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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) – Mixed (bone-mounted external clamps) • Posture • Muscle activity – Animal models: length-dependent activity – Human/clinical Fournier study • ‘Residual’ muscle activity depends on length • Muscle mass preserved at long length • Reduced activity (short) without extra atrophy Lieber study • External Fixator – Immobilize only one joint – No wiggling • Quadriceps – Vasti: single joint knee extensors – Rectus femoris: biarticular KE and hip flexor Muscle-specific atrophy Vastus Medialis Rectus Femoris Dark: fast Light: slow Use and mechanics influence atrophy • RF is relatively spared (biarticular) • Fiber type – Slow fibers in slow VM sensitive – Fast fibers in fast VL sensitive Ubiquitin/Proteasome • • • • • Predominant pathway for protein degradation Anti-ribosome Ubiquitin Poly-Ub Proteasome Pollard & Earnshaw, 2008 EM of proteasome “Atrogene” signaling • MuRF + Atrogin/MafBx – Muscle specific E3 ligases – Seem to drive atrophy Growth Factors Akt “Stress” FOXO1/ 3a HSP70 MuRF Atrogin Protein Degradation Transgenic HSP70 expression reduces immobilization-atrophy Senf & al., 2008 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 Space: Loss of function • Rapid loss of strength (20% 3 weeks) • Slower, variable loss of mass ~15% 5 weeks Adams & al., 2003 Spaceflight muscle disruption • • • • SLS-1 (1991) 9 days 25% atrophy Expanded interstitia Ground control Riley & al., 1996 9 days SLS-1 + 3h Spaceflight muscle disruption • Sarcomere disruption • Z-disk streaming Spaceflight: fiber adaptation • Sandona & al 2012 – Mice Drawer System (MDS) – 91 days on ISS • Fiber properties • Transcriptional profiling Image: NASA 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 Spaceflight-induced genes • “Stress Response” IGF1 – PERK – HSP70 – NFkB PERK HSP70 NFkB • Atrophy – MuRF – Atrogin • Channels PKCe Soleus EDL PKCd KATP Ubiquitin ligases NaV1.4 Atrogin MuRF -5 0 5 10 15 Fold induction with 90 day spaceflight 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 Muscle atrophy during bedrest • Nitrogen balance – Net amino acid intake-excretion – Protein accretion estimate Negative nitrogen balanceatrophy • Strength loss:selective Sterngth Change (%) 0 Weeks (16 wk bed+recovery) 5 10 15 20 25 60 40 Knee Ext Knee Flex 20 0 -20 -40 -60 Stein & Schulter 1997 Muscle-specific atrophy • By MRI volume Miokovic, & al.,2012 Acute ‘atrophy’ with bed rest • 24 hours BR/HDT • 0.5, 2, 5 hour upright • 15% apparent atrophy overnight • Apparent hypertrophy in neck muscles • Full recovery in 0.5-2 hours • Fluid shift Calf, horizontal Calf, head-down Neck, head-down Neck, horizontal Conley & al., 1996 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 Suspension Atrophy • Young rats (~100g) • Soleus – 40% atrophy – 100% loss-of-growth – Mass preserved by casting Control Pair-fed • Protein accretion – Control: +13%/-8%/day – Suspended:+11%/-28% Suspended and casted Suspended Time (weeks) Goldspink & al., 1986 Atrogene signaling during HS • Rat Medial Gastroc – Rapid muscle mass loss – Preceded by MuRF/MAFbx • Transgenic MAFbx – Smaller cells Bodine & al., 2001 Proteolytic systems during HS • Lysosomes – Acidic, autophagic compartment – Cathepsin proteases • Calpains – Calcium-activated cytosolic Taillandier & al 1996 Enns & al., 2007 Calpain action during HS • cp mice express calpain inhibitor • Doesn’t (much) change loss of mass • Substantial sparing of force production Salazaar & al., 2010 Calpain Targets • Structural: Desmin, nebulin, utrophin • Suspension disrupts sarcomere structure • Calpastatin (cp) mice retain struct & force capacity • Calpains ‘release’ sarcomere matrix to facilitate digestion Salazaar & al., 2010 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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