Overlooked Gene Influences Muscle Regeneration

The AUF1 gene is an important controller of muscle stem cells' ability to regenerate new muscle, and could represent a potential sarcopenia therapy

New research has identified AUF1 as a potential regulator of muscle regeneration; building on previous findings that alterations in levels of the AUF1 protein are linked to degenerative muscle diseases.

"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. 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"What does AUF1 do?

Genes are translated into mRNA, which is then read and made into a protein product by the ribosome. Controlling the stability of amount of viable mRNA therefore impacts on gene expression, and AUF1 plays an important role in the targeted destuction of mRNA in response to particular signals. In response to skeletal muscle injury and depletion, AUF1 produces a crucial regulatory protein that alters mRNA levels of a number of genes; boosting regeneration to form new muscle tissue. One of the genes affected by AUF1 is MMP9, which is a metallopeptidase that degrades a number of proteins found in the extracellular matrix (such as collagen).

The structure of MMP9

When researchers engineered mice that were missing this AUF1 gene, they showed increased MMP9 activity and a diminished muscle repair response - 'corrupting' muscle stem cell niches and preventing regeneration. This led to a progressive loss of muscle mass.

There's hope

While AUF1 may be involved in the aging process in some manner, when mice lacking the gene were given a drug that targets and blocks harmful MMP9 activity, muscle repair was apparently restored. This means that drugs inhibiting or blocking MMP9 may possible help restore muscle mass, and potentially represent a new therapeutic target for sarcopenia.

"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. It was once thought that AUF1 did no more than tag mRNAs that were not needed so they could be disposed of, a utilitarian protein of little interest. To the contrary, our results suggest that AUF1 has evolved to be a key regulator of stem cell fate and the related regenerative ability of adult tissues"