Key News in Family Medicine April 17, 2019 (2 of 2)

In our muscles are stem cells, invisible motors that stimulate tissue growth and repair. Understanding the signal (s) that direct muscle stem cells into action may reveal new ways to promote muscle growth. However, these mechanisms are poorly understood.

Scientists at Sanford Burnham Prebys have discovered a molecular signaling pathway that combines the proteins Stat3 and Fam3a, which governs how muscle stem cells decide to self-renew or differentiate. This idea could lead to muscle building therapies for muscular dystrophies muscular decline. The study was published in Nature Communications.

"Muscle stem cells can" burn out "by trying to regenerate tissues during the natural aging process or because of a chronic muscle disease," said Alessandra Sacco, PhD, senior author of the journal and Associate Professor, Development, Aging and Regeneration Program at Sanford Burnham Prebys. "We believe we have found promising drug targets that cause muscle stem cells to" make the right decision "and stimulate muscle repair, potentially contributing to muscle tissue regeneration and maintenance in chronic conditions such as muscular dystrophy and aging. "

Muscle wasting occurs as part of the natural aging process, called sarcopenia, or because of genetic diseases such as muscular dystrophy. Sarcopenia affects nearly 10% of adults over 50 and nearly half of 80 years. This disease causes a loss of autonomy and contributes to falls, one of the leading causes of accidental death in people 65 years and older. Muscular dystrophies are a group of more than 30 genetic diseases characterized by progressive muscular weakness and degeneration. A cure does not exist.

Muscle stem cells choose between two fates during their lifetime: either differentiate into adult muscle cells or renew themselves to reconstitute the stem cell population. The accumulated evidence shows that mitochondrial respiration (cellular respiration) is a key switch that causes muscle stem cells to differentiate, energy-intensive processes, instead of self-renewing.

In this study, scientists used mouse models to demonstrate that Stat3 promotes mitochondrial respiration. Because Stat3 regulates many cellular processes, scientists have combed genes expressed during muscle growth to find additional Stat3-regulated proteins that could serve as more specific targets.

These efforts made it possible to discover the Fam3a protein. Further work, including the generation of a mouse model and cell lines lacking Fam3a, has shown that the protein is necessary for differentiation of muscle stem cells and muscle growth. The researchers also showed that Fam3a is secreted by muscle cells during muscle repair and that protein treatment, restored mitochondrial respiration and stem cell differentiation in Stat3-free muscle stem cells, demonstrates the essential role of Fam3a in the determining the fate of muscle stem cells.

"As the number of people over the age of 65 increases with the aging of the baby boomer generation, it is important not only to extend the life span, but also the life expectancy – the years in which we can stay healthy and active, "says David Sala, PhD, the first author of the article and postdoctoral researcher at Sacco Lab. "The ability to stimulate and maintain muscle tissue function can help more people lead active and independent lives. The results of our research may also find applications for muscle disorders, such as muscular dystrophy. "

Scientists are already conducting preclinical studies to validate Fam3a as a therapeutic target. They also hope that their results could be applied to stem cells that differentiate to create other tissues, which could help treat other degenerative tissue diseases.