Kappa Delta Elizabeth Winston Lanier Award Recognizes Groundbreaking Research on Rotator Cuff Repair

Brian T. Feeley, MD, FAAOS, was bestowed with the 2025 Kappa Delta Elizabeth Winston Lanier Award for his research to advance the understanding of muscle degeneration in rotator cuff injuries and how it affects repair outcomes. In the past 15 years, Dr. Feeley and his team have found the source of fatty infiltration, which causes muscle atrophy and leads to poor functional outcomes in rotator cuff repairs. This award recognizes research in musculoskeletal disease or injury with great potential to advance patient care.

“Our central premise was that fatty infiltration fundamentally is an intramuscular cellular problem in which something within the muscle was turning into fat,” said Dr. Feeley, who is an orthopaedic surgeon, chief of the Division of Sports Medicine and Shoulder Surgery, and director of the Muscle Stem Cell Lab at the University of California, San Francisco (UCSF). “We didn’t think fat would infiltrate the muscle, as it is inherently lazy. The second premise was that there has to be a reason that fatty infiltration is occurring. If that is true, fat is normally a store for energy, so maybe the muscle is storing energy for possible regeneration.”

Understanding key atrophy and fatty infiltration pathways
When Dr. Feeley and his colleagues began their research, there was no small animal model that could reproduce the development of muscle atrophy and fatty infiltration. The team—including Xuhui Liu, MD, adjunct professor in the Department of Orthopaedic Surgery at UCSF; Steven Garcia, MD, orthopaedic surgery resident at UCSF; Hubert T. Kim, MD, PhD, FAAOS, vice chair of orthopaedic surgery at UCSF and chief of surgical service at the San Francisco VA Medical Center; and Michael Davies, MD, sports medicine fellow at Hospital for Special Surgery in New York City—developed a mouse model that demonstrated consistent and reproducible muscle atrophy, muscle fibrosis, and fatty infiltration, providing researchers with an animal model to study pathophysiologic changes that occur in rotator cuff tears. A key advantage of mouse models is that mice use their rotator cuffs similarly to humans for such tasks as feeding and grooming.

That mouse model led to the first study showing the regulation of muscle atrophy–related genes in a rotator cuff model of injury, and the team identified a link between a particular molecular pathway—Akt/mTOR—and fatty infiltration in the rotator cuff model.

The Akt/mTOR pathway is believed to control protein degradation during muscle atrophy. With this knowledge, the researchers inhibited the development of fatty infiltration with the administration of 1.5 mg/kg of rapamycin daily, which blocked mTOR activity and decreased fatty infiltration for the first time in an animal model of rotator cuff tears.

Identifying cellular source of fatty infiltration
Previous research discovered a mesenchymal cell that had a unique cell-surface marker within muscle. These cells allowed researchers to track them over time and examine how they could differentiate into several other cell types with the proper stimulus—the fibroadipoprogenitor cell (FAP). Dr. Feeley aimed to understand whether FAPs were the cellular source of fatty infiltration in the mouse models of rotator cuff tears. The researchers were able to track the fate of FAPs within muscle over time, finding that after a rotator cuff injury, FAP numbers increased and were located with two fat markers.

The team then used a mouse model to knock out or deplete FAPs within muscle. Loss of fatty infiltration was seen following rotator cuff injury, confirming that FAPs are the cellular source responsible for fatty infiltration.

Revealing roles and complexities of FAPs
Although FAPs are responsible for fatty infiltration, which is a degenerative function, other studies have shown that FAPs could also be capable of regenerative and pathologic responses to muscle injury. The research team set out to determine whether FAPs could show regenerative traits when given the right conditions, potentially acting as a hidden source of stem cells in muscles that could be activated to help repair muscle tissue.

