Timing Is Everything: Enzyme inhibitor first encourages, then blocks cells from becoming muscle (Muscle; Chromatin)

Yoda wields a mean light saber, but even a Jedi gets weak with age. Scientists hope to rekindle the force in aging muscle by sending more cells to its aid. A new study supports the existence of a regulatory toggle that directs precursor cells down a muscle-bound path and suggests a target for drugs that promote the process. Muscle tissue develops from cells called myoblasts, which can either divide to make more myoblasts or convert into full-blown muscle cells. Previous work suggested that some enzymes that add acetyl groups to proteins encourage specialization, whereas several that remove acetyl groups thwart it. But the effects of the acetyltransferases and deacetylases implicated in muscle formation aren't straightforward: Deacetylase inhibitors (DIs) would be expected to instigate muscle cell formation, but instead they inhibit it. Last year, Sartorelli and colleagues showed that a deacetylase called HDAC1 binds to a protein called MyoD when precursor cells are dividing; the duo shuts off muscle-specific genes, which prevents myoblasts from specializing. When other cues cause the muscle-formation phase to begin, HDAC1 drops MyoD and picks up a different partner, RB. The swap allows the HDAC1-RB team to quell cell-division genes. In the new study, the group used cultured human and mouse myoblasts to test whether HDAC1's fickle behavior explained the effect of DIs. The researchers exposed cells to DIs, either while they were dividing or after they had been put in a medium that spurs myoblasts to become muscle cells. Compared with untreated cells, those exposed to DIs while dividing were more likely to express muscle genes and to assume shapes characteristic of muscle cells. Cells exposed to inhibitors for the first time in the medium, on the other hand, were less likely to show signs of becoming muscle cells. The results suggest that when added to dividing cells, DIs relieve the HDAC1-MyoD block on muscle genes that keeps myoblasts unspecialized. When cells have already embarked on the muscle cell pathway, DIs instead thwart deacetylase pairs that are active at that stage--such as the HDAC1-RB couple that normally dampens cell-division genes--and thus inhibit cells from becoming muscle. The results suggest that under the right circumstances, blocking deacetylases might nudge cells to specialize, says stem cell biologist Michael Rudnicki of the Ottawa Health Research Institute in Canada, although the inhibitors used in this study are likely too toxic for therapeutic purposes in humans. The team is planning to test whether cells induced to form muscle can restore muscle function when transplanted into a mouse model of muscular dystrophy. If that work pans out, it could help keep us as powerful during advancing years as a mythological knight. --R. John Davenport S. Iezzi, G. Cossu, C. Nervi, V. Sartorelli, P. L. Puri, Stage-specific modulation of skeletal myogenesis by inhibitors of nuclear deacetylases. Proc. Natl. Acad. Sci. U.S.A. 99 , 7757-7762 (2002). [Abstract] [Full Text]

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