The researchers studied muscle from mice with the same mutation in the ACVR1 gene that people with FOP have. They focused on two specific types of muscle tissue stem cells: fibro-adipogenetic progenitors (FAPs) and muscle stem cells (MuSCs). Typically, muscle injury repair requires a careful balance of these two cell types. Injured tissue responds by an expansion of FAP cells, which are assigned to recruit muscle stem cells that will regenerate the damaged muscle tissue. After about three days, FAPs die off, their job done. At the same time, MuSCs transition toward a more mature, differentiated state, called muscle fiber, essential to organized movement of our muscles.
In the mice with the ACVR1 mutation that Mourkioti, Shore, and their co-authors studied, apoptosis – the process through which FAP cells die as a part of proper muscle regeneration – had slowed significantly, leading to a high presence of FAPs past their usual lifespan. This altered their balance with the MuSCs. The injured tissue also showed a diminished capacity for muscle stem cell maturation and, as a result, muscle fibers were considerably smaller in mice carrying the ACVR1 mutation compared to muscle fibers in mice without the mutation.
“The prolonged persistence of diseased FAPs within the regenerating muscle contributes to the altered muscle environment in FOP, which reduces muscle regeneration and allows the over-abundant FAPs to contribute to the formation of extra-skeletal bone,” Mourkioti said. “This provides a completely new perspective on how excess extra-skeletal bone is formed – and how it could be prevented.”
The current targets for treating FOP focus on slowing extra-skeletal bone growth. This research may provide a pivotal new direction. “We propose that therapeutic interventions should consider promoting the regenerating potential of muscles together with the reduction of ectopic bone formation,” Shore and Mourkioti wrote. “By addressing both stem cell populations and their roles in the origin of FOP, there is the possibility of greatly enhanced therapies.”
The discovery was published in NPJ Regenerative Medicine.
Source: Perelman School of Medicine at the University of Pennsylvania
Source: Healthcare in Europe
