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Scientists Hammer Out Pathway That Promotes Muscle Cell Survival in Mice

Marc Montminy, professor in the Clayton Foundation Laboratories for Peptide Biology, and his colleagues have identified an enzyme that pumps up a cell's ability to maintain healthy muscle and restores normal muscle function in genetically engineered mice with weak muscles. The study, published in Nature Medicine, is the first to explore the part this enzyme, known as salt-inducible kinase-1, or SIK1, plays in a cascade of events triggered by exercise-induced hormones and other signals.

"In addition to muscle, this regulatory circuit is present in brain and heart tissue, where it also seems to control cell survival," said Montminy, senior author of the study. "Potentially, understanding the role of this enzyme in muscle cells may shed light on the underlying mechanisms of many diseases that affect cell survival, such as muscular dystrophy, neurodegenerative diseases, and congestive heart failure."

Montminy's team, led by postdoctoral researcher Rebecca Berdeaux, first became interested in the enzyme when they observed that mice engineered to have a defect in a molecular switch, called cAMP responsive element binding protein (CREB), had hunched backs, muscle wasting, and other signs of unhealthy muscles.

Then, the researchers noticed that mice lacking CREB activity in their muscle cells also had a genetic brake, called histone deacetylase 5 (HDAC5), stuck in place. "SIK1 provides an unexpected link between two important mechanisms of gene regulation, CREB and HDAC5, and this pathway plays a major role in maintaining normal muscle function," said Berdeaux.