[Apr. 15, 2023: Staff Writer, The Brighter Side of News]
Enzyme GCN5 is key in skeletal muscle loss due to aging. (CREDIT: Creative Commons)
A recent study published in the Journal of Cell Biology has shown that the enzyme GCN5 plays a crucial role in maintaining the expression of key structural proteins in skeletal muscle, which are essential for breathing, posture, and locomotion.
This discovery, made by an international team led by researchers at the Faculty of Medicine at the University of Ottawa, could contribute to future therapeutics for muscle degeneration due to old age, cancer, and muscular dystrophy.
Dr. Keir Menzies, a molecular biologist at the Faculty of Medicine’s Biochemistry, Microbiology, and Immunology department, and an associate professor at the Interdisciplinary School of Health Sciences, led the team in a span of roughly five years, during which they experimented with a muscle-specific mouse “knockout” of GCN5, a well-studied enzyme that regulates multiple cellular processes such as metabolism and inflammation.
The scientists produced lab mice in which specific genes are disrupted, or knocked out, to unveil animal models of human disease and better understand how genes work.
Multiple experiments were done to examine the role of the GCN5 enzyme in muscle fiber, and what they found was a notable 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 lab animals’ muscle fibers became dramatically weaker as they scurried downhill, like those of old mice, while wild-type mice were not similarly impacted.
Dr. Menzies, the senior author of the study, says the findings are akin to what is observed in advanced aging or myopathies and muscular dystrophy, a group of genetic diseases that result in 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 pivotal to a slew of cellular processes and found by the Menzies lab to be a target of GCN5.
Dystrophin is the body’s most important protein for maintaining the membrane of muscle cells, serving as a kind of anchor and cushioning shock absorber in cells of muscles. Without it, muscles are very susceptible to physical stress, and the withering of muscles can lead to crippling and deadly consequences.
(a) Bar graph showing all positively correlated musculoskeletal diseases obtained from BSCE by using all differentially expressed genes from the Gcn5skm−/− bioset as an input for the meta-analysis. (CREDIT: Rockefeller University Press)
“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,” says Dr. Menzies. He noted that the paper also reaffirmed other research showing that GCN5 doesn’t alter the content of muscle mitochondria, the powerhouses in cells, and another major influencer of muscle health.
The research builds on data showing that dystrophin is “important for maintaining general muscle integrity and muscle health,” according to Dr. Menzies.
This is significant because dystrophin is the body’s most important protein for maintaining the membrane of muscle cells, serving as a kind of anchor and cushioning shock absorber in cells of muscles. Without it, muscles are very susceptible to physical stress, and the withering of muscles can lead to crippling and deadly consequences.
Dystrophin acts as a shock absorber within the muscle cells, reducing any damage caused by muscle contractions. (CREDIT: Shutterstock)
Dr. Menzies suggests the research could help to create a foundation for developing therapeutics down the line. “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, muscular dystrophy, or aging,” he says.
Muscular dystrophy affects approximately 1 in every 5,000 males, according to the Muscular Dystrophy Association, and is characterized by progressive muscle weakness and degeneration. There is currently no known cure for the disease, and treatment options are limited to managing symptoms and improving quality of life.
The uOttawa-led research on GCN5 and dystrophin could provide a potential avenue for developing new therapies to treat muscular dystrophy and other muscle degenerative diseases.
Dr. Menzies and his team plan to continue their research by investigating the downstream targets of GCN5 and identifying potential drug candidates that could regulate its activity. They also hope to further explore the role of dystrophin in muscle health and investigate whether boosting its expression could be a viable treatment option for muscular dystrophy.
The team’s findings have already garnered attention from the scientific community, with experts praising the research as a significant step forward in understanding the mechanisms underlying muscle degeneration.
“This study provides important insights into the role of GCN5 in maintaining muscle health and highlights the critical role of dystrophin in muscle integrity,” says Dr. Mark Tarnopolsky, a professor of pediatrics and medicine at McMaster University who was not involved in the study.
Dr. Tarnopolsky adds that the research has “important implications for the development of new treatments for muscle degenerative diseases and underscores the importance of investing in basic research to advance our understanding of these conditions.”
The uOttawa-led study also highlights the importance of international collaboration in scientific research. The research involved scientists from Canada, Australia, Italy, and the United States, demonstrating the global impact of scientific collaboration in advancing knowledge and improving human health.
“This study is a testament to the power of international collaboration in scientific research,” says Dr. Menzies. “By bringing together researchers from different countries and different disciplines, we were able to make significant progress in understanding the mechanisms underlying muscle degeneration and identifying potential targets for new therapeutics.”
As the global population continues to age, the incidence of muscle degenerative diseases is likely to increase, making research in this area all the more important. The uOttawa-led study on GCN5 and dystrophin represents a promising step forward in the development of new therapies to treat these devastating conditions and improve quality of life for patients around the world.
What are the symptoms of muscle atrophy?
According to the Cleveland clinic, the symptoms of muscle atrophy differ depending on the cause of your condition. The most obvious sign of muscle atrophy is reduced muscle mass. Other signs of muscle atrophy may include:
One arm or one leg is smaller than the other.
Weakness in one arm and or one leg.
Numbness or tingling in your arms and legs.
Trouble walking or balancing.
Difficulty swallowing or speaking.
Gradual memory loss.
What causes muscle atrophy?
The cause of muscle atrophy depends on the type you have according to the Cleveland Clinic. Disuse (physiologic) atrophy is caused by not using your muscles enough. If you stop using your muscles, your body won’t waste the energy it needs to take care of them. Instead, your body will start to break your muscles down, which causes them to decrease in size and strength.
Disuse atrophy may affect you if you:
Lead a sedentary lifestyle.
Don’t get enough exercise.
Sit at a desk job all day.
Are on best rest.
Have a genetic disorder such as muscular dystrophy or Charcot-Marie-Tooth disease.
Can’t move your limbs due to a stroke or other conditions such as dermatomyositis.
Have age-related atrophy (sarcopenia).
Neurogenic atrophy is caused by an injury or disease affecting nerves that connect to your muscles. When these nerves are damaged, they can’t trigger the muscle contractions that are needed to stimulate muscle activity.
When your muscles don’t contract, your body thinks you don’t need them anymore. So your body starts breaking them down, which causes them to decrease in size and strength. Diseases and other conditions that can affect these nerves include:
Amyotrophic lateral sclerosis (ALS).
Carpal tunnel syndrome.
Spinal cord injury.
For more science news stories check out our New Discoveries section at The Brighter Side of News.
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