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Reversal of Fatty Infiltration After Suprascapular Nerve Compression Release Is Dependent on UCP1 Expression in Mice

Wang, Zili, MD; Feeley, Brian T., MD; Kim, Hubert T., MD, PhD; Liu, Xuhui, MD

Clinical Orthopaedics and Related Research®: August 2018 - Volume 476 - Issue 8 - p 1665–1679
doi: 10.1097/CORR.0000000000000335
BASIC RESEARCH
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Background In large rotator cuff tears, retraction of the supraspinatus muscle creates suprascapular nerve traction and compression. However, suprascapular nerve transection, when used in previous models, is different from chronic compression of the suprascapular nerve in patients. To define the role of suprascapular nerve chronic injury in rotator cuff muscle atrophy and fatty infiltration, we developed a novel reversible suprascapular nerve compression mouse model.

Questions/purposes We asked: (1) Can suprascapular nerve injury be induced by compression but reversed after compression release? (2) Can muscle fatty infiltration be induced by suprascapular nerve compression and reversed after compression release? (3) Is white fat browning involved in fatty infiltration resorption?

Methods Mice in a common strain of C57BL/6J were randomly assigned to suprascapular nerve transection (n = 10), nerve compression (n = 10), nerve compression and release (n = 10), or sham control (n = 10) groups. To study the role or white fat browning on muscle fatty infiltration, additional UCP1 reporter mice (n = 4 for nerve compression and n = 4 for nerve compression release) and knockout mice (n = 4 for nerve compression and n = 4 for nerve compression release) were used. Nerve injury was testified using osmium tetroxide staining and neural muscular junction staining and then semiquantified by counting the degenerating axons and disrupted junctions. Muscle fatty infiltration was evaluated using Oil Red O staining and then semiquantified by measuring the area fraction of fat. Immunofluorescent and Oil Red O staining on UCP1 transgenic mice was conducted to testify whether white fat browning was involved in fatty infiltration resorption. Ratios of UCP1 positively stained area and fat area to muscle cross-section area were measured to semiquantify UCP1 expression and fatty infiltration in muscle by blinded reviewers. Analysis of variance with Tukey post hoc comparisons was used for statistical analysis between groups.

Results Suprascapular nerve injury was induced by compression but reversed after release. The ratios of degenerating axons were: sham control: 6% ± 3% (95% confidence interval [CI], 3%-10%); nerve compression: 58% ± 10% (95% CI, 45%-70% versus sham, p < 0.001); and nerve compression and release: 15% ± 9% (95% CI, 5%-26% versus sham, p = 0.050). The supraspinatus muscle percentage area of fatty infiltration increased after 6 weeks of nerve compression (19% ± 1%; 95% CI, 18%-20%; p < 0.001) but showed no difference after compression release for 6 weeks (5% ± 3%; 95% CI, 1%-10%; p = 0.054) compared with sham (2% ± 1%; 95% CI, 1%-3%). However, the fat area fraction in UCP1 knockout mice did not change after nerve compression release (6% ± 1%; 95% CI, 4%-8% at 2 weeks after compression and 5% ± 0.32%; 95% CI, 4%-6% after 2 weeks of release; p = 0.1095).

Conclusions We developed a clinically relevant, reversible suprascapular nerve compression mouse model. Fatty infiltration resorption after compression release was mediated through white fat browning.

Clinical Relevance If the mechanism of browning of white fat in rotator cuff muscle fatty infiltration can be confirmed in humans, a UCP1 agonist may be an effective treatment for patients with suprascapular nerve injury.

Z. Wang, Department of Orthopaedic Surgery, Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China

Z. Wang, B. T. Feeley, H. T. Kim, X. Liu, San Francisco Veterans Affairs Medical Center, Department of Veterans Affairs, San Francisco, CA, USA; and the Department of Orthopedic Surgery, University of California at San Francisco, San Francisco, CA, USA

X. Liu, San Francisco Veterans Affairs Medical Center, Department of Veterans Affairs, 1700 Owens Street, San Francisco, CA 94158, USA, email: liu.xuhui@ucsf.edu

The institution of one of the authors (ZW; Third Xiangya Hospital of Central South University) received, during the study period, a training fund in the amount of USD 20,400 per year from the China Scholarship Council to support studying at the University of California, San Francisco. The institution of the authors (ZW, BTF, HTK, XL; San Francisco Veterans Affairs Medical Center) received, during the study period, funding from the VA BLR&D Merit review grant (HTK; 1 I01 BX002680-01A2) in the amount of USD 150,000 per year. The institution of the authors (ZW, BTF, HTK, XL; University of California at San Francisco) received, during the study period, funding from the UCSF Core Center for Musculoskeletal Biology and Medicine (BTF; National Institutes of Health 1P30AR066262-01) in the amount of USD 40,000 per year.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.

Each author certifies that his institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

This work was performed at the San Francisco Veterans Affair Health Medical Center, San Francisco, CA, USA.

Received October 31, 2017

Accepted April 12, 2018

© 2018 Lippincott Williams & Wilkins LWW
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