With age, the function and regenerative abilities of skeletal muscles decrease. Therefore, the elderly can find it difficult to recover from injury or surgery.
A new study from the laboratory of Chen-Ming Fan from Johns Hopkins University has shown that a protein called β1-integrin is crucial for muscle regeneration. β1-integrin seems to provide a promising target for therapeutic intervention to combat muscle aging or disease.
Muscle stem cells are the primary source of muscle regeneration after muscle injury from exercise, accidents, or surgery. These specialized adult stem cells lie dormant in the muscle tissue, and muscles even have them stored off to the side of the individual muscle fibers. Because of their location, these muscle stem cells are known as muscle “satellite cells.” After damage, these satellite cells awaken and proliferate, and go on to make new muscle fibers and restore muscle function. Some satellite cells return to dormancy, which allows the muscle to keep a reservoir of healing cells that can repair the muscle over and over again. Fan and her colleagues determined that proteins called integrins, and in particular, β1-integrin, are integral for maintaining the cycle of hibernation, activation, proliferation, and then return to hibernation, in muscle stem cells.
Integrins are cell surface proteins that provide tight connections between cells and the immediate external environment.
Without integrins, almost every stage of the regeneration is disrupted. Fan and her group predicted that defects in β1-integrin likely contribute to 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. Inefficient muscular healing in the elderly is a significant clinical problem. Therapeutic approaches would be quite welcome by the aging population and their physicians. One way to improve muscle regeneration would be to stimulate muscle satellite cells in older individuals.
Fan and others determined that β1-integrin function is diminished in aged muscle stem cells. When they artificially activated integrins in aged mice, their regenerative abilities were restored to youthful levels. Improvement in regeneration, strength, and function were also seen when this treatment was applied to animals with muscular dystrophy, which underscores the potential importance of such an approach for the treatment of muscle disorders.
Muscle stem cells use β1-integrin to interact with many other proteins in the external environment of the muscle. Among this forest of proteins in the external environment of the muscle, Fan and her coworkers found one called fibronectin that might be the most relevant. They discovered that aged muscles contain substantially less fibronectin compared to young muscles. Like β1-integrin, eliminating fibronectin from young muscles makes them function as though they were old. However, restoring fibronectin to aged muscle tissue restores muscle regeneration to youthful levels. Fan’s group demonstrated a strong link between β1-integrin, fibronectin and muscle stem cell regeneration.
Taken together, the results show that aged muscle stem cells with compromised β1-integrin activity and aged muscles with insufficient amount of fibronectin both root causes of muscle aging. This makes β1-integrin and fibronectin very promising therapeutic targets.
This work appeared in the following journal: Michelle Rozo et al., “Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice,” Nature Medicine, 2016; DOI: 10.1038/nm.4116.