Expression of the STAT3 gene influences a number of vital cellular processes, such as mitochondrial activity, cellular differentiation, and cellular proliferation. Researchers have investigated its activity in the context of spurring greater regenerative activity in heart muscles, for example. Arguably this is a good example of a regulatory gene that is involved in too many processes to make it a good target for therapeutics, however. More specific, lower-level mechanisms for specific desired goals would be helpful. That requires slow and costly investigative work, however, picking apart the relationships between proteins and their roles.
Researchers have uncovered a molecular signaling pathway involving Stat3 and Fam3a proteins that regulates how muscle stem cells decide whether to self-renew or differentiate - an insight that could lead to muscle-boosting therapeutics for muscular dystrophies or age-related muscle decline. "Muscle stem cells can 'burn out' trying to regenerate tissue during the natural aging process or due to chronic muscle disease. We believe we have found promising drug targets that direct muscle stem cells to 'make the right decision' and stimulate muscle repair, potentially helping muscle tissue regeneration and maintaining tissue function in chronic conditions such as muscular dystrophy and aging."
Muscle wasting occurs as part of the natural aging process, called sarcopenia, or due to genetic diseases such as muscular dystrophy. Sarcopenia affects nearly 10 percent of adults over the age of 50 and nearly half of individuals in their 80s. Muscle stem cells select between two fates over a person's lifetime: Either differentiate to become adult muscle cells or self-renew to replenish the stem cell population. Accumulating evidence shows that mitochondrial respiration is a key switch that drives muscle stem cells to differentiate, an energy-intensive process, instead of self-renew.
In the study, the scientists used mouse models to demonstrate that Stat3 promotes mitochondrial respiration. Because Stat3 regulates many cellular processes, the scientists combed through genes expressed during muscle growth to find additional proteins regulated by Stat3 that might serve as more specific targets. These efforts uncovered the protein Fam3a. Further work conducted, including generating a mouse model and cell lines that lack Fam3a, demonstrated that the protein is required for muscle stem cell differentiation and muscle growth. The researchers also showed that Fam3a is secreted by muscle cells during muscle repair, and treatment with the protein restored mitochondrial respiration and stem cell differentiation in muscle stem cells that lacked Stat3 - all demonstrating the integral role of Fam3a in determining muscle stem cells' fate.