Study Identifies GCN5 Enzyme as Important Regulator of Muscle Health
A protein called GCN5 is vital for normal muscle health and helps to coordinate the expression of several important muscle proteins, including dystrophin, according to a study done in mice.
The results suggest that targeting GCN5 may be a useful therapeutic avenue in diseases of the muscles, such as muscular dystrophy.
The study, “GCN5 maintains muscle integrity by acetylating YY1 to promote dystrophin expression,” was published in the Journal of Cell Biology.
GCN5 belongs to a group of proteins called lysine acetyltransferases. These proteins work to modify other proteins — specifically by adding chemical motifs called acetyl groups, a process called “acetylation.” The addition or removal of acetyl regulates the activity of various proteins, and helps to coordinate a number of cellular processes.
Here, an international group of scientists showed that GCN5 normally adds acetyl to another protein, called Yin Yang 1 (YY1), in muscle cells. YY1 is a transcription factor — by binding to the cell’s DNA, it controls how different genes are “read” by the cell. Normally, GCN5 works to “turn off” YY1 in muscle cells, the team showed.
The scientists then generated mice that lacked GCN5 in their muscle cells. They showed that, in these mice, the muscle cells produce lower-than-normal amounts of several important muscle proteins, most notably dystrophin, which normally helps to cushion muscle cells during contractions. Deficits in dystrophin are the cause of Becker muscular dystrophy and Duchenne muscular dystrophy, two forms of muscular dystrophy.
“Our publication shows that if you knock out GCN5, the one major thing we see is a lack of dystrophin, without seeing any real disruption of any other mechanisms,” Keir Menzies, PhD, the study’s senior author from the University of Ottawa, said in a press release.
Additionally, mice lacking GCN5 exhibited a marked decline in muscle health during physical stress, such as downhill treadmill running — the mice became substantially weaker as they ran downhill.
“We found that if you delete GCN5 expression from muscle it will no longer be able to handle extreme physical stress,” said Menzies, noting that the changes seen in these mice are generally comparable to what is seen in humans with muscular dystrophy.
The scientists also conducted an analysis of human data, and they found a statistically significant association between YY1 gene activity and muscle fiber size: individuals with greater YY1 gene activity tended to have smaller muscle fibers, whereas low gene activity was associated with larger muscle fibers. Since GCN5 normally reduces YY1 protein activity, these findings are overall consistent with the mouse data.
“These findings may therefore be useful for the discovery of new therapeutics that regulate GCN5 activity, or its downstream targets, for maintaining healthy muscle during cancer, myopathies [muscle diseases], muscular dystrophy or aging,” Menzies said.
More broadly, the researchers concluded, “this work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging.”