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Can Muscle Atrophy Be Reversed?

OREF grant recipient studies biology of muscle loss in massive rotator cuff tears

Jay D. Lenn

Surgical repair of small rotator cuff tears is a common procedure, and patients usually do quite well. However, repairing large, massive rotator cuff tears is more challenging and outcomes are not as predictable. Large tears have a higher rate of recurrence and lower function even after successful repair. These problems are due, in part, to injury-related remodeling of the muscle, including irreversible muscle atrophy and fatty infiltration of muscle tissue. Also, massive tears may result in nerve damage that can exacerbate muscle degeneration.

To enhance healing of massive tears, many recent studies have focused on strategies such as double-row fixation techniques or the use of growth factors to improve tendon-to-bone healing. Fewer studies have focused on the pathophysiologic changes in rotator cuff muscles.

Brian T. Feeley, MD, assistant professor of orthopaedic surgery at the University of California, San Francisco, is one of the researchers investigating those changes. He received a 2010 Orthopaedic Research and Education Foundation (OREF) Young Investigator Grant to identify the molecular pathways that regulate atrophy and fatty infiltration in a rat model of massive rotator cuff tears.

MRI scan of a patient with a large rotator cuff tear. There is minimal atrophy in the supraspinatus (SS), but considerable atrophy and fatty infiltration in the infraspinatus muscle (IS).
Courtesy of Brian T. Feeley, MD

“I’m interested in why the muscle undergoes changes that are often unique to the rotator cuff when compared with muscle injury in other parts of the body. Even in the setting of a successful repair, the muscle rarely regenerates. If we can understand the mechanisms behind the muscle degeneration, we may be able to find ways to reverse the damage,” he explained.

OREF offers the 1-year Young Investigator Grant to physicians who are currently enrolled in surgical training or have completed training within the last 4 years. Like other research grants in the OREF portfolio, it’s intended to promote scientific training for the next generation of orthopaedists.

Creating injuries for analysis
A massive rotator cuff tear is generally defined as including more than one tendon and spanning more than 5 centimeters. Although studies have shown that such severe injuries are more likely to result in atrophy and fatty infiltration, the molecular pathways leading to these events are not well understood.

To create a research model that mimics the histology and muscle changes in humans, tendons of rat supraspinatus and infraspinatus muscles were surgically “torn.” To simulate disruption of the rotator cuff nerve supply, Dr. Feeley and his research team transected the suprascapular nerve. They performed surgeries on 100 rats—25 animals in each of the following injury profile groups:

  • Massive rotator cuff tear
  • Nerve transection
  • Massive rotator cuff tear and nerve transection
  • Sham injury (control group)

Assessing muscle pathology
Each of the treatment groups was then divided into five subgroups. To track pathologic changes over time, the researchers analyzed each subgroup at multiple time points. The analysis included the following measures:

  • Muscle weight to quantify degree of atrophy
  • Histologic analysis of the muscle to measure atrophy and fatty infiltration
  • High-resolution magnetic resonance imaging (MRI) to evaluate muscle changes and fatty infiltration

Additionally, Dr. Feeley and his colleagues performed protein expression analyses at the same time intervals to identify key molecular events associated with the observed cellular changes. They measured the expression of proteins previously shown to be associated with muscle atrophy.

High-resolution MRI three-dimensional (3D) reconstruction from a rotator cuff that underwent transection of the supraspinatus (red) and infraspinatus (blue) rotator cuff tendon. Fat is represented as yellow. With the 3D reconstruction, the researchers are able to quantitate muscle volume and degree of atrophy more accurately following rotator cuff tears.
Courtesy of Brian T. Feeley, MD

The research group found altered expression of the intracellular signaling pathway Akt/mTOR. This pathway is believed to be critical in regulating muscle mass in normal muscle. This information provides a target for potential therapeutic treatments to reverse the muscle atrophy seen following rotator cuff tears and repairs.

Translating the research into clinical practice
The time-dependent changes observed in molecular pathways—as well as the corresponding remodeling of muscle tissues—have provided Dr. Feeley and his team with a roadmap of the pathology of muscle loss in massive rotator cuff tears.

Dr. Feeley noted, “In the relatively short term, understanding this pathology may help us identify the point at which changes in muscle become irreversible or identify what factors contribute to irreversible change. This could help guide our conversations with patients about probable treatment outcomes. We might be able to say, ‘This muscle is too small to regenerate or there’s too much fatty infiltration in the muscle for regeneration.’”

The ultimate goal is to develop treatment strategies that could alter the molecular pathways directing muscle change. “For instance, if we identify a pathway that is turned off within muscle cells after tendon injury and if we can stimulate those pathways and turn them back on after a repair, then maybe patients will be able to regenerate muscle—and, in the end, use the repaired shoulder more effectively,” Dr. Feeley explained.

He reported that the OREF-funded research enabled him to develop the small animal models and the pilot data needed to move forward and seek long-term, sustainable funding for his investigation from the National Institutes of Health.

Jay D. Lenn is a contributing writer for OREF. He can be reached at communications@oref.org

AAOS Now
June 2012 Issue
http://www.aaos.org/news/aaosnow/jun12/research2.asp