5/8/2014 Understanding the Development of Muscle Atrophy and Fatty Infiltration in Massive Rotator Cuff Tears Brian Feeley, MD Xuhui Liu, MD Hubert Kim, MD, PhD Department of Orthopaedic Surgery, University of California, San Francisco Disclosures • Funding Sources: – UCSF (Academic Senate) – OREF Young Investigator Award – OREF Career Development Award – NIH (R03AR060871—1A1) Kappa Delta Presentation, ORS 2014 Rotator Cuff Tears: 2000-2007 How does muscle quality affect orthopaedic outcomes? -Large and massive tears do not heal well -Atrophy and Fatty Infiltration are important factors in outcomes after RCT “Muscle atrophy and fatty infiltration of the rotator cuff muscles play a significant role in determining functional outcome after cuff repair. A successful repair did not lead to improvement or reversal of muscle degeneration and a failed repair resulted in significantly more progression.” Gladstone et al, AJSM 2007. -Molecular pathways are not known -Limited animal models to study pathophysiology muscle changes after RCT 1 5/8/2014 Development of a small animal model of massive RCT: Part I Sham 0.4 intact Tendon transection (TT) TT Development of a small animal model of massive RCT: Part I TT+DN 0.3 Picric acid stain for fibrosis Oil Red O Stain for fat 0.2 0.1 TT+Denervation (DN) 0 Suprspinatus weight Infraspinatus weight Liu et al JOR 2011 Liu et al JOR 2011 Development of a small animal model of massive RCT: Part II Rat model: Minimal healing (20%) Moderate atrophy, fibrosis not much fatty infiltration Development of a small animal model of massive RCT: Part II Mouse model • Isolated denervation • Combined groups Significant atrophy at 12 weeks Suprascapular nerve Liu, et al JBJS 2012 Summary mouse model: separate incision for DN-better atrophy, FI, fibrosis Liu, et al JBJS 2012 2 5/8/2014 Molecular Mechanisms of Muscle Atrophy and Fatty Infiltration RCT/mechanical unloading leads to a decrease in Akt/mTOR activity and muscle atrophy Ideal Pathway…. Molecular pathway that controls muscle size Mech. ? Mech ? ? Possibly has a role in fatty infiltration Define targets for therapeutic modulation (i.e. muscle specific) Liu X, et al JOR 2012 Denervation of the RCT increases Akt/mTOR activity Sham How does TT result in muscle atrophy? T T D N CSR PI3K Akt FOXO mTOR Atrogin-1 Ubiquitin Proteosome Autophagy Lysosome Protein synthesis In situ mTOR activity Protein Degradation Atrophy Ubiquitin/Proteosome Activity (Classic atrophy pathway) TT Liu X, et al JOR 2012 Lysosomal/Autophagy Pathway (alternative pathway) Treated Joshi et al JOR 2014 DN TT DN Summary: TT: Atrophy via increased Lysosomal activity DN: Atrophy via increased Ub/Proteosome 3 5/8/2014 Early Atrophy in RCT: a clinical scenario Can Fatty Infiltration be Inhibited via Akt/mTOR Pathway? Increased Lysosomal degradation Loss of mechanical load Mild muscle atrophy AKT/mTOR Pathway Increased UbiquitinProteosome pathway Marked muscle atrophy Late Liu X, et al JOR 2012, Joshi, et al. JOR 2014 Akt Can Fatty Infiltration be Inhibited via Akt/mTOR Pathway? Rapamycin inhibits development of fatty infiltration Rapamycin mTOR SREBP1 p-mTOR PPARy SREBP-1 Adipogenesis Immunohistochemistry P-mTOR Western Blot, Protein Expression PPARγ SREBP1 Sham Vehicle TT+DN TT+DN (No Treatment) PPARγ 250 FATTY INFILTRATION TT+DN Joshi, et al JOR 2013 “We found a significantly increased expression of Myf-5 and PPARgamma after tenotomy” Frey et al, JOR 2009. Intensity of Band (arbitrary unit) Traction on SSN Denervation Rap + 200 150 100 * 50 0 Rap + Rap - * TT+DN * p-mTOR SREBP-1 PPARγ Joshi, et al JOR 2013 4 5/8/2014 Regulation of Fibrosis after RCT TGF-B Signaling is upregulated after rotator cuff tears TGF-B1 RCT Goodman Mol Endo 2013 RCT Sham RCT RCT Terada JBJS 2013 Liu et al JSES, 2014, in press; 2014 ORS (abstract #1012) Significant increase in fibrosis after RCT—is this responsible for non-compliant muscle? Summary…so far • Rat and mouse model of massive RCT are reasonable to study muscle changes after RCT • Mechanical unloading and denervation cause different effects on muscle genotype • Akt/mTOR pathway is an important regulator of atrophy/FI • TGF-B likely important in fibrosis, may be upstream regulator of Akt/mTOR Rotator cuff tear Tendon degeneration Muscle degeneration Cartilage degeneration Kramer, JSES 2013 Muscle atrophy Fatty infiltration Akt/mTOR FOXO MuRF-1 MAFBx Lysosome Akt/mTOR SREBP-1 PPARy Muscle fibrosis TGF-B (JSES 2014, in press) MMP-13 (ORS 2014) UCSF Muscle Lab Xuhui Liu, MD Hubert Kim, MD, PhD Niko Laron, MD Sanjum Samagh, MD Sunil Joshi Bharat Ravishankar UCSF C. Benjamin Ma, MD Tamara Alliston, PhD Jeff Lotz, PhD Funding UCSF Academic Senate OREF NIH (R03AR060871—1A1) Thank you 2 weeks 6 weeks Future shoulder surgeons UCSF-VA Lab 5
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