New target for muscle stem cell regeneration found

Investigators at NYU Langone Medical Center and the University of Colorado at Boulder have identified a gene in mice that triggers the repair of injured muscle by adult stem cells. The findings could help develop new therapies for muscular dystrophy and other genetic muscle disorders.

Specifically, the team found that the AUF1 gene appears to play a crucial role in replacing injured muscle tissue throughout life and successfully treated mice lacking the gene with a drug to boost its activity. The work builds on previous research that has found a correlation between changes in the action of AUF1 to human muscle disease.

Some tissues have reserves of specialized stem cells that exist into adulthood. These stem cells are maintained for the purpose of eventually maturing into replacement cells to regenerate those that may become damaged throughout life.

Defects in this muscle cell regeneration process are found in more than 30 genetic neuromuscular disorders--including Duchenne muscular dystrophy, limb girdle muscular dystrophy and sarcopenia--and cause muscles to weaken or waste away.

When healthy skeletal muscle is injured, muscle stem cells receive a signal that triggers a tissue repair process. Researchers found that this process is controlled by the AUF1 gene through a protein encoded by the gene known as MMP9 that acts as a “master regulator” switch of adult muscle regeneration. This enzyme breaks down other proteins and thus regulates their levels of expression.

Researchers engineered mice to lack the AUF1 gene and observed increased MMP9 activity and reduced stem cell-driven repair compared to normal mice. The missing gene resulted in self-sabotage in the mice; groups of stem cells responsible for normal repair muscle instead caused a breakdown in skeletal muscle in the mice.

Investigators then treated AUF1 knockout mice with a cancer drug that blocks MMP9 activity and found that the drug restored normal muscle stem cell function and muscle regeneration. The findings point to a possible new way to treat a variety of muscle disorders using a repurposed drug.

The results, which were published in the journal Cell Reports, also suggest that the AUF1 gene is linked to sarcopenia, the natural loss of muscle tissues with age.

"This provides a potential path to clinical treatments that accelerate muscle regeneration following traumatic injury, or in patients with certain types of adult onset muscular dystrophy," said Robert Schneider, the Albert B. Sabin Professor of Microbiology and Molecular Pathogenesis and associate dean for the Office of Therapeutics Alliances at NYU Langone, in a university statement.

- read the study in Cell Reports