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Loss of β1-integrin and Fibronectin Implicated in Muscle Stem Cell Decline

Researchers are making inroads into the biochemistry of age-related stem cell decline in muscles, the tissue most studied in this part of the field. Here, another protein is added to the list of those that change with age and seem to play an important role in this process, given that researchers can use it to restore the loss of muscle regeneration in old animals:

Muscle stem cells are the primary source of muscle regeneration after injury. These specialized adult stem cells lie dormant in the muscle tissue - off to the side of the individual muscle fibers, which is why they were originally dubbed satellite cells. When muscle fibers are damaged, they activate and proliferate. Most of the new cells go on to make new muscle fibers and restore muscle function. Some return to dormancy, which allows the muscle to keep repairing itself over and over again. Researchers determined that the function of integrins (or, more specifically, the protein called β1-integrin) is absolutely crucial for maintaining the cycle of hibernation, activation, proliferation, and then return to hibernation, in muscle stem cells. Integrins are proteins that 'integrate' the outside to the inside of the cell, providing a connection to the immediate external environment, and without them, almost every stage of the regenerative process is disrupted. The team theorized that defects in β1-integrin likely contribute to phenomena like aging, which is associated with reduced muscle stem cell function and decreased quantities of muscle stem cells. This means that healing after injury or surgery is very slow, which can cause a long period of immobility and an accompanying loss of muscle mass.

Researchers determined that the function of β1-integrin is diminished in aged muscle stem cells. Furthermore, when they artificially activated integrin in mice with aged muscles, their regenerative abilities were restored to youthful levels. Importantly, improvement in regeneration, strength, and function were also seen when this treatment was applied to animals with muscular dystrophy, underscoring its potential importance for the treatment of muscle disorders. Muscle stem cells use b1-integrin to interact with many other proteins in the muscle external environment. Among these many proteins, they found a clue that one called fibronectin might be most relevant. They discovered that aged muscles contain substantially reduced levels of fibronectin compared to young muscles. Like b1-integrin, eliminating fibronectin from young muscles makes them appear as if they were old, and restoring fibronectin to aged muscle tissue restores muscle regeneration to youthful levels. Their joint efforts demonstrated a strong link between b1-integrin, fibronectin and muscle stem cell regeneration. "Taken together, our results show that aged muscle stem cells with compromised b1-integrin activity and aged muscles with insufficient amount of fibronectin are both root causes of muscle aging. This makes b1-integrin and fibronectin very promising therapeutic targets."

Link: https://carnegiescience.edu/node/2058

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