Researchers identify key culprit causing muscle atrophy

Aug 13, 2012
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). Credit: Adams lab, University of Iowa

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 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 .

Scott Ebert, a graduate student at the UI, is the first author on the paper, titled, "Stress-induced Gadd45a expression reprograms myonuclei and causes 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.

Explore further: Classical enzymatic theory revised by including water motions

add to favorites email to friend print save as pdf

Related Stories

Apple peel makes mice mighty

Jun 07, 2011

For Popeye, spinach was the key to extra muscle. For the mice in a new University of Iowa study, it was apples, or more precisely a waxy substance called ursolic acid that's found in apple peel.

Muscle atrophy through thick but not thin

Jun 08, 2009

During desperate times, such as fasting, or muscle wasting that afflicts cancer or AIDS patients, the body cannibalizes itself, atrophying and breaking down skeletal muscle proteins to liberate amino acids. In a new study ...

How work tells muscles to grow

Jan 03, 2012

We take it for granted, but the fact that our muscles grow when we work them makes them rather unique. Now, researchers have identified a key ingredient needed for that bulking up to take place. A factor produced in working ...

Key finding in rare muscle disease

Jan 17, 2007

The finding is in the current issue of Annals of Neurology, a leading international neurology journal, in work led by Professor Nigel Laing and Dr Kristen Nowak of the Laboratory for Molecular Genetics at the Western Austra ...

Recommended for you

Molecules that came in handy for first life on Earth

Nov 24, 2014

For the first time, chemists have successfully produced amino acid-like molecules that all have the same 'handedness', from simple building blocks and in a single test tube. Could this be how life started. ...

Jumping hurdles in the RNA world

Nov 21, 2014

Astrobiologists have shown that the formation of RNA from prebiotic reactions may not be as problematic as scientists once thought.

User comments : 4

Adjust slider to filter visible comments by rank

Display comments: newest first

Roland
5 / 5 (3) Aug 13, 2012
When bears hibernate, their muscles don't atrophy. It would be interesting to monitor this protein during that period, in bears, or in bear muscle cells in vitro.
Tausch
3 / 5 (2) Aug 14, 2012
@Roland
Agreed. Malnutrition or stress during hibernation is not possible.
That leaves age. Do all bears have this with advanced age?
Torbjorn_Larsson_OM
3.7 / 5 (3) Aug 14, 2012
We all have to bear advanced age.

But yes, that is an intriguing hook into this!
Tausch
1 / 5 (1) Aug 17, 2012
Wonderful word play on the word 'bear'. Hut ab.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.