Researchers discover genetic mechanism to oppose skeletal muscle breakdown
Voluntary movement and metabolic health are controlled by skeletal muscle. Changes in muscle size are often associated with a person’s strength or physical ability. However, with normal aging, immobilization, malnutrition or chronic illnesses, muscle mass is lost, and this critically leads to deterioration in quality of life.
Federica Accornero, PhD, associate professor in the Department of Physiology and Cell Biology at The Ohio State University College of Medicine, is researching the genetic mechanisms that contribute to and regulate muscle aging.
“All individuals experience loss of muscle strength and mass as they age,” says Accornero.
Accornero and her team are researching the cellular mechanisms of a specific form of skeletal muscle deterioration — pathologic muscle wasting. This is muscle loss caused by chronic diseases such as heart failure, AIDS, cancer or dystrophies. Pathologic muscle loss in older adults is closely related to the loss of physical function, an increased risk of falls and mortality.
This research is crucial to develop therapeutic interventions for those experiencing muscle wasting. To do this, Accornero says that researchers must deepen their molecular understanding of gene expression regulating muscle aging.
In their most recent publication in Nature Communications, Accornero and her research team detail what they have learned. This fundamental discovery highlights a previously unrecognized way to regulate muscle size and function, essential in developing therapeutic strategies to counteract muscle wasting.
This fundamental discovery involves newly identified regulators of muscular cell size: METTL3 and its product, m6A, which act by regulating activin receptors and myostatin pathways. Each of these interconnected components play an important part in muscle maintenance.
Accornero and her research team established the relationship between these four components in their most recent study. METTL3 is an enzyme that deposits a modified version of RNA called m6A onto activin receptors. These activin receptors are the same receptors used by myostatin, a protein that inhibits muscle growth. Therefore, controlling the levels of METTL3 and m6A actually controls muscle growth.
Even more impressive, these findings are not necessarily limited to skeletal muscle. Every cell expresses METTL3, m6A, activin receptors and myostatin. In a previous study, Accornero and her research team established that this same pathway controls heart function.
Accornero emphasizes the importance of their findings and how these breakthrough discoveries are redefining their field.
She says the new findings position METTL3 and m6A as global regulators of cell size, which applies to skeletal muscle, cardiac muscle and potentially beyond those tissues.
“This is a game changer in terms of understanding the genetic mechanisms of muscle wasting, muscle diseases, and the correlation with heart diseases,” Accornero says.
“Our work filled the knowledge gap on our understanding on how muscle is loss with aging and can lead to the development of therapeutic strategies to counteract muscle wasting in the elderly and beyond.”
This discovery has laid the foundation for the future of patient care. Now, researchers can begin to investigate cellular based interventions to oppose the muscle breakdown associated with aging, chronic diseases and, possibly, heart diseases.
Photo by Alexander Jawfox on Unsplash.
