Healthy Muscles: Scientists Identify Pathway That Promotes Muscle Cell Survival

[Guest guest]

Healthy Muscles: Scientists Identify Pathway That Promotes Muscle

Cell Survival In Mice

http://www.sciencedaily.com/releases/2007/04/070430094024.htm

Scientists at the Salk Institute for Biological Studies 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 online in

Nature Medicine, is the first to explore the part this enzyme plays

in a cascade of events triggered by exercise-induced hormones and

other signals.

In this particular pathway, a molecular switch turns on a set of

muscle-specific genes in response to exercise by releasing a brake

that normally keeps these genes off. Learning how this pathway

affects cellular responses may provide clues for improving cellular

health in diseases affecting muscle and other cell types.

" In addition to muscle, this regulatory circuit is present in brain

and heart tissue, where it also seems to control cell survival, "

said Marc Montminy, M.D., Ph.D., professor in the Clayton Foundation

Laboratories for Peptide Biology at the Salk Institute and senior

author of the study. " Therefore, we believe that understanding the

role of this enzyme in muscle cells may someday 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 Berdeaux,

Ph.D., 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. Although CREB had

long been studied for its role in glucose regulation in metabolic

tissues like the liver and pancreas, its function in muscle tissue

was unknown. Then, the researchers noticed that mice lacking CREB

activity in their muscle cells also had a genetic brake, called

histone deacetylase (HDAC), stuck in place. Without loosening the

brake by a chemical modification process known as phosphorylation,

muscle-specific genes could not be activated and the mice lacked

proper muscle function.

In order to determine how CREB acts to regulate HDAC, Berdeaux and

colleagues looked for phosphorylation sites in the HDAC protein.

They discovered that one of many proteins turned on and off by the

CREB switch, a little-known enzyme called salt-inducible kinase-1,

or SIK1, specifically recognizes and phosphorylates HDAC.

Then, to explore the possibility that SIK1 is the enzyme controlling

the HDAC brake in muscle cells, the researchers reduced SIK1

activity in muscle cells grown in the lab using a technique that

silences gene expression. Less SIK1 activity resulted in less

phosphorylated HDAC. With the unphosphorylated HDAC brake now firmly

in place, expression of muscle-specific target genes was also

reduced. Conversely, when the researchers boosted SIK1 levels or

inhibited HDAC activity with a drug, muscle cell health was restored

in mice genetically engineered to lack CREB and suffering from

muscle weakness as a result.

" We've discovered that SIK1 provides a completely unexpected link

between two important mechanisms of gene regulation, CREB and HDAC,

and have shown that this pathway plays a major role in maintaining

normal muscle function, " said Berdeaux. " Now it remains to be seen

how this pathway works in muscle under different conditions, such as

during exercise, as well as what part it plays in maintaining cell

survival in other tissue types and in other species. "

Indeed, all mammals have SIK1, not just mice, and even worms and

fruit flies use variations of the enzyme. And as Montminy

adds, " Application of this same pathway over and over across species

further emphasizes its importance.