Hyaluronic acid, a key substance that promotes muscle regeneration

In a new study published in Science, researchers from the Ottawa Hospital Research Institute (OHRI) revealed a unique form of cell communication that controls muscle repair and demonstrated that hyaluronic acid, a natural substance applied in cosmetics and osteoarthritis injections, is a key molecule to control this basic interaction. The study opens new avenues for promoting muscle regeneration.

After muscle injury, muscle stem cells must coordinate with immune cells in inflamed tissue to ensure effective repair. But how these cells coordinate to ensure efficient removal of dead tissue before making new muscle fibers remains unknown.

Professor Jeffrey Dilworth, corresponding author of the article, said: "When muscle is damaged, it is important for immune cells to rapidly enter the tissue and eliminate the damage before stem cells begin to repair. Our study suggests that muscle stem cells are ready to start repairing immediately, but immune cells maintain stem cells in a resting state when performing clean-up work. About 40 hours later, when the clean-up work is completed, the muscle stem cells issue an internal alarm, 'wake up' and start repairing."

Dr. Dilworth and his team identified hyaluronic acid as a key component of this internal alarm clock, which tells muscle stem cells when to wake up. When muscle damage occurs, stem cells begin to produce hyaluronic acid and coat themselves. Once the covering becomes thick enough, it blocks sleep signals from immune cells and revives muscle stem cells.

Dr. Dilworth and his team also used mouse and human tissue to discover how muscle stem cells use an epigenetic mark on the Has2 gene to control hyaluronic acid production.

Mechanistic studies suggest that inflammatory cytokine signaling from the regenerative niche impairs the ability of resting state muscle stem cells to re-enter the cell cycle. Histone H3K27 demethylase JMJD3 (but not UTX), which overcomes inhibitory inflammatory signals in muscle stem cells by removing the trimethylated H3K27 (H3K27me3) mark on the Has2 locus, initiates hyaluronic acid production, and then establishes an extracellular matrix, which can integrate signals indicating that muscle stem cells exit the resting state. Thus, JMJD3-driven hyaluronan synthesis exerts a pro-regenerative effect, allowing muscle stem cells to adapt to inflammation and initiate muscle repair.

Overall, this study reveals the role of the epigenetic modifying enzyme JMJD3 in guiding muscle stem cells to adapt to the regenerative niche by promoting the expression of the JMJD3 target gene Has2. The resulting hyaluronic acid allows muscle stem cells to integrate pro-regenerative signals from the local environment to facilitate repair of damaged muscles.

"Interestingly, aging is associated with chronic inflammation, muscle weakness, and reduced ability of muscle stem cells to awaken and repair damage," said lead author Dr. Kiran Nakka. "If we can find a way to improve hyaluronic acid production in muscle stem cells of the elderly, it may help muscle repair."

The authors point out that the regenerative effect of hyaluronic acid seems to depend on its production by muscle stem cells. The team is currently investigating whether drugs that alter the epigenetics of muscle stem cells can be used to increase their hyaluronic acid production.

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