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Unloading Adaptation • Experimental models of decreased use – (Immobilization) – (Hindlimb suspension) – Denervation – Spinal isolation • Factors contributing to atrophy • Clinical consequences of immobilization 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 Degeneration-Regeneration • Initial insult – Reduced protein synthesis/Elevated degradation – Fiber deconstruction/death • Recovery – SC activation – Restored protein syn Degradation/mg • Reinnervation Synthesis/mg – Fiber reorg – Relative hypertrophy Degradation/muscle Synthesis/muscle Goldspink, 1976 Schwann Cell Axon Control 1 Week Synaptic cleft: Primary Secondary Axon dies rapidly, Schwann cell & ECM remain. Secondary synaptic clefts shrink & separate Saito & Zacks, 1969 3 Weeks (reinnervation Muscle wasting • Myofiber size decrease • Connective tissue hypertrophy • Adipocyte invasion Soleus, denervated 7 months Adipocytes Soleus, denervated 7 weeks Myofiber degeneration • Dramatic loss of myofibrils & myofibril order Soleus structure after 21 days denervation (Tomanek & Lund, 1973) Fiber-type specific • Fast Fibers, esp in fast muscle, degenerate • Mass & function preserved by electrical stim Niederle & Mayr, 1978 Dow & al., 2004 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 Regeneration New, small myofibers develop either as discrete structures outside the basal lamina (left), or as separate appendages inside the BL (right) EmbMHC Laminin NCAM Borisov & al., 2001 Regeneration Small, immature (EmbMHC+) fiber adjacent to (presumably) preserved original fiber EmbMHC (regenerating fiber) Three relatively mature fibers with faint laminin boundaries within thicker laminin shell of (presumably) original fiber Laminin (fiber boundaries) SlowMHC (mature fiber) Borisov & al., 2001 Reinnervation • Muscle-nerve match • Axon-fiber not matched • Loss of contractile specialization – MU innervation ratio – Fiber size:phenotype Twitch contraction records contralateral and reinnervated LG & Sol (Gillespie & al. 1986) Motor Unit territories before & after reinnrvation (Bodine-Fowler & al 1993) Electrical stim preserves morphology • Rat EDL, 2 mos; 200x 0.2 s @100 Hz/day Kostrominova & al., 2005 Gene expression altered by ES • Degen/Regen – AML1NCAM – Myogenin/MRF4/MyoD – Reduced by ES • Myosin – Den: IIbIIa – Stim: IIaIIb Kostrominova & al., 2005 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 NCAM influences nerve growth • Culture neurons on muscle slices • Processes follow cell surface • Greater growth on denervated (high NCAM) Neuron NCAM Axon growth stops on NCAM plaques Covault &al., 1987 Electrical stimulation of damaged nerve • Low intensity; no force • Retrograde transmission of AP • Improves reinnervation Al-Majed & al., 2000 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 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 MU properties post-SI FF-Pre Slower, Less sag, Less force, Larger Tw/Tet FF-Post FR-Pre FR-Post 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 SI response is weaker than denveration • Rate and extent of mass/force decline lower • Upregulation of MRFs lower & shorter Tibialis Anterior Medial Gastrocnemius Hyatt & al., 2003 • Less SC activation in SI than DEN DAPI (nucleus) M-Cadherin (SC) BrDU (DNA synthesis) Spinal isolation summary • Limited Degeneration-Regeneration – “Moderating” of phenotype (IIIa; IIbIIa) – Loss of mass, but structure is preserved • Spinal neurons don’t repair Training and spinal transection • Careful training, tapering weight support – Spontaneous weight support (standing) – Treadmill-assisted leg motion (stepping) Mass Po Post-mortem spinal cord, showing complete lesion Pre/post step postures 4.0 2500 3.5 2000 3.0 2.5 1500 2.0 1000 1.5 1.0 500 0.5 0.0 0 Roy & al., 1998 Belanger & al., 1996 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