Whether you're old, have been ill, or suffered an injury, you've watched gloomily as your muscles have atrophied. The deterioration of muscleeven slight or gradualis about as common to the human condition as breathing.
Yet despite its everyday nature, scientists know little about what causes skeletal muscles to atrophy. They know proteins are responsible, but there are thousands of possible suspects, and parsing the key actors from the poseurs is tricky.
In a new paper, researchers from the University of Iowa report major progress. The team has identified a single protein, called Gadd45a, and determined that it orchestrates 40 percent of the gene activity that ultimately causes skeletal muscle to atrophy. Moreover, the researchers have learned that Gadd45a does its devilish work inside the muscle cell's nucleus, causing such a ruckus as it reprograms hundreds of genes that it changes the nucleus's shape.
"We now understand a key molecular mechanism of skeletal muscle atrophy," says Christopher Adams, associate professor of internal medicine at the UI and corresponding author on the paper published in the Journal of Biological Chemistry. "This finding could help us find a therapy for treating muscle atrophy in patients, and we now know a great place to start is by reducing Gadd45a."
Adams and his team zeroed in on Gadd45a like sleuths following a trail of clues. The researchers knew from previous work that when skeletal muscle is stressed from malnutrition, nerve damage, or inactivity, it increases its production of a protein called ATF4. That protein, in turn, initiates muscle atrophy by activating a slew of genes.
But the details remained elusive. For example, are all the genes equally important or do some play larger roles than others?
To find out, Adams and his colleagues conducted a series of experiments to discover the critical ATF4 target genes. The tests showed that ATF4 caused muscle atrophy
|Contact: Richard Lewis|
University of Iowa