Age-related reactivation of embryonic gene Hoxa9 leads to skeletal muscle aging
Researchers from the Leibniz Institute on Aging (FLI; Jena, Germany) have demonstrated that one of the Hox genes regulating embryogenesis, Hoxa9, is reactivated in old age, to the detriment of skeletal muscle regeneration.
Researchers from the Leibniz Institute on Aging (FLI; Jena, Germany) have demonstrated that one of the Hox genes regulating embryogenesis, Hoxa9, is re-activated in old age and limits the functionality of muscle stem cells, resulting in the lack of skeletal muscle regeneration that occurs in the elderly. The identification of this epigenetically activated gene indicates a novel pathway to target in the development of regenerative therapies against muscle aging.
The Hox family play a hugely important part in regulating embryogenesis, which is a hugely complicated process requiring precise temperospatial organization of a huge number of pathways. Hox genes are rarely found activated after birth, but the team from the FLI identified Hoxa9 as being significantly active in murine muscle stem cells after injury; leading to a decline in the regenerative capacity of skeletal muscle.
This was surprising, it would be logical to assume that a gene involved in development and activated after injury would be beneficial rather than detrimental. Dr Julia von Maltzahn, leading the research group on muscle stem cells at the FLI, explained: “A decline in stem cell functionality leads to an unavoidable decrease in the regenerative capacity of the whole skeletal muscle. With age, this may weaken the muscular strength after injury.”
Professor K Lenhard Rudolph, Scientific Director at the FLI, also commented: “From an evolutionary perspective, Hox-genes are very old. They regulate organ development across almost the entire animal kingdom — from flies up to humans. It is a huge surprise that the faulty re-activation of these genes leads to stem cell aging in muscle. This finding will fundamentally influence our understanding of the courses of aging.”
When the reactivation was chemically inhibited in aging mice, muscle regeneration was improved, suggesting that targeting this gene or pathway may help improve muscle regeneration in the elderly. Next steps include investigating whether the same reactivation process occurs in humans, and then whether it can be inhibited as in the mice. A collaborative study with the Jena Center for Soft Matters (Dr Anja Träger) is aiming to investigate whether a nanoparticle-induced, target-specific inhibition of Hox-genes in muscle stem cells is feasible and, if so, would it be sufficient to improve muscle regeneration and maintenance.
Sources: Schwoerer S, Becker F, Feller C et al. Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals. Nature doi:10.1038/nature20603 (2016) (in press); http://www.leibniz-fli.de/institute/public-relations/detailpage/?tx_news_pi1%5Bnews%5D=3310&cHash=ae73ca113a31518e540f04461d4b95b8