1. Key Culprit Causing Muscle Atrophy Identified To find out, Adams and his colleagues conducted a
series of experiments to discover the critical ATF4
NAME _______________ Date _______Per#___ target genes. The tests showed that ATF4 caused
muscle atrophy by activating the Gadd45a gene.
UI researchers have identified a key protein involved Further tests showed Gadd45a didn't need its protein
in muscle atrophy. The protein, Gadd45a, benefactor to do its atrophy work either, meaning it
reprograms hundreds of genes inside a muscle cell's could act independently of the ATF4 pathway.
nucleus, causing the nucleus to dramatically change
from a cigar shape (top) to a swollen bulb (bottom). "Basically, when we did the experiments, thousands
(Credit: Images courtesy of Christopher Adams lab, of mRNAs (the genetic messengers) were measured,
University of Iowa.) but only one jumped out, and it was Gadd45a," says
Adams, also a faculty scholar at the Fraternal Order
ScienceDaily (Aug. 13, 2012) — Whether you're old, of Eagles Diabetes Research Center at the UI. "It was
have been ill, or suffered an injury, you've watched the only one that met all the tests' criteria."
gloomily as your muscles have atrophied. The
deterioration of muscle -- even slight or gradual -- is The researchers learned that Gadd45a affected
about as common to the human condition as muscles in two main ways: it instructed muscle cells
breathing. to produce fewer proteins (needed to maintain
muscle), and it caused proteins already existing in
Yet despite its everyday nature, scientists know little muscle fibers to break down. The result on both
about what causes skeletal muscles to atrophy. They counts: muscle atrophy.
know proteins are responsible, but there are
thousands of possible suspects, and parsing the key The team then turned to find out how Gadd45a did its
actors from the poseurs is tricky. In a new paper, work. The nucleus of a muscle cell that is stressed
researchers from the University of Iowa report major changes from a cigar shape to a swollen bulb, with
progress. The team has identified a single protein, enlarged nucleoli (protein containers inside the
called Gadd45a, and determined that it orchestrates nucleus). When Adams and his team injected
40 percent of the gene activity that ultimately causes Gadd45a into a muscle cell, the nucleus changed
skeletal muscle to atrophy. Moreover, the researchers shape the same way as if it were stressed.
have learned that Gadd45a does its devilish work
inside the muscle cell's nucleus, causing such a "To put this all together, it means Gadd45a is going
ruckus as it reprograms hundreds of genes that it into the muscle nucleus, and it totally changes it, so
changes the nucleus's shape. much so that the changes are visible," Adams said.
"It's turning genes on, and it's turning genes off. It's
"We now understand a key molecular mechanism of changed the cell."
skeletal muscle atrophy," says Christopher Adams,
associate professor of internal medicine at the UI and Gadd45a changes roughly 600 genes associated with
corresponding author on the paper published in the muscle atrophy, by increasing mRNAs charged either
Journal of Biological Chemistry. "This finding could with breaking down muscle proteins or reducing
help us find a therapy for treating muscle atrophy in muscle protein growth. The total is about 40 percent
patients, and we now know a great place to start is by of all mRNAs believed to be involved in muscle
reducing Gadd45a." deterioration in humans, the researchers reported in
the paper.
Adams and his team zeroed in on Gadd45a like
sleuths following a trail of clues. The researchers "Gadd45a is like a central switch for muscle
knew from previous work that when skeletal muscle atrophy," Adams says. "If you can block it, you can
is stressed from malnutrition, nerve damage, or conceivably stunt muscle atrophy to a large extent."
inactivity, it increases its production of a protein
called ATF4. That protein, in turn, initiates muscle Review Questions – Write a Summary containing:
atrophy by activating a slew of genes. But the details
remained elusive. For example, are all the genes 1. What is the main idea of the article?
equally important or do some play larger roles than
others? 2. What information presented in the article
supports the main idea?
