The debt we owe to retroviruses

It was already known that genes inherited from ancient retroviruses are essential to the formation of the placenta in mammals. Now it appears that genes with retrovirus origins may also be responsible for the more developed muscle mass seen in males.

Retroviruses carry proteins on their surface that are able to mediate fusion of their envelope with the membrane of a target cell. Once released inside that cell, their genetic material becomes integrated in the host’s chromosomes. In the rare cases where the infected cell is involved in reproduction, the viral genes may be transmitted to progeny. Nearly 8% of the mammalian genome is made up of vestiges of retroviruses, or “endogenous” retroviruses. Most of them are inactive, but some remain capable of producing proteins. This is the case of syncytins, proteins that are present in all mammals and encoded by genes inherited from retroviruses captured by their ancestors. Five years ago it was discovered that syncytins contribute to formation of the placenta in mammals.

New research has revealed an additional and unexpected effect of these proteins: they endow males with more muscle mass than females. Like the syncytiotrophoblast, muscle mass develops from fused stem cells. In the genetically-modified male mice, these fibers were 20% smaller and displayed 20% fewer nuclei than in standard males; they were then similar to those seen in females, as was their total muscle mass. It therefore appears that the inactivation of syncytins leads to a fusion deficit during muscle growth, but only in males. Researchers observed the same phenomenon in the case of muscle regeneration following a lesion: the male mice incapable of producing syncytins experienced less effective regeneration than the other males, but it was comparable to that seen in females. Furthermore, the regenerating muscle fibers produced syncytin – once again, only in males.

If this discovery were to be confirmed in other mammals, it might account for the muscle dimorphism observed between males and females, a difference that is not seen so systematically in egg laying animals. By cultivating muscle stem cells from different mammalian species (mouse, sheep, dog, human), the scientists have advanced some way along the path: they indeed showed that syncytins contributed to the formation of muscle fibers in all the species tested. It is now necessary to demonstrate whether, in these species as well, the action of syncytins is also male-specific.

 

Genetic Evidence That Captured Retroviral Envelope syncytins Contribute to Myoblast Fusion and Muscle Sexual Dimorphism in Mice. (2016) PLoS Genet 12(9): e1006289. doi: 10.1371/journal.pgen.1006289
Syncytins are envelope genes from endogenous retroviruses, “captured” for a role in placentation. They mediate cell-cell fusion, resulting in the formation of a syncytium (the syncytiotrophoblast) at the fetomaternal interface. These genes have been found in all placental mammals in which they have been searched for. Cell-cell fusion is also pivotal for muscle fiber formation and repair, where the myotubes are formed from the fusion of mononucleated myoblasts into large multinucleated structures. Here we show, taking advantage of mice knocked out for syncytins, that these captured genes contribute to myoblast fusion, with a >20% reduction in muscle mass, mean muscle fiber area and number of nuclei per fiber in knocked out mice for one of the two murine syncytin genes. Remarkably, this reduction is only observed in males, which subsequently show muscle quantitative traits more similar to those of females. In addition, we show that syncytins also contribute to muscle repair after cardiotoxin-induced injury, with again a male-specific effect on the rate and extent of regeneration. Finally, ex vivo experiments carried out on murine myoblasts demonstrate the direct involvement of syncytins in fusion, with a >40% reduction in fusion index upon addition of siRNA against both syncytins. Importantly, similar effects are observed with primary myoblasts from sheep, dog and human, with a 20–40% reduction upon addition of siRNA against the corresponding syncytins. Altogether, these results show a direct contribution of the fusogenic syncytins to myogenesis, with a demonstrated male-dependence of the effect in mice, suggesting that these captured genes could be responsible for the muscle sexual dimorphism observed in placental mammals.

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