Muscle Repair: New Pathways & Reversing Aging in Mice

A molecular mechanism that constrains skeletal muscle regeneration has been identified by researchers at Cornell University, potentially paving the way for improved treatments for muscular dystrophy and severe muscle injury. The findings, published February 16 in the Journal of Clinical Investigation, center on the role of platelet-derived growth factor receptor beta (PDGFRb) in regulating muscle repair.

The research team, led by Daniel Berry, the Andre Bensadoun, Ph.D. ’60 Associate Professor in the College of Human Ecology, discovered that PDGFRb, a receptor protein found in cell membranes, acts as a key modulator of myocyte function in adult muscle cells. Initial observations arose while investigating the effects of a small molecule inhibitor, related to the cancer drug imatinib, on fat tissue. Unexpected changes in muscle function in test subjects prompted a deeper investigation into PDGFRb’s role.

“We don’t fully understand how muscle regeneration occurs after injury or during aging,” Berry said. To directly test PDGFRb’s function, the team generated a muscle-specific deletion of the receptor. Experiments revealed that removing PDGFRb enhanced muscle regeneration and increased the size of muscle fibers, while activating PDGFRb impaired the repair process. “We started looking at muscle development and metabolism, and uncovered an unexpected role in regeneration,” Berry explained.

The process of muscle repair involves the fusion of muscle cells, known as myocytes. While the importance of this fusion is known, the molecular pathways that signal this process have remained largely undefined. The study indicates that PDGFRb functions as a “checkpoint” in this process, controlling the rate and extent of muscle repair. Researchers conducted both in vitro and in vivo experiments to confirm these findings.

According to a report from Muscular Dystrophy News, the discovery could guide the development of future treatments for conditions like muscular dystrophy (MD), a group of disorders characterized by progressive muscle weakness and degeneration caused by genetic mutations. The research suggests that manipulating PDGFRb activity could potentially enhance muscle repair in individuals with MD or those recovering from severe muscle injuries.

Siwen Xue, a doctoral student in molecular nutrition, and Abigail Benvie, Ph.D. ’24, now a postdoctoral fellow at Yale University, are co-first authors of the study. The team’s operate builds on previous research into glucose and fat metabolism, as the initial inhibitor altered these systemic effects, leading them to investigate whether PDGFRb signaling in muscle was a contributing factor.

Researchers are continuing to investigate the precise mechanisms by which PDGFRb regulates muscle regeneration, with the goal of identifying potential therapeutic targets. Further studies are planned to explore the long-term effects of PDGFRb modulation and its potential application in treating various muscle-related conditions.