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Sep 28, 2012

Muscle Aging Linked to Stem Cell Overdrive

  • A protein that drives the generation of new muscle fibers from stem cells during development and after injury paradoxically also appears to be responsible for the gradual decline in our muscles’ ability to repair as we age. In vitro and in vivo studies by scientists at Massachusetts General Hospital (MGH), Kings College London, and Harvard Stem Cell Institute have found that the protein, fibroblast growth factor-2 (fgf2), is naturally overexpressed in aging muscles, and effectively sends muscle stem cells into overdrive, preventing them from replenishing their own populations and reducing their ability to keep muscles in tiptop condition.

    A rare population of muscle stem cells—also called satellite cells—is found in every skeletal muscle. The cells reside in a dormant, or quiescent state, but can be mobilized rapidly to differentiate into new muscle cells following injury, and also generate a replacement pool of stem cells that revert back to a healthy dormant state until next required.

    Initial studies in mice by scientists at MGH showed that the numbers of these dormant satellite cells in muscle decline with age, and the cells also lose markers of quiescence and self-renewal and gain markers of differentiation and apoptosis. In their hunt for factors expressed in the muscle fiber that might trigger this change in satellite cells, they found that fgf2—which is one of the natural triggers for stem cell mobilization and differentiation—are markedly elevated in the niche, or microenvironment, that surrounds stem cells in aging muscle.

    Critically, in vitro and in vivo mouse studies demonstrated that the high levels of fgf2 in aged muscle effectively kicks the stem cells out of their quiescent state and triggers them to proliferate and differentiate, preventing the replenishment of the pool of quiescent stem cells, and effectively leading to a depleted satellite cell population and thus reduced ability of muscle to regenerate.

    Andrew S. Brack, M.D., and colleagues also showed that either blocking fgf2 signaling or chemically inhibiting fgf2 using tamoxifen significantly increased the numbers of satellite cells in aged muscle, and boosted the ability of muscles in old mice to undergo self-repair and regenerate after injury. “To our knowledge, this is the first identification of a ligand that specifically increases within a mammalian aged niche that can promote breaks in quiescence leading to declines in stem cell function and number during homeostasis,” they write in their published paper in Nature, which is titled “The aged niche disrupts muscle stem cell quiescence.”

    Dr. Brack puts the results into the context of an athlete’s training schedule. “Analogous to the importance of recovery for athletes training for a sporting event, we now know that it is essential for adult stem cells to rest between bouts of expenditure. Preventing stem cell recuperation leads to their eventual demise...That makes sense to us as humans, in terms of the need to sleep and to eat a healthy diet, but that the need to rest also plays out at the level of stem cells is quite remarkable.”

    What isn’t yet known is why levels of fgf2 are naturally increased in aged muscle. The MGH and Kings’ College investigators suggest it may be a cell-autonomous response that is trying to keep aging muscle in good condition. Their findings in mice also need to be validated in humans to see if the same mechanism is responsible for stem cell depletion in human muscle fibers, and age-related loss of muscle mass and muscle wastage.

    Even so, states co-author Albert Basson, M.D., at Kings College, the findings open up the possibility that it may one day be possible to develop treatments to rejuvenate old, tired muscles. “If we could do this, we may be able to enable people to live more mobile, independent lives as they age...Preventing or reversing muscle wasting in old age in humans is still a way off, but this study has for the first time revealed a process that could be responsible for age-related muscle wasting.”


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