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Unloading Adaptation

Unloading Adaptation. Experimental models of decreased use Immobilization Hindlimb suspension Spaceflight (Denervation) Factors contributing to atrophy Clinical consequences of immobilization. Immobilization. Mechanical fixation External (cast) Internal (pins)

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Unloading Adaptation

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  1. Unloading Adaptation • Experimental models of decreased use • Immobilization • Hindlimb suspension • Spaceflight • (Denervation) • Factors contributing to atrophy • Clinical consequences of immobilization

  2. Immobilization • Mechanical fixation • External (cast) • Internal (pins) • Mixed (bone-mounted external clamps) • Posture • Muscle activity • Animal models: length-dependent activity • Human/clinical

  3. Fournier study • ‘Residual’ muscle activity depends on length • Muscle mass preserved at long length • Reduced activity (short) without extra atrophy

  4. Lieber study • External Fixator • Immobilize only one joint • No wiggling • Quadriceps • Vasti: single joint knee extensors • Rectus femoris: biarticular KE and hip flexor

  5. Muscle-specific atrophy Vastus Medialis Rectus Femoris Dark: fast Light: slow

  6. Use and mechanics influence atrophy • RF is relatively spared (biarticular) • Fiber type • Slow fibers in slow VM sensitive • Fast fibers in fast VL sensitive

  7. Ubiquitin/Proteasome • Predominant pathway for protein degradation • Anti-ribosome • Ubiquitin • Poly-Ub • Proteasome Pollard & Earnshaw, 2008 EM of proteasome

  8. “Atrogene” signaling • MuRF + Atrogin/MafBx • Muscle specific E3 ligases • Seem to drive atrophy Growth Factors Akt “Stress” FOXO1/3a HSP70 MuRF Atrogin Transgenic HSP70 expression reduces immobilization-atrophy Senf & al., 2008 Protein Degradation

  9. Unloading • Reduce force, maintain mobility • Spaceflight • Maintains mobility, decreases ROM • Inertial loading • Rapid loss of bone and muscle • 6° head-down bed rest • Space-mimetic • Cardiovascular & hemodynamic • Hindlimb suspension

  10. Space: Loss of function • Rapid loss of strength (20% 3 weeks) • Slower, variable loss of mass ~15% 5 weeks Adams & al., 2003

  11. Spaceflight muscle disruption • SLS-1 (1991) • 9 days • 25% atrophy • Expandedinterstitia Ground control 9 days SLS-1 + 3h Riley & al., 1996

  12. Spaceflight muscle disruption • Sarcomere disruption • Z-disk streaming

  13. Spaceflight: fiber adaptation • Sandona & al 2012 • Mice Drawer System (MDS) • 91 days on ISS • Fiber properties • Transcriptionalprofiling Image: NASA

  14. Muscle-specific atrophy • EDL: fast muscle doesn’t care (much) • Soleus: postural muscle A few type 2b fibers A few type 1 fibers No atrophy Atrophy

  15. Spaceflight-induced genes • “Stress Response” • PERK • HSP70 • NFkB • Atrophy • MuRF • Atrogin • Channels Ubiquitin ligases Fold induction with 90 day spaceflight

  16. 6° head-down bedrest • 30-90 days • Blood draws • Biopsies/scans • Space-mimetic • Fluid shift • Cardiorespiratory • Similar magnitude muscle/bone strength loss Photo: NASA Ames

  17. Muscle atrophy during bedrest • Nitrogen balance • Net amino acid intake-excretion • Protein accretionestimate • Strength loss:selective Negative nitrogen balanceatrophy Weeks (16 wk bed+recovery) 0 5 10 15 20 25 60 Knee Ext 40 Knee Flex 20 Sterngth Change (%) 0 - 20 - 40 - 60 Stein & Schulter 1997

  18. Muscle-specific atrophy • By MRI volume Miokovic, & al.,2012

  19. Acute ‘atrophy’ with bed rest • 24 hours BR/HDT • 0.5, 2, 5 hour upright • 15% apparentatrophy overnight • Apparenthypertrophy inneck muscles • Full recovery in0.5-2 hours • Fluid shift Calf, horizontal Calf, head-down Neck, head-down Neck, horizontal Conley & al., 1996

  20. Hindlimb suspension • Rodent model • Capture tail in low stress mesh/friction tape • Suspend by runner system • Hindlimbs just elevated • Fluid shift • Unload, esp anti-grav • Stretch flexors Shimano & Volpon, 2007

  21. Suspension Atrophy • Young rats (~100g) • Soleus • 40% atrophy • 100% loss-of-growth • Mass preserved by casting • Protein accretion • Control: +13%/-8%/day • Suspended:+11%/-28% Control Pair-fed Suspended and casted Suspended Time (weeks) Goldspink & al., 1986

  22. Atrogene signaling during HS • Rat Medial Gastroc • Rapid muscle mass loss • Preceded by MuRF/MAFbx • Transgenic MAFbx • Smaller cells Bodine & al., 2001

  23. Proteolytic systems during HS • Lysosomes • Acidic, autophagic compartment • Cathepsin proteases • Calpains • Calcium-activated cytosolic Taillandier & al 1996 Enns & al., 2007

  24. Calpain action during HS • cp mice express calpain inhibitor • Doesn’t (much) change loss of mass • Substantial sparing of force production Salazaar & al., 2010

  25. Calpain Targets • Structural: Desmin, nebulin, utrophin • Suspension disruptssarcomere structure • Calpastatin (cp)mice retain struct &force capacity • Calpains ‘release’sarcomere matrix tofacilitate digestion Salazaar & al., 2010

  26. Summary • Models of decreased use • Atrophy rules • Immobility, inactivity  atrophy • Strength loss precedes mass loss • Large fibers are more sensitive • Active degradation pathways • Proteasome (MuRF/MAFbx) • Lysosomes (cathepsin) • Calpains (sarcomere stability)

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