Whether you’re old, have been ill, or suffered an injury, you’ve watched gloomily as your muscles have atrophied. The deterioration of muscle – even slight or gradual – is 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 by activating the Gadd45a gene. Further tests showed Gadd45a didn’t need its protein benefactor to do its atrophy work either, meaning it could act independently of the ATF4 pathway.
“Basically, when we did the experiments, thousands of mRNAs (the genetic messengers) were measured, but only one jumped out, and it was Gadd45a,” says Adams, also a faculty scholar at the Fraternal Order of Eagles Diabetes Research Center at the UI. “It was the only one that met all the tests’ criteria.”
The researchers learned that Gadd45a affected muscles in two main ways: it instructed muscle cells to produce fewer proteins (needed to maintain muscle), and it caused proteins already existing in muscle fibers to break down. The result on both counts: muscle atrophy.
The team then turned to find out how Gadd45a did its work. The nucleus of a muscle cell that is stressed changes from a cigar shape to a swollen bulb, with enlarged nucleoli (protein containers inside the nucleus). When Adams and his team injected Gadd45a into a muscle cell, the nucleus changed shape the same way as if it were stressed.
“To put this all together, it means Gadd45a is going into the muscle nucleus, and it totally changes it, so much so that the changes are visible,” Adams said. “It’s turning genes on, and it’s turning genes off. It’s changed the cell.”
Gadd45a changes roughly 600 genes associated with muscle atrophy, by increasing mRNAs charged either with breaking down muscle proteins or reducing muscle protein growth. The total is about 40 percent of all mRNAs believed to be involved in muscle deterioration in humans, the researchers reported in the paper.
“Gadd45a is like a central switch for muscle atrophy,” Adams says. “If you can block it, you can conceivably stunt muscle atrophy to a large extent.”
The researchers aim to find out how to block Gadd45a and to find the other signaling pathways involved in muscle atrophy.
UI researchers have identified a key protein involved in muscle atrophy. The protein, Gadd45a, reprograms hundreds of genes inside a muscle cell’s nucleus, causing the nucleus to dramatically change from a cigar shape (top) to a swollen bulb (bottom). Images courtesy of Christopher Adams lab, University of Iowa.
The National Institutes of Health, the Doris Duke Charitable Foundation, the American Diabetes Association, the U.S. Department of Veterans Affairs, and the Fraternal Order of Eagles Diabetes Research Center at the UI funded the research.
Scott Ebert, a graduate student at the UI, is the first author on the paper, titled, “Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy,” and published on Aug. 10. Contributing authors include Michael Dyle, Kale Bongers, Daniel Fox, Jason Dierdorff, and Eric Foster at the UI; and Steven Kunkel and Steven Bullard, of the UI and the Iowa City Veterans Medical Center. Adams also has an affiliation with the Iowa City Veterans Medical Center.
University of Iowa