Researchers in the Division of Nutritional Sciences have identified a molecular mechanism that constrains skeletal muscle regeneration and myofiber repair, a finding that could lead to improved treatment for conditions like muscular dystrophy and severe injury.
To repair muscle, muscle cells, or myocytes, fuse to one another. But the molecular pathways that signal this cell-to-cell fusion have remained poorly defined.
"We don't fully understand how muscle regeneration occurs after injury or during aging," said Daniel Berry, the Andre Bensadoun, Ph.D. '60 Associate Professor in the College of Human Ecology.
The team, led by Berry, found that platelet-derived growth factor receptor beta (PDGFRb), a receptor protein located in cell membranes, is a key modulator of myocyte function in adult muscle cells. They published their findings Feb. 16 in the Journal of Clinical Investigation. The co-first authors are Siwen Xue, a doctoral student in molecular nutrition, and Abigail Benvie, Ph.D. '24, now a postdoctoral fellow at Yale University.
The team uncovered PDGFRb's effects on muscle tissue while researching the effects on fat tissue of a small molecule inhibitor related to the cancer drug imatinib. They noticed that subjects' muscle function changed in a way that could be related to PDGFRb.
"That observation prompted us to generate a muscle-specific deletion of PDGFRb to directly test its role in muscle," Berry said. "Because the inhibitor altered glucose and fat metabolism, we wanted to determine whether PDGFRb signaling in muscle was contributing to those systemic effects."
Through in vitro and in vivo experiments, they found that genetic deletion of PDGFRb enhanced muscle regeneration and increased myofiber size, whereas PDGFRb activation impaired muscle repair.
"We started looking at muscle development and metabolism, and uncovered an unexpected role in regeneration," Berry said. "We found that muscle could recover faster when we deleted the receptor, and when we activated the receptor, recovery slowed down."
Further study indicated that when the researchers treated muscle cells with the PDGFRb-inhibiting drug, muscle development improved. In other words, the growth factor receptor serves as a checkpoint in muscle regeneration - and a potential target for therapies to improve functional muscle repair.
Berry said that this is a new function for PDGFRb.
"The surprising finding was its role in regeneration," he said. "We think of tyrosine kinase receptors as drivers of cell growth and survival, not as determinants of cell fusion. That represents a previously unrecognized function."
The research team collaborated with Anna Thalacker-Mercer, formerly a researcher at Cornell and now an associate professor at the University of Alabama, Birmingham, to translate their initial findings from mouse models to human models. Ben Cosgrove, associate professor of biomedical engineering in Cornell Duffield Engineering, and Jamie Blum, Ph.D. '21, an assistant professor at the Salk Institute for Biological Studies, also contributed to the research.
Now Berry is studying muscle development during the embryonic stage and how that shapes muscle formation over an animal's lifetime.
"Ultimately," Berry said, "once we understand how muscle repair is regulated, we can begin to design strategies to preserve muscle during aging, disease or rapid weight loss."
Emily Groff is the assistant director of communications in the College of Human Ecology.
