New research reveals protein pathway that can slow muscle repair
Discovery may help guide future treatments for muscular dystrophy
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Researchers have identified a molecular pathway that helps regulate how muscle repairs itself — a discovery that may help guide the development of future treatments for conditions such as muscular dystrophy (MD) and severe muscle injuries, a study reports.
The pathway depends on a protein called platelet-derived growth factor receptor beta, or PDGFRb, and appears to act as a molecular “checkpoint” in muscle repair, essentially a control point that can slow or allow repair depending on how active it is.
“Once we understand how muscle repair is regulated, we can begin to design strategies to preserve muscle during aging, disease or rapid weight loss,” Daniel Berry, PhD, a professor at Cornell University in New York, said in a university news story.
Understanding the newly identified muscle repair pathway
The findings were described in the study, “PDGFRβ signaling restrains myocyte function to limit the regenerative capacity of skeletal muscle,” published in The Journal of Clinical Investigation.
MD is a group of disorders characterized by progressive muscle weakness and degeneration caused by genetic mutations that affect muscle cells. Skeletal muscles, the muscles attached to bones that control voluntary movements, are most often affected.
When muscles are damaged by disease, injury, or aging, the body begins a repair process in which muscle cells (myocytes) fuse together to form long structures called myotubes, which later mature into muscle fibers. However, the molecular signals that control this fusion process remain poorly defined.
“We don’t fully understand how muscle regeneration occurs after injury or during aging,” Berry said.
PDGFRb is a type of cell-surface receptor known as a tyrosine kinase that helps regulate cell growth, movement, and differentiation in various tissues.
In earlier research, Berry’s team unexpectedly observed effects of PDGFRb on muscle tissue while studying the effects of fat tissue on a small-molecule inhibitor related to a cancer drug. This finding prompted them to explore PDGFRb’s role in muscle more directly.
“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.”
Activating PDGFRb slows muscle fusion
First, when the team activated PDGFRb in mouse muscle cells, the cells remained small and underdeveloped and failed to form the long myotubes typically seen during muscle repair. When PDGFRb was blocked with a selective inhibitor (SU16f), cells fused more readily, forming thicker and longer myotubes containing more nuclei, features associated with more mature muscle fibers in laboratory models.
Importantly, PDGFRb did not change the number of muscle stem cells or how quickly they multiplied. Instead, it specifically influenced whether these cells could successfully fuse.
To determine whether these findings applied in living animals, the researchers injured a leg muscle in mice and adjusted PDGFRb activity during recovery.
When PDGFRb was inhibited with SU16f, injured muscles showed signs of improved regeneration in mice, including larger muscle fibers that contained more nuclei. In contrast, activating PDGFRb was associated with delayed regeneration. Regenerating fibers were smaller, more disorganized, and showed features consistent with delayed maturation.
Genetic experiments supported these findings. Mice engineered to lack PDGFRb specifically in their muscle stem cells showed enhanced regeneration after injury. Meanwhile, mice engineered to have constantly active PDGFRb showed ongoing regeneration defects.
“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 investigation suggested that PDGFRb influences how muscle cells change shape — an essential step before fusion can occur.
To merge, muscle cells must spread out and form stable contact points with neighboring cells. When PDGFRb was overactive, cells remained rounded and failed to establish these connections. When PDGFRb was blocked, cells spread out more effectively, creating broader contact surfaces that promoted fusion.
STAT1 identified as key signaling mediator
The researchers then identified the downstream signaling protein, STAT1, as a key mediator of this effect. Activation of PDGFRb triggered STAT1 signaling, which appeared to interfere with muscle cell fusion.
Using fludarabine — an FDA-approved medication that inhibits STAT1 — the scientists were able to restore fusion in laboratory models even when PDGFRb remained overactive. In injured mice, fludarabine was associated with improved muscle structure and larger regenerating fibers, with features consistent with more typical repair patterns.
To explore whether the same mechanism might operate in humans, the researchers studied muscle progenitor cells grown from muscle biopsies obtained from young women.
The pattern was similar. Activating PDGFRb suppressed fusion and reduced the formation of mature muscle fibers in these cell models. Blocking PDGFRb with SU16f enhanced fusion, increased the number of nuclei within fibers, and promoted longer, thicker myotubes. Inhibiting STAT1 with fludarabine also enhanced fusion in the human cell models.
Berry said the findings point to a previously unrecognized role for the PDGFRb receptor in muscle regeneration.
“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.”