To do this, they developed a chronic injury where the tendon was injured along with the suprascapular nerve, followed by repair 6 weeks after the injury. This model mirrored what is seen in the clinical setting—a high overall success rate but without a full return of muscle quality. The study tested mouse and human FAPs in vitro with B agonists, with several outcomes suggesting FAPs are closer to beige fat, a type of fat cell that burns energy; these FAPs were termed beige FAP. When researchers induced beige FAP–transplanted cells into a rotator cuff model of injury and repaired with B agonists, the repair group had virtual elimination of fatty infiltration and improved markers of muscle atrophy, demonstrating that pharmacologic stimulation of FAPs could improve muscle function.

Using single-cell RNA sequencing, Dr. Feeley and his team are currently studying how FAPs can play a role in regenerative strategies in rotator cuff injuries. Treating FAPs with B agonists and performing single-cell RNA sequencing showed two key pathways that hold promise for muscle regeneration (Fig. 1). Six distinct subpopulations of human FAPs were found to have the presence of a fat cell that generates heat by dissipating energy and extracellular vesicle (EV)–associated markers. EVs are secreted by cells and consist of lipids, nucleic acids, and proteins. The researchers hypothesized that this could be a mechanism by which FAPs promote regeneration. The team partnered with Robert Raffai, PhD, professor-in-residence in surgery at UCSF, to show that mice treated with EVs at the time of rotator cuff injury demonstrated markedly reduced muscle atrophy and fatty infiltration as compared with treatment with control EVs or saline. This shows that EVs are a potential strategy to harness the regenerative potential of B agonist–treated human FAPs.

“We’ve shown in mice that it would be a reasonable next step to look at a pharmacologic treatment in a large animal model and then proceed to a clinical trial, which could be feasible in the next 3 to 5 years,” Dr. Feeley said.

“Some of our recent studies have looked at not only if a pharmacologic treatment works but the mechanisms behind that. We’ve studied different potential avenues based on our single-cell data—FAPs treated with a B agonist or a drug stimulant that seem to secrete EVs that promote muscle regeneration, which is specific to those cells. We can imagine a treatment where you bank the B agonist–treated FAPs and administer them directly into the muscle at the time of surgery to promote muscle regeneration,” he added.

Building better tools
To capture pain and kinematic movement data in an unbiased manner following rotator cuff repair, the group formed a collaboration with Jarret Weinrich, PhD, assistant adjunct professor in the UCSF Department of Anesthesia and Perioperative Care, to design machine-learning software for pain and kinematic analysis. It can track unbiased motion patterns following rotator cuff injury and repair, which mimics what is seen in a clinical setting. Patients with rotator cuff injuries often have different levels of pain and pain perception. These types of tools allow researchers to determine how pain specifically affects function after rotator cuff injury and how interventions, including repair and pharmacologic therapies, can decrease pain and function.

In a preliminary study, Dr. Feeley and his colleagues discovered that treatment with gabapentin may help sufficiently mitigate pain for rotator cuff patients. The team is currently conducting studies looking at the relationship between spinal cord plasticity and motor function using pharmacotherapies as treatment strategies to improve outcomes for patients with pain as their primary concern in rotator cuff degeneration.

“One of the drivers of better outcomes is how well the muscle functions after surgery. So, for practicing clinicians, it is important to understand the mechanisms behind how our muscles work and the generalizability of all basic science studies, whether you are a shoulder or spine surgeon,” Dr. Feeley said.

“We already know we can do great hip and knee replacements, but the variability in patient outcomes is pretty large. Shoulder surgeons are a bit ahead of other specialists because we understand how muscle quality affects not only rotator cuff injuries, but also the pull of the shoulder. This, in turn, impacts clinical outcomes for patients,” he added.

Molly Todd Rudy is a freelance writer for AAOS Now.

References

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2. Uezumi A, Ito T, Morikawa D, et al: Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J Cell Sci 2011;124(Pt 21):3654-64. doi: 10.1242/jcs.086629.
3. 3. Agha O, Diaz A, Davies M, et al: Rotator cuff tear degeneration and the role of fibro-adipogenic progenitors. Ann N Y Acad Sci 2021;1490(1):13-28. doi: 1111/nyas.14437.
4. Malecova B, Gatto S, Etxaniz U, et al: Dynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy. Nat Commun 2018;9(1):3670. doi: 10.1038/s41467-018-06068-6.