Disclosures Understanding the Development of Muscle Atrophy and - - PowerPoint PPT Presentation

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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 Kappa Delta Presentation, ORS 2014

Disclosures

• Funding Sources:

– UCSF (Academic Senate) – OREF Young Investigator Award – OREF Career Development Award – NIH (R03AR060871—1A1)

Rotator Cuff Tears: 2000-2007

• Large and massive tears do not heal well
• Atrophy and Fatty Infiltration are

important factors in outcomes after RCT

• Molecular pathways are not known
• Limited animal models to study

pathophysiology muscle changes after RCT

“Muscle atrophy and fatty infiltration of the rotator cuff muscles play a significant role in determining functional

• utcome 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.

How does muscle quality affect orthopaedic outcomes?

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Development of a small animal model of massive RCT: Part I

Liu et al JOR 2011

0.1 0.2 0.3 0.4

Suprspinatus weight Infraspinatus weight Sham TT TT+DN

intact

Tendon transection (TT) TT+Denervation (DN)

Development of a small animal model of massive RCT: Part I

Liu et al JOR 2011

Rat model: Minimal healing (20%) Moderate atrophy, fibrosis not much fatty infiltration Picric acid stain for fibrosis Oil Red O Stain for fat Development of a small animal model of massive RCT: Part II Mouse model

• Isolated denervation
• Combined groups

Liu, et al JBJS 2012

Suprascapular nerve Significant atrophy at 12 weeks Development of a small animal model of massive RCT: Part II Summary mouse model: separate incision for DN-better atrophy, FI, fibrosis

Liu, et al JBJS 2012

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Molecular Mechanisms of Muscle Atrophy and Fatty Infiltration Molecular pathway that controls muscle size Possibly has a role in fatty infiltration Define targets for therapeutic modulation (i.e. muscle specific)

Mech.

Ideal Pathway….

RCT/mechanical unloading leads to a decrease in Akt/mTOR activity and muscle atrophy

Liu X, et al JOR 2012

?

? Mech ?

T T D N Sham Treated

In situ mTOR activity Denervation of the RCT increases Akt/mTOR activity

Liu X, et al JOR 2012

How does TT result in muscle atrophy?

Joshi et al JOR 2014

Lysosomal/Autophagy Pathway (alternative pathway) Ubiquitin/Proteosome Activity (Classic atrophy pathway) Summary: TT: Atrophy via increased Lysosomal activity DN: Atrophy via increased Ub/Proteosome

CSR PI3K Akt

mTOR FOXO Atrogin-1 Ubiquitin Proteosome Autophagy Lysosome Protein synthesis Protein Degradation Atrophy

TT

TT

DN DN

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Early

Loss of mechanical load AKT/mTOR Pathway Traction on SSN Denervation Increased Lysosomal degradation Mild muscle atrophy Increased Ubiquitin- Proteosome pathway Marked muscle atrophy

Late

Liu X, et al JOR 2012, Joshi, et al. JOR 2014

Atrophy in RCT: a clinical scenario

Can Fatty Infiltration be Inhibited via Akt/mTOR Pathway?

“We found a significantly increased expression of Myf-5 and PPARgamma after tenotomy” Frey et al, JOR 2009.

Western Blot, Protein Expression

SREBP1 P-mTOR PPARγ

Immunohistochemistry Can Fatty Infiltration be Inhibited via Akt/mTOR Pathway?

Joshi, et al JOR 2013

Akt mTOR SREBP1 PPARy Adipogenesis FATTY INFILTRATION

Sham TT+DN

SREBP-1 p-mTOR Rapamycin PPARγ Vehicle TT+DN 50 100 150 200 250 p-mTOR SREBP-1 PPARγ

Intensity of Band (arbitrary unit)

Rap + Rap - TT+DN

* * *

TT+DN (No Treatment) Rap +

Rapamycin inhibits development of fatty infiltration

Joshi, et al JOR 2013

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Regulation of Fibrosis after RCT Significant increase in fibrosis after RCT—is this responsible for non-compliant muscle?

Terada JBJS 2013 Goodman Mol Endo 2013

RCT RCT RCT

TGF-B Signaling is upregulated after rotator cuff tears

Liu et al JSES, 2014, in press; 2014 ORS (abstract #1012) TGF-B1

2 weeks 6 weeks RCT Sham

• 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 Summary…so far

Rotator cuff tear Tendon degeneration Muscle degeneration Cartilage degeneration Muscle atrophy Muscle fibrosis Fatty infiltration

Akt/mTOR FOXO MuRF-1 MAFBx Lysosome Akt/mTOR SREBP-1 PPARy TGF-B (JSES 2014, in press) MMP-13 (ORS 2014) Kramer, JSES 2013

Thank you 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) Future shoulder surgeons UCSF-VA Lab