New gene targets for muscle regeneration
New research has suggested that the mRNA-decay protein AUF1 is essential to determining whether stem cell pools retain the ability to regenerate muscle after injury and during aging, opening up avenues to accelerating muscle regeneration.
The study, performed by researchers at NYU Langone Medical Center (NY, USA) and the University of Colorado at Boulder (CO, USA), examined AUF1, a protein that was previously thought to be of little interest, yet that has been linked in the past to some muscle diseases.
The researchers utilized auf1−/− mice, which exhibited accelerated skeletal muscle wasting with age, impaired muscle repair after injury, and reduced stem-cell-driven repair. Further investigation demonstrated that one of the mRNA targets of AUF1 is MMP9, a regulator of adult muscle regeneration. The lack of AUF1 resulted in increased levels of MMP9, which affects the pools of stem cells that would normally repair muscle and destroys the niche where they await activation. Blocking MMP9 activity restored muscle stem cell function and muscle regeneration, an effect achieved by repurposing a cancer drug that blocks MMP9.
“This work places the origin of certain muscle diseases squarely within muscle stem cells, and shows that AUF1 is a vital controller of adult muscle stem cell fate,” commented Robert Schneider (NYU Langone), corresponding author of the study. “The stem cell supply is remarkably depleted when the AUF1 signal is defective, leaving muscles to deteriorate a little more each time repair fails after an injury.”
“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,” he continued. “We may be able to treat a variety of degenerative diseases by enhancing resident tissue stem cells through targeting MMP9 and its pathways, even those with normal AUF1.”
— Written by Francesca Lake
Sources: Chenette DM, Cadwallader AB, Antwine TL et al. Targeted mRNA decay by RNA binding protein AUF1 regulates adult muscle stem cell fate, promoting skeletal muscle integrity. Cell Rep. doi: 10.1016/j.celrep.2016.06.095 (In Press) (2016); http://nyulangone.org/press-releases/gene-found-to-control-regeneration-of-injured-muscle-by-adult-stem-cells