National Space Biomedical Research Institute Gene discovery linked to muscle atrophy in numerous conditions HOUSTON-(March 20, 2002)-A newly identified gene, atrogin-1, is involved in muscle loss associated with cancer, diabetes, fasting and kidney disease as well as in the atrophy occurring with disuse, inactivity, and nerve or spinal injury.
This discovery, funded by the National Space Biomedical Research Institute (NSBRI) and the Muscular Dystrophy Association, increases the understanding of how muscles atrophy and may lead to development of new treatments for muscle wasting on Earth and in space.
"Through a study of rat muscles, we determined that atrogin-1 is found only in muscle," said Dr. Alfred Goldberg, professor of cell biology at Harvard Medical School and associate leader of NSBRI's team of scientists focusing on muscle loss in space. "In normal muscles, the amount is low; however, there is a dramatic increase in the production of the atrogin-1 protein in conditions where muscles lose size and strength."
In healthy muscles, there is a continual process of muscle protein production and breakdown. With muscle-wasting conditions, this cycle gets out of balance. Protein breakdown occurs more rapidly than protein production, leading to loss of muscle weight.
"Proteins in cells are destroyed in a structure called the proteasome," Goldberg said. "From clues in its gene sequence, we guessed that atrogin-1 was a component of this pathway of protein breakdown and succeeded in proving atrogin-1 targets other proteins for destruction."
Goldberg and associates, Dr. Marcelo Gomes, Dr. Stewart Lecker and Dr. Thomas Jagoe, set out to look for genes activated only during muscle atrophy. Using gene microarray analysis, the group studied muscle samples from healthy rats and those experiencing various muscle-wasting conditions.
"Genes code for the various proteins in our cells, and the information in our genes is expressed through the use of molecular messengers, called messenger RNAs," Goldberg said. His group searched atrophying muscles for new types of messenger RNAs since these molecules convey the news of what genes are being expressed.
"We found a fragment of a messenger RNA that increased dramatically in muscle atrophy," he said. "Cloning techniques allowed us to discover the atrogin-1 gene's full sequence and to produce the protein that it codes for. We then determined that it played a role in atrophy, where it seems to trigger the excessive protein breakdown."
Goldberg's group chose the name, atrogin-1, as short for atrophy-related gene. Their findings appear in the Dec. 4 issue of the Proceedings of the National Academy of Science.
In earlier studies, the group was the first to establish that muscle atrophy is due primarily to excessive protein breakdown and the first to indicate that a similar biochemical process was responsible for muscle loss in many different diseases.
Goldberg feels the atrophy process is similar in humans.
"Almost everything we know about human muscle function was first discovered in experimental animals," he said. "The atrogin-1 gene in humans is almost identical to that in mice and rats."
Many could potentially benefit from drugs designed to block or slow down muscle atrophy, from cancer patients to the bedridden to those losing muscle while in a cast. Even astronauts on long missions, who lose muscle while in space, will need a means to control muscle loss.
"If you could inhibit atrogin-1 or block a cell's ability to make it, you could reduce muscle wasting," Goldberg said. "Atrogin-1 is an attractive target for drug therapy since it is only found in muscle and plays a critical role in the atrophy process."
Goldberg's lab is now analyzing muscle biopsies of people with muscle-wasting diseases to determine if atrogin-1 is involved in human disease.
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The NSBRI, funded by NASA, is a consortium of institutions studying the health risks related to long-duration space flight. Members include Baylor College of Medicine, Brookhaven National Laboratory, Harvard, The Johns Hopkins University, Massachusetts Institute of Technology, Morehouse School of Medicine, Mount Sinai School of Medicine, Rice University, Texas A&M University, University of Arkansas for Medical Sciences, University of Pennsylvania Health System and University of Washington.
