ROSEMONT, Ill., Feb. 7, 2025 /PRNewswire/ -- Brian T. Feeley, MD, FAAOS, was bestowed with the 2025 Kappa Delta Elizabeth Winston Lanier Award for his research in advancing the understanding of muscle degeneration in rotator cuff injuries and how it affects repair outcomes. Throughout the last 15 years, Dr. Feeley and his team 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.

To read more about the award, please click here.

Rotator cuff injuries are extremely common in the United States, with nearly 2 million adults visiting their physician yearly due to a rotator cuff tearⁱ and affecting between 6.8% and 22.4% of the population over age 40.ⁱⁱ Most tears are caused by normal wear and tear over time, putting those over 40 at the greatest risk. Tears can cause arm weakness and pain, inhibiting daily activities.ⁱ Even after successful repair, muscle atrophy and fatty infiltration (an abnormal accumulation of fat in muscle) can remain, resulting in higher retear rates and decreased patient function.

"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, orthopedic surgeon, chief, Division of Sports Medicine and Shoulder Surgery, and director, 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 wasn't a 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 Orthopedic Surgery at UCSF; Steven Garcia, MD, orthopaedic surgery resident PGY5 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, Hospital for Special Surgery in New York City ― developed a mouse model that demonstrated consistent and reproducible muscle atrophy, muscle fibrosis and fatty infiltration, allowing researchers an animal model that could study pathophysiologic changes that occur in rotator cuff tears. A key advantage of mouse models is that mice use their rotator cuff 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, where 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 (an immunosuppressive drug) 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 (cells that develop into connective tissue, blood vessels and lymphatic tissue) that had a unique cell surface marker within muscle. These cells allowed researchers to track it over time and how these cells could differentiate into several other cell types with the proper stimulus ― the fibroadipoprogenitor cell (FAP).^iii,iv Dr. Feeley aimed to understand if 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. Following rotator cuff injury, a loss of fatty infiltration was seen, confirming FAPs are the cellular source responsible for fatty infiltration.

Revealing Roles and Complexities of FAPs
While FAPs are  responsible for fatty infiltration, which is a degenerative function, other studies showed that FAPs could also be capable of regenerative and pathologic responses to muscle injury.^v,vi The research team set out to determine if 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 (a motor and sensory nerve in the shoulder), followed by repair six 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. By testing mouse and human FAPs in vitro with B-agonists (a class of drugs that relax muscles), there were several outcomes suggesting FAPs are closer to beige fat, a type of fat cell that burns energy, terming these FAPs beige-FAP. By inducing beige-FAP transplanted cells into a rotator cuff model of injury and after repair 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 found there were two key pathways that hold promise for muscle regeneration. 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-associated markers. Extracellular vesicles (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 could be promoting regeneration. The team partnered with Robert Raffai, PhD, professor in residence 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 three to five years," said Dr. Feeley. "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."

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. They can track unbiased motion patterns following rotator cuff injury and repair, which mimics what is seen in a clinical setting. Patients often present rotator cuff injuries with 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 (a neuropathic pain medication) 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 a treatment strategy 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, ," said Dr. Feeley. "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."

About the Kappa Delta Awards
The Kappa Delta Awards, the first of which was established by the Kappa Delta Sorority and awarded in 1950, are presented by the AAOS to persons who have performed research in orthopaedic surgery that is of high significance and impact. The sorority would later add two more awards, valued at $20,000 each. Two awards are named for the sorority national past presidents who were instrumental in the creation of the awards: Elizabeth Winston Lanier and Ann Doner Vaughn. The third is known as the Young Investigator Award.

For more information, please visit aaos.org/kappadelta. Learn more about the Kappa Delta Foundation, here.

About the AAOS
With more than 39,000 members, the American Academy of Orthopaedic Surgeons is the world's largest medical association of musculoskeletal specialists. The AAOS is the trusted leader in advancing musculoskeletal health. It provides the highest quality, most comprehensive education to help orthopaedic surgeons and allied health professionals at every career level to best treat patients in their daily practices. The AAOS is the source for information on bone and joint conditions, treatments and related musculoskeletal health care issues; and it leads the health care discussion on advancing quality.

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Disclosure
Funding and Conflicts of Interest
For a list of disclosures, funding and conflicts of interest, email media@aaos.org. 

ⁱ American Academy of Orthopaedic Surgeons, OrthoInfo. Rotator Cuff Tears. Published June 2022. Accessed Jan. 10, 2025.  https://orthoinfo.aaos.org/en/diseases--conditions/rotator-cuff-tears/
ⁱⁱ Kuhn JE. Prevalence, Natural History, and Nonoperative Treatment of Rotator Cuff Disease. Operative Techniques in Sports Medicine. Volume 31, Issue 1, 2023. https://doi.org/10.1016/j.otsm.2023.150978.
ⁱⁱⁱ Uezumi A, Fukada S, Yamamoto N, et al. 2010. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol 12:143-152.
^ivUezumi A, Ito T, Morikawa D, et al. 2011. Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J Cell Sci 124:3654-3664.
^vAgha O, Diaz A, Davies M, et al. 2021. Rotator cuff tear degeneration and the role of fibro-adipogenic progenitors. Ann N Y Acad Sci 1490:13-28.
^vi Malecova B, Gatto S, Etxaniz U, et al. 2018. Dynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy. Nat Commun 9:3670.

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SOURCE American Academy of Orthopaedic Surgeons