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