Viruses are notorious for their ability to cause disease, making us weak and infirm, but their close relationship with human biology is much less known. Retroviruses, which insert their genetic material into our genomes to copy themselves, leave behind genes that help our immune system work and shape the development of embryos and placenta.
Scientists posted an article in PLOS Genetics in which they reported that syncytin, a viral protein that promotes placenta formation, also increases muscle mass in male mice. These findings may partly explain a longstanding mystery in biology: why males of many mammalian species tend to be more muscular than females.
“As soon as I read this, my mind began to sketch possible consequences,” says evolutionary biologist Aris Katsurakis of the University of Oxford, UK.
Viral legacy
About 8% of the 3 billion pairs A, T, G, and C that make up our DNA are viral detritus. Many of these viral remains have become useless junk, but not all, as the discoveries made over the past 15 years show.
In 2000, scientists discovered that syncytin, a protein that promotes placenta formation, was actually a viral protein that humans later "borrowed." Initially, this viral protein allowed the retrovirus to fuse with host cells, depositing its genome in a safe haven of cytoplasm. Syncytin is slightly different from the ancient form of this protein; it directs certain placental cells to fuse with cells in the mother's mother to form the outer layer of the placenta.
Subsequent studies have shown that different groups of mammals have different types of syncytin protein, suggesting that mammals have repeatedly borrowed retroviral proteins and repurposed them for placental development.
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“It's scary to think that this cell fusion was prompted by a virus that we acquired 30 million years ago,” says Lars-Inge Larsson, a pathologist at the University of Copenhagen.
Growth factor
A recent study led by virologist Thierry Heidmann of the French National Center for Scientific Research (CNRS) in Villejuif and the Université Paris-Sud in Orsay looked at what happens when syncytin is removed from the mouse genome. Removal of both copies was fatal, however, removal of syncytin B and the retention of syncytin A resulted in the male offspring being small and frail. These animals weighed 18% less than litters with both syncytin copies.
Scientists originally thought that the loss of syncytin created a damaged placenta that made it difficult for mice to grow before birth. Subsequent discoveries in other laboratories showed that syncytin was active in immune cells and immature muscle cells (myoblasts) as well as in the placenta, so Heidmann revised his hypothesis.
Mature muscle cells, he knew, were formed by the fusion of numerous immature myoblasts. Given that cell fusion is involved in both processes, Heidmann and his colleagues suggested that syncytin may also play a role in them. Further analysis of the previous data showed that the decrease in body weight in male mice without syncytin B was due to a decrease in their muscle mass. Cellular studies showed that the muscles in males without protein had 20% fewer muscle fibers and the number of nuclei in the fibers than the muscles of untouched males.
“We were very, very surprised that the differences were in males, but not in females,” Heidmann says.
Playing with muscles
Subsequent experiments carried out by Heidmann's team aimed to observe mouse myoblasts as they mature into muscle cells and showed that both synticin genes are active in this process, and blocking proteins reduces cell fusion by more than 40%. Cell culture studies in sheep, dogs, and humans have shown similar decreases in myoblast fusion function when scientists blocked synticin activity.
“This is the first powerful indication that retroviral envelope proteins play an important role outside the placenta,” says Cedric Feshot, an evolutionary biologist at the University of Utah in Salt Lake City.
Heidmann emphasizes that synticins are not the only important proteins in muscle fusion and that his group still does not know why these proteins stimulate muscle growth in males but not in females. And given that the synticins in mice were taken from completely different viruses than those in humans, Feshot advises not to assume that they are equally important for the development of human muscles.
Still, he says, it's clear that these viral proteins, scattered throughout our genome, are far more important than anyone would have guessed.
“What we're seeing is probably just the tip of the iceberg,” Feshot says.
ILYA KHEL