mTOR regulates fatty infiltration through SREBP-1 and PPARγ after a combined massive rotator cuff tear and suprascapular nerve injury in rats

Authors

  • Sunil K. Joshi,

    1. San Francisco Veterans Affairs Medical Center, Department of Veterans Affairs, University of California, 1500 Owens Avenue, San Francisco, California 94153
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  • Xuhui Liu,

    1. San Francisco Veterans Affairs Medical Center, Department of Veterans Affairs, University of California, 1500 Owens Avenue, San Francisco, California 94153
    2. Department of Orthopaedic Surgery, University of California, San Francisco, California
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  • Sanjum P. Samagh,

    1. Department of Orthopaedic Surgery, University of California, San Francisco, California
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  • David H. Lovett,

    1. San Francisco Veterans Affairs Medical Center, Department of Veterans Affairs, University of California, 1500 Owens Avenue, San Francisco, California 94153
    2. Department of Medicine, University of California, San Francisco, California
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  • Sue C. Bodine,

    1. Department of Physiology and Membrane Biology, University of California, Davis, California
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  • Hubert T. Kim,

    1. San Francisco Veterans Affairs Medical Center, Department of Veterans Affairs, University of California, 1500 Owens Avenue, San Francisco, California 94153
    2. Department of Orthopaedic Surgery, University of California, San Francisco, California
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  • Brian T. Feeley

    Corresponding author
    1. San Francisco Veterans Affairs Medical Center, Department of Veterans Affairs, University of California, 1500 Owens Avenue, San Francisco, California 94153
    2. Department of Orthopaedic Surgery, University of California, San Francisco, California
    • San Francisco Veterans Affairs Medical Center, Department of Veterans Affairs, University of California, 1500 Owens Avenue, San Francisco, California 94153. T: 415-353-7586; F: 415-885-3838.
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  • Sunil K. Joshi and Xuhui Liu made an equal contribution to this work.

Abstract

Rotator cuff tears (RCTs) are among the most common injuries seen in orthopedic patients. Chronic tears can result in the development of muscular atrophy and fatty infiltration. Despite the prevalence of RCTs, little is known about the underlying molecular pathways that produce these changes. Recently, we have shown that mammalian target of rapamycin (mTOR) signaling plays an important role in muscle atrophy that results from massive RCTs in a rat model. The purpose of this study was therefore to extend our understanding of mTOR signaling and evaluate its role in fatty infiltration after a combined tendon transection and suprascapular nerve denervation surgery. Akt/mTOR signaling was significantly increased and resulted in the up-regulation of two transcription factors: SREBP-1 and PPARγ. We also saw an increase in expression of adipogenic markers: C/EBP-α and FASN. Upon treatment with rapamycin, an inhibitor of mTOR, we observed a decrease in mTOR signaling, activity of transcription factors, and reduction in fatty infiltration. Therefore, our study suggests that mTOR signaling mediates rotator cuff fatty infiltration via SREBP-1 and PPARγ. Clinically, our finding may alter current treatment methods to address rotator cuff fatty infiltration. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 724–730, 2013

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