotthardt, adding that “it is known, however, from earlier clinical studies 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.”
“Obviously, it is important for the muscle to produce these amino acids itself – otherwise the amino acids might not reach the places where they are needed,” speculates the MDC scientist. A therapeutic starting point, he says, could be the attempt to induce the human muscle to produce NEAAs itself by activating corresponding metabolic pathways with suitable agents during longer rest periods.
Tissue samples from bedridden patients
In order to find out which signaling pathways need to be activated in the muscle, Gotthardt and his team compared the activity of genes in grizzly bears, humans and mice. The required data came from elderly or bedridden patients and from mice suffering from muscle atrophy – for example, as a result of reduced movement after the application of a plaster cast. “We wanted to find out which genes are regulated differently between animals that hibernate and those that do not,” explains Gotthardt.
However, the scientists came across a whole series of such genes. To narrow down the possible candidates that could prove to be a starting point for muscle atrophy therapy, the team subsequently carried out experiments with nematode worms. “In worms, individual genes can be deactivated relatively easily and one can quickly see what effects this has on muscle growth,” explains Gotthardt.
A gene for circadian rhythms
With the help of these experiments, his team has now found a handful of genes whose influence they hope to further investigate in future experiments with mice. These include the genes Pdk4 and Serpinf1, which are involved in glucose and amino acid metabolism, and the gene Rora, which contributes to the development of circadian rhythms. “We will now examine the effects of deactivating these genes,” says Gotthardt. “After all, they are only suitable as therapeutic targets if there are either limited side effects or none at all.”
Literature
Douaa Mugahid et al. (2019): “Proteomic and Transcriptomic Changes in Hibernating Grizzly Bears Reveal Metabolic and Signaling Pathways that Protect against Muscle Atrophy,” Scientific Reports, DOI: 10.1038/s41598-019-56007-8
Max Delbrueck Center for Molecular Medicine (MDC)
The Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in Berlin in 1992. It is named for the German-American physicist Max Delbrueck, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC’s mission is to study molecular mechanisms in order to understand the origins of disease and thus be able to diagnose, prevent, and fight it better and more effectively. In these efforts the MDC cooperates with Charite – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) as well as with national partners such as the German Center for Cardiovascular Research (DZHK) and numerous international research institutions. More than 1,600 staff and guests from nearly 60 countries work at the MDC, just under 1,300 of them in scientific research. The MDC is funded by the German Federal Ministry of Education and Research (90 percent) and the State of Berlin (10 percent), and is a member of the Helmholtz Association of German Research Centers. http://www. mdc-berlin. de
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