An international team led by researchers from the University of Ottawa’s Faculty of Medicine has published findings that could contribute to future therapies for muscle degeneration due to aging and diseases like cancer and muscular dystrophy.
In a study published in the Cell Biology Journal, which publishes peer-reviewed research on cellular structure and function, the authors said their work demonstrates the importance of the GCN5 enzyme in maintaining the expression of key structural proteins in skeletal muscle. These are the muscles attached to the bones that are responsible for breathing, posture and locomotion.
“We found that if you suppress the expression of GCN5 from the muscle, it will no longer be able to handle extreme physical stress,” says Dr. Keir Menzies, a molecular biologist in the Department of Biochemistry, Microbiology and Immunology at the School of Medicine. and co-appointed as an Associate Professor in the Interdisciplinary School of Health Sciences.
Over a period of approximately five years, the international collaboration led by the University of Ottawa painstakingly experimented with a specific muscle “knockout” in mice of GCN5, a well-studied enzyme that regulates multiple cellular processes. such as metabolism and inflammation. Through a series of manipulations, scientists produce laboratory mice in which specific genes are disrupted, or knocked out, to unveil animal models of human disease and better understand how genes work.
In this case, several experiments were performed to examine the role that the GCN5 enzyme plays in the muscle fiber. What they found with this line of muscle-specific knockout mice was a noticeable decline in muscle health during physical stress, such as downhill treadmill running, a type of exercise known by athletes to cause micro – tears in muscle fibers to stimulate muscle growth. The muscle fibers of the lab animals weakened considerably as they descended, like those of the old mice, while the wild-type mice were not affected in the same way.
Dr. Menzies, the study’s lead author, says the findings are akin to what’s seen in advanced aging, or myopathies and muscular dystrophy, a group of genetic conditions that cause progressive weakness and loss of muscle mass. It was supported by human data, including an observed negative correlation between muscle fiber diameter and Yin Yang 1, a highly multifunctional protein that is essential for a host of cellular processes and which the Menzies lab found to be a target of GCN5.
Ultimately, the team’s research revealed that GCN5 stimulates the expression of key structural muscle proteins, including dystrophin, and that a lack of it will reduce them.
This is important because dystrophin is the body’s most important protein for maintaining muscle cell membranes, serving as a sort of anchor and shock absorber within muscle cells. Without it, the muscles are very sensitive to physical stress and the withering of the muscles can have disabling and fatal consequences.
Our publication shows that if you knock out GCN5, the only major thing we see is a lack of dystrophin, without seeing any real disruption of other mechanisms.”
Dr. Keir Menzies, Molecular Biologist
He noted that the paper also reaffirmed other research showing that GCN5 does not alter the contents of muscle mitochondria, the powerhouses of cells and another major influencer of muscle health.
The research is backed by data showing that dystrophin is “important for the maintenance of overall muscle integrity and muscle health,” according to Dr. Menzies.
Dr. Menzies suggests the research could help create a foundation for developing therapies down the line. “These findings may therefore be useful for the discovery of new therapies that regulate the activity of GCN5, or its downstream targets, to maintain healthy muscles during cancer, myopathies, muscular dystrophy or aging,” he says. .
Addicks, GC, et al. (2022) GCN5 maintains muscle integrity by acetylating YY1 to promote dystrophin expression. Journal of Cell Biology. doi.org/10.1083/jcb.202104022.