Researchers at the University of Ottawa report they have discovered a unique form of cell communication that controls muscle repair. Their new study in mice and human tissues demonstrates that hyaluronic acid may be the key molecule that manages this fundamental interaction.

The findings are published in the journal Science in a paper titled, “JMJD3 activated hyaluronan synthesis drives muscle regeneration in an inflammatory environment.”

“Muscle stem cells (MuSCs) reside in a specialized niche that ensures their regenerative capacity,” wrote the researchers. “Although we know that innate immune cells infiltrate the niche in response to injury, it remains unclear how MuSCs adapt to this altered environment for initiating repair. Here, we demonstrate that inflammatory cytokine signaling from the regenerative niche impairs the ability of quiescent MuSCs to reenter the cell cycle.”

“When muscles get damaged, it is important for immune cells to quickly enter the tissue and remove the damage before stem cells begin repair,” explained Jeffrey Dilworth, PhD, senior scientist at the Ottawa Hospital and professor at the University of Ottawa and senior author on the study. “Our study shows that muscle stem cells are primed to start repair right away, but the immune cells maintain the stem cells in a resting state while they finish the cleanup job. After about 40 hours, once the cleanup job is finished, an internal alarm goes off in the muscle stem cells that allows them to wake up and start repair.”

The researchers identified that when muscle damage occurs, stem cells start producing and coating themselves with hyaluronic acid. Once the coating gets thick enough, it blocks the sleep signal from the immune cells and causes the muscle stem cells to wake up.

Using mouse and human tissues, Dilworth and his team also discovered how muscle stem cells control the production of hyaluronic acid using epigenetic marks on the Has2 gene.

“Interestingly, aging is associated with chronic inflammation, muscle weakness, and a reduced ability of muscle stem cells to wake up and repair damage,” said lead author Kiran Nakka, PhD, a research associate with Dilworth who conducted this research as part of his postdoctoral studies. “If we could find a way to enhance hyaluronic acid production in the muscle stem cells of older people it might help with muscle repair.”

The authors noted that the regenerative effect of hyaluronic acid seems to depend on it being produced by the muscle stem cells. The team is currently examining if drugs that modify the epigenetics of muscle stem cells could be used to increase their production of hyaluronic acid.

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