Defining the Underlying Factors Contributing to Contracture Development

Roger Cornwall, MD, had already been practicing as a pediatric orthopaedic surgeon for five years when he stumbled upon a finding that would end up defining his life’s work. When modifying a contracture surgery to prevent a common complication, he uncovered a mistake in the current dogma: The problem wasn’t with the functioning muscle. It was with the denervated muscle. And it was due to an issue with muscle length regulation.

That initial challenge, roughly 15 years ago, flipped the existing belief about contractures’ cause on its head, and it spurred Cornwall to pursue the biological mechanisms that regulate muscle length.

Today, Cornwall and his research team, co-led by Qingnian Goh, PhD, have uncovered several breakthroughs in their findings, but the theme he keeps coming back to is connections. “Everywhere we’ve looked, we’ve found connections through this work—between signaling pathways, between disorders and between genes. I know that if we could get a lot of people excited about muscle length as a biological problem and increase the connections between people and labs and interests, we could make a lot of progress.”

Targeting Muscle Length at the Cellular Level

Cornwall, professor of orthopaedic surgery at Cincinnati Children’s Division of Pediatric Orthopaedics, and his fellow researchers first found that contractures occur because paralyzed muscles lack the ability to grow normally in length when deprived of critical signaling input from normal nerve fibers during early muscle development. They further learned that healthy longitudinal muscle growth depends primarily on a balance between the synthesis and breakdown of muscle proteins. The team tested bortezomib, a chemotherapy drug known to inhibit protein breakdown, in pre-clinical models as a possible way to rebalance muscle growth at the cellular level. While the drug successfully halted protein degradation in cells, researchers found that the toxicity levels were too high to be given to otherwise healthy babies.

Still, the findings provided the first proof of concept that contractures could be cured medically without surgery.

From there, Cornwall and his team began focusing on the specific mechanisms that regulate the protein degradation process. One of the ways they’ve done that is through identifying signaling pathways and genes involved in muscle length regulation in contractures.

So far, they’ve found promising leads in both areas, including two signaling pathways—myostatin and JNK—that, when inhibited, restore muscle growth. They’ve also identified two genes—one that’s increased and working too much in contractures and one that’s not working well enough.

Incidentally, the gene that isn’t working well enough is an inhibitor of the myostatin signaling pathway.

“We’re trying to paint a picture with all these puzzle pieces and figure out where they go,” Cornwall says. “But we continue to identify specific cellular processes, genes and signaling pathways that, if targeted, can prevent contractures. And we continue to find connections, like the gene and signaling pathway feeding together.”

Identifying Common Pathways

Along the way, Cornwall and his research team have kept their work as relevant to as broad a population of pediatric patients as possible. Through this approach, they’ve identified that the same failure of muscle length in pediatric patients with brachial plexus birth injuries also occurs in cerebral palsy.

“Everything we’re finding for brachial plexus injury, we’re finding parallels to cerebral palsy,” he says.

In addition, Cornwall and his fellow researchers determined that the most recent gene they identified, called LTBP4, is also a main driver of the severity of muscle loss and weakness in patients with Duchenne muscular dystrophy.

“That finding is exciting for a couple of reasons,” Cornwall says. “Namely, because we keep discovering similarities across different conditions, suggesting that if we can crack this nut in brachial plexus injuries, we may be able to affect a lot of different musculoskeletal conditions that we treat as pediatric orthopaedic surgeons.”

Identifying common pathways underlying muscle length regulation across multiple conditions has vast implications for treatment potential—and for future research.

“The other part that’s scientifically interesting is the advances we’re making in sorting out the biology of how muscle grows and develops,” Cornwall says.

Building Momentum Around an Underappreciated Dimension of Muscle Growth

Another connection Cornwall and his team are currently working to fully uncover is a divergence at the biological level between how muscle cross-sectional area and muscle length are regulated. Muscle grows in cross-sectional area—what determines the strength of muscle—differently than it grows in length, Cornwall says. But the current assumption is that muscle grows in all directions the same way. While the divergence has been a consistent finding, Cornwall says he and his team hope to parse out the dimensional specificity more.

In the future, Cornwall also believes researchers will be able to predict, prenatally, a baby’s susceptibility to a brachial plexus injury. That’s based on his team’s discovery of genetic variations that, preliminary data suggest, can help stratify the risk for injury and for the severity of injury.

“If we could identify the risk better and prevent the injuries and also identify those at risk of bad contractures and treat them medically, then we would have fewer people with bad contractures that end up needing palliative surgery,” Cornwall says.

Although his pie-in-the-sky goal is to live long enough to see the last surgery performed for muscular contractures, Cornwall says he has a more realistic goal to cement the understanding of contractures as a biological problem and spur more research interest in myobrevopathy, a term he and his team coined to describe disorders of short muscle.

“We’ve done a pretty good job of that already,” he says, “but as orthopaedic surgeons, we’re physically oriented, not biologically oriented, so it takes constant reminding that this is actually a biological problem. If that could be more firmly established, it would help.”

Cornwall, who serves as vice president of the Orthopaedic Research Society, notes that widespread acceptance would lead to more investigators worldwide studying contractures and muscle length—what he calls an underappreciated dimension of muscle growth and function—and that, ultimately, would lead to solutions.

“I do think it’s slowly catching on,” he says.

(Published March 2026)

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