Unloading Adaptation Experimental models of decreased use – (Immobilization) – (Hindlimb...
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![Page 1: Unloading Adaptation Experimental models of decreased use – (Immobilization) – (Hindlimb suspension) – Denervation – Spinal isolation Factors contributing.](https://reader035.fdocuments.us/reader035/viewer/2022062423/56649e745503460f94b749ce/html5/thumbnails/1.jpg)
Unloading Adaptation• Experimental models of decreased use
– (Immobilization)– (Hindlimb suspension)– Denervation– Spinal isolation
• Factors contributing to atrophy• Clinical consequences of immobilization
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Denervation• Nerve transection
– Remove coordinated descending input– Potential mobility in surrounding muscles
• Repair processes– Nerve regrowth: Same fibers? Same junction?– Muscle-derived signals?
• Muscle remodeling– Inactivityatrophy– Neuromuscular junction remodeling
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Degeneration-Regeneration• Initial insult
– Reduced protein synthesis/Elevated degradation– Fiber deconstruction/death
• Recovery– SC activation– Restored
protein syn
• Reinnervation– Fiber reorg– Relative
hypertrophy
Goldspink, 1976
Degradation/mg
Synthesis/mg
Degradation/muscle
Synthesis/muscle
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Schwann CellAxon
Synaptic cleft: Primary Secondary
Control 1 Week
3 Weeks (reinnervation
Axon dies rapidly, Schwann cell & ECM remain.Secondary synaptic clefts shrink & separate
Saito & Zacks, 1969
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Muscle wasting• Myofiber size
decrease• Connective tissue
hypertrophy• Adipocyte invasion
Soleus, denervated 7 months
Soleus, denervated 7 weeks
Adipocytes
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Myofiber degeneration• Dramatic loss of myofibrils & myofibril order
Soleus structure after 21 days denervation (Tomanek & Lund, 1973)
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Fiber-type specific• Fast Fibers, esp in fast muscle, degenerate• Mass & function preserved
by electrical stim
Niederle & Mayr, 1978 Dow & al., 2004
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Mechanisms of degeneration• Increased proteolysis
– Increase MuRF/MAFbx & proteasome– Increase cathepsins– Decrease PGC-1a
• Reduced metabolic capacity– Decrease glycolysis (LDH, PK, triose isomerase)– Decrease ETC (NADH, malate dehydrogenase, ATP
synthase)
• Increase ECM– Collagen, fibronectin, fibrillin
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Regeneration
Borisov & al., 2001
Laminin NCAMEmbMHCNew, small myofibers develop either as discrete structures outside the basal lamina (left), or as separate appendages inside the BL (right)
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Regeneration
SlowMHC(mature fiber)
EmbMHC(regenerating fiber)
Laminin(fiber boundaries)
Borisov & al., 2001
Three relatively mature fibers with faint laminin boundaries within thicker laminin shell of (presumably) original fiber
Small, immature (EmbMHC+) fiber adjacent to (presumably) preserved original fiber
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Reinnervation• Muscle-nerve match• Axon-fiber not matched• Loss of contractile specialization
– MU innervation ratio– Fiber size:phenotype
Motor Unit territories before & after reinnrvation (Bodine-Fowler & al 1993)
Twitch contraction records contralateral and reinnervated LG & Sol (Gillespie & al. 1986)
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Electrical stim preserves morphology• Rat EDL, 2 mos; 200x 0.2 s @100 Hz/day
Kostrominova & al., 2005
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Gene expression altered by ES• Degen/Regen
– AML1NCAM– Myogenin/MRF4/MyoD– Reduced by ES
• Myosin– Den: IIbIIa– Stim: IIaIIb
Kostrominova & al., 2005
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Electrical stimulation of denervated muscle
• Neural cell adhesion molecule– Normal: only NMJ nuclei– Denervated: all nuclei
• Potential benefits– Increased ‘receptivity’ of muscle– Increase axonal branching/guidance
Normal Denervated Denervated+ES
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NCAM influences nerve growth• Culture neurons on muscle
slices• Processes follow cell surface• Greater growth on denervated
(high NCAM)
Covault &al., 1987
NeuronNCAM
Axon growth stops on NCAM plaques
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Electrical stimulation of damaged nerve
• Low intensity; no force• Retrograde transmission of AP• Improves reinnervation
Al-Majed & al., 2000
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Denervation summary• Degeneration-Regeneration
– Increased protein degradation and synthesis– “Moderating” of phenotype (IIIa; IIbIIa)– Loss of mass and order– Loss of myonuclear specialization (NMJ)
• Reinnervation– Usually original MEP– Muscle-specific, not fiber-specific– Disrupts Size Principle– Loss of proprioception
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Spinal Isolation• Transect spinal cord
– Proximal to muscle of interest: no descending input– Distal: no ascending reflex
• Transect dorsal roots– Sensory– Reduce reflex hyperactivity
• Muscle inactive, nerve intact• Spinal cord injury model
Hyatt & al., 2003
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MU properties post-SI
FF-Pre
FF-Post
FR-Pre
FR-Post
Slower,Less sag,Less force,Larger Tw/Tet
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Physiological Response to SI• Grossly similar to denervation
– Slow muscle fast– Fast muscle slow
• Moderating of metabolic processes– Lower SDH in slow muscles– Higher GPDH in slow muscles
• Inactive muscles revert to a ‘neutral’ phenotype
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SI response is weaker than denveration• Rate and extent of mass/force decline lower• Upregulation of MRFs lower & shorter
Hyatt & al., 2003
Tibialis Anterior Medial Gastrocnemius
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• Less SC activationin SI than DEN
DAPI (nucleus)M-Cadherin (SC)BrDU (DNA synthesis)
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Spinal isolation summary• Limited Degeneration-Regeneration
– “Moderating” of phenotype (IIIa; IIbIIa)– Loss of mass, but structure is preserved
• Spinal neurons don’t repair
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Training and spinal transection• Careful training, tapering weight support
– Spontaneous weight support(standing)
– Treadmill-assisted leg motion(stepping)
Belanger & al., 1996
Post-mortem spinal cord, showing complete lesion
Pre/post step postures
0
500
1000
1500
2000
2500
Po
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Mass
Roy & al., 1998
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Summary• Muscle wasting program: active degeneration
– FOXOMuRF/Atrogin-1– Proteasome proteins (ubiquitin, S26)– Autophagy proteins (cathepsin)
• Decreased metabolic capacity– Mitochondrial apoptosis– Reduced PGC-1a
• Loss of fiber type specialization• Atrophy is its own program, separate from
absence of hypertrophy