Bonnie Purvis Warren, president of the Kappa Delta Foundation; Brian Feeley, MD, winner of the Kappa Delta Young Investigator Award; and Peter Amadio, MD, chair of the AAOS Research Development Committee.

AAOS Now

Published 4/1/2014

Understanding Muscle Atrophy and FI in Massive RCTs

Award-winning research may lead to improved outcomes after rotator cuff repair

Brian Feeley, MD, received the 2014 Kappa Delta Young Investigator Award for his pioneering research into the molecular pathways that govern muscle atrophy and fatty infiltration (FI) in rotator cuff tears (RCTs). Throughout a 5-year period, Dr. Feeley and his fellow researchers developed a small animal model of RCTs and used this model to identify the ways in which RCTs affect surrounding muscle.

“We found that an intracellular signaling pathway believed to be critical in regulating muscle mass in normal muscle (Akt/mTOR) has a central role in the development of muscle atrophy and FI through its modulation of downstream effectors,” noted Dr. Feeley. “Our results also showed that inhibiting this pathway can effectively decrease the development of FI.”

Targeted therapies based on the data he and his colleagues collected may enhance the outcomes of patients who undergo rotator cuff repair in the future, asserted Dr. Feeley.

“Given the importance of muscle atrophy in other disease states such as cancer, aging, and diabetes, we believe that the results of these current studies have the potential for a broader impact across medicine,” he said.

The need for a rotator cuff model
Although muscle atrophy is a common problem that affects many patients, much remains to be discovered regarding how it develops, noted Dr. Feeley.

“The molecular pathways that govern the development of muscle atrophy and FI are poorly understood, and, therefore, targeted molecular therapies are lacking,” he explained.

Arthroscopic surgery often yields positive outcomes for patients with small or medium-sized RCTs, but the prognosis is not as good for patients with large and massive tears. Patients with these larger tears often sustain recurrent tears and have poor muscle function after undergoing rotator cuff repair, even after tears are successfully repaired.

Poor outcomes after attempted repair of massive RCTs, noted Dr. Feeley, have been linked to atrophy of the supraspinatus and infraspinatus muscle, as well as FI of the muscles.

“It also appears that there is a component of denervation of the rotator cuff in these massive tears, which likely has an important role in the advanced atrophy and FI seen in these injuries,” said Dr. Feeley. Both FI and muscle atrophy have been demonstrated to be irreversible in many cases, even after a massive tear is successfully repaired.

“RCTs are among the musculoskeletal injuries that orthopaedic surgeons treat initially with nonsurgical management and may undergo many physiologic changes prior to attempted repair,” noted Dr. Feeley. “Thus, studying muscle atrophy and its related pathophysiology in a rotator cuff model has immediate clinical relevance and the ability to translate our findings across the broader scope of muscle disease processes.”

Studying the molecular changes occurring in muscle during atrophy “may enable the development of therapeutic modalities that would inhibit or reverse FI and atrophy after repair of massive RCTs.”

A series of studies
Dr. Feeley and his colleagues conducted studies focused on seven different areas, starting with a rat model of massive RCTs.

“The purpose of this study was to better replicate what is seen clinically in massive RCTs by transecting the supraspinatus, infraspinatus, and teres minor tendons in the rat model,” explained Dr. Feeley.

Using this model, Dr. Feeley and his fellow researchers found that they could reproducibly create muscle atrophy and FI in a small animal model. Next, they were able to demonstrate consistent and reproducible muscle atrophy, FI, and muscle fibrosis—“changes that were increased by denervation of the muscle.”

Additional studies focused on the following areas:

  • magnetic resonance imaging (MRI) quantification of muscle atrophy and FI in a mouse RCT model
  • evaluation of the Akt/mTOR pathway in the development of muscle atrophy after an RCT
  • the role of Akt/mTOR in the development of FI
  • evaluation of the disparate mechanisms of muscle atrophy after tendon transection and denervation
  • the role of transforming growth factor-beta (TGF-β) in the development of muscle injury after rotator cuff tears

Research implications
The work accomplished by Dr. Feeley and his colleagues demonstrates that a reliable small animal model of RCTs can be used to create and study muscle atrophy and FI.

“Based on our results, we believe that denervation has an important, previously poorly defined role in the development of both atrophy and FI,” said Dr. Feeley. “We have also used small animal high-resolution MRI to noninvasively evaluate muscle atrophy and FI and can use this strategy to quantify the amount of fat present.”

Yet another important conclusion, noted Dr. Feeley, is that denervation of the rotator cuff muscle and mechanical uncoupling of the rotator cuff from the proximal humerus regulate the Akt/mTOR pathway in different ways, resulting in FI and a decrease in muscle.

“Our current work focuses on utilizing our small animal model to investigate the regulation of the Akt/mTOR pathway as well as the TGF-β pathway in the regulation of muscle changes after a rotator cuff tear,” noted Dr. Feeley. “We have defined the Akt/mTOR pathway as an important regulator of muscle size as well as FI through its regulation of the protein SREBP-1.”

Dr. Feeley and his colleagues recently identified TGF-β as a potential ‘master regulator’ of pathophysiologic changes after an RCT.

“Our data support these cells as a potential key cell line responsible for the pathophysiologic changes after an RCT,” he noted.

In the future, Dr. Feeley and his fellow researchers anticipate using the small animal RCT model to assess the potential ability of small molecule inhibitors of pathways to be used in treating atrophy and FI.

“Most importantly, investigation into the cellular source of the fibroblasts and adipocytes that appear to infiltrate into the interstitial portions of the muscle and cause the irreversible changes that occur after large rotator cuff tears may provide an alternative avenue for treatment strategies,” stated Dr. Feeley. “We believe that these endothelial lineage stem cells could be driven toward a muscle phenotype after rotator cuff repair, thus improving the outcomes after rotator cuff repair, given the correct stimulus.”

Dr. Feeley’s coauthors are Xuhui Liu, MD, and Hubert Kim, MD, PhD.

Drs. Feeley and Liu report no conflicts. Dr. Kim—The Knee.

Bottom Line

  • This research demonstrates that a reliable small animal model of rotator cuff tears can be used to create and study muscle atrophy and FI.
  • Data suggest that the Akt/mTOR pathway has a central role in the development of muscle atrophy and FI through its modulation of downstream effectors.
  • The research also indicates that inhibition of the Akt/mTOR pathway can effectively decrease the development of FI.
  • Targeted therapies based on the data from this research may enhance the outcomes of patients who undergo rotator cuff repair in the future and may also have broader applications for conditions involving muscle atrophy, such as aging, diabetes, and cancer.

Additional Information:
Can Muscle Atrophy Be Reversed?