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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)

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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
Immobilization
  • Mechanical fixation
    • External (cast)
    • Internal (pins)
    • Mixed (bone-mounted external clamps)
  • Posture
  • Muscle activity
    • Animal models: length-dependent activity
    • Human/clinical
fournier study
Fournier study
  • ‘Residual’ muscle activity depends on length
  • Muscle mass preserved at long length
  • Reduced activity (short) without extra atrophy
lieber study
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
Muscle-specific atrophy

Vastus Medialis

Rectus Femoris

Dark: fast

Light: slow

use and mechanics influence atrophy
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
Ubiquitin/Proteasome
  • Predominant pathway for protein degradation
  • Anti-ribosome
  • Ubiquitin
  • Poly-Ub
  • Proteasome

Pollard & Earnshaw, 2008

EM of proteasome

atrogene signaling
“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

unloading
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
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
Spaceflight muscle disruption
  • SLS-1 (1991)
  • 9 days
  • 25% atrophy
  • Expandedinterstitia

Ground control

9 days SLS-1 + 3h

Riley & al., 1996

spaceflight muscle disruption1
Spaceflight muscle disruption
  • Sarcomere disruption
  • Z-disk streaming
spaceflight fiber adaptation
Spaceflight: fiber adaptation
  • Sandona & al 2012
    • Mice Drawer System (MDS)
    • 91 days on ISS
  • Fiber properties
  • Transcriptionalprofiling

Image: NASA

muscle specific atrophy1
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
Spaceflight-induced genes
  • “Stress Response”
    • PERK
    • HSP70
    • NFkB
  • Atrophy
    • MuRF
    • Atrogin
  • Channels

Ubiquitin ligases

Fold induction with 90 day spaceflight

6 head down bedrest
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
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

muscle specific atrophy2
Muscle-specific atrophy
  • By MRI volume

Miokovic, & al.,2012

acute atrophy with bed rest
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

hindlimb suspension
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
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

atrogene signaling during hs
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
Proteolytic systems during HS
  • Lysosomes
    • Acidic, autophagic compartment
    • Cathepsin proteases
  • Calpains
    • Calcium-activated cytosolic

Taillandier & al 1996

Enns & al., 2007

calpain action during hs
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
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

summary
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)