compensatory hypertrophy growth to compensate for overload – esp overload due to synergist...
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Compensatory Hypertrophy• Growth to compensate for overload
– esp overload due to synergist ablation
• Describe models of muscle growth– Synergist Ablation– Chronic stretch– Limb Lengthening– Intermittent electrical stimulation
• Describe multiple modes of remodeling– Neural– Protein synthesis– Satellite cell proliferation
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Functional overload• Fiber area is an important determinant of P0
and power– What drives fiber hypertrophy?– What can go wrong?
• Animal models– Synergist ablation– Weighting– Electrical stimulation
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Synergist Ablation• Triceps surae synergists
– Soleus, plantaris, gastrocnemius– Ankle extensor/knee flexor– Rat: 5%, 18%, 77%
• Ablation– Surgically remove 2 of 3 muscles– Recovery over weeks
• Response– 100-200% mass increase– “Slowing” of fiber type
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OverloadHypertrophy• Very rapid mass increase• Very rapid fiber size increase
Tsika, Herrick & Baldwin 1987Time (weeks)
Pla
ntar
is m
ass
(mg)
0
100
200
300
400
500
600
0 5 10
Control
Overload
Plyley & al 1998
Fib
er A
rea
Cap
illar
ies
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Mass vs function• Edema/inflammation
– Immediate weight change is water– Inflammatory response is necessary
• Gait alterations– Digitigrade-->Plantargrade-->Digitigrade– Stretch
• Protein synthesis• Fiber size
10 days
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Inflammatory response• Neutrophils, Macrophages• Produce growth & repair factors• Satellite cell synergy
Armstrong & al., 1979
Interstitial nuclei appear within 4-8 hrNormal muscle
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Inflammatory contribution to hypertrophy
• Damage removal?• SC activation?
Novak & al., 2009
NSAID blocks MAC accumulation and muscle growth
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Satellite cells are required for hypertrophy
• Irradiation treatment– DNA damage– Blocks mitosis
• Prior irradiation blocks hypertrophy
• Cellular signaling is preserved
Adams et al., 2002
3x mass after 90 days
Unless irradiated
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Synergist ablation• Process
– Edema/inflammation– Growth factor signaling– Satellite cell activation– Protein accumulation
• Stimulus– Exaggerated activation of unaccustomed fibers– Damage– Stretch (digitigradeplantargrade)
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Chronic Stretch• Fiber length is an important determinant of
Vmax, L0, and range of motion– What drives postnatal (longitudinal) growth of
muscle?– Are there adult benefits?– What can go wrong?
• Animal models– Limb weighting (chick)– Limb immobilization
Alway, et al., 1989
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Postnatal growth• Gerard Crawford (1954)
– Insert wires in juvenile muscles– Watch them separate over time– Muscles grow uniformly along their length– Proportional to range of motion
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Immobilization retards growth• Williams & Goldspink
– Plaster casts on baby mice– Sarcomere addition
severely retarded– Rapidly recovers with
mobilization
• Range of motion is important
Normal
Immobilized
LongShort
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Immobilization in adults• Fiber length adjusts to immobilization length• Range of motion is not important• Muscle fiber vs
tendon lengthchange
Muscle length
For
ce
ShortenedControl
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Architectural remodeling w/immobilization
• Spector et al., 1982– Immobilized rats 4 wks– Muscle mass preserved in lengthening– Loss of PCSA independent of length
• Lateral and longitudinal growth are separate
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How much stretch is needed?• Short immobilization (mouse)• Daily cast removal & stretch• 15-30 minutes stretch counters 24 hours short• Transient growth
stimuli are muchmore powerfulthan atrophy
Williams, 1990
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Adult growth at ends• Protein accumulates at ends
(radiotracer incorporation)• Muscle mRNA & proteins• Contrast with juvenile growth
Vinculin accumulates at fiber endsDix & Eisenberg, 1990Yu & al., 2003
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Stretch/shortening• Process
– Sarcomere length deviates from L0– L0 is restored
• Sarcomere addition/regression• Tendon addition/regression
• Stimulus– Transient stretch is enough– Insensitive to shortening– Longitudinal growth is a different process from
diameter growth
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Limb lengthening• Corrective surgery
– Congenital asymmetry– Developmental/traumatic asymmetry– Replace bone defects
• Distraction osteogenesis– “Ilizarov” external fixator– Section bone, pull pieces apart– Cut ends grow together
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Limb Lengthening
Ilizarov device on a dog at implant At 1 week (Fitch & al., 1996)
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Limits to limb lengthening• Large changes in bone length possible (20%+)• Major complications are muscular & cutaneous
– Decreased range of motion– Loss of power/force
Simpson & al 1995
Normal muscle fibers Lengthened at 3%/day
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Slow muscle adaptation• Muscle growth seems slower than bone• Too fast, and muscle may never catch up
Length-tension curves for control (+) and 20% lengthened (x) over20 days 7 days
(+13 days at long position)
Simpson & al 1995
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Muscle and tendon competition• Young muscle adapts to ROM
– Immobilized tendon grows toreduce fiber growth
• Adult muscle adapts to L0
– Less sensitive to ROM?– Tendon less plastic?– Immobilization model minimizes
ROM
• Tendon and perimysial hypertrophy under tension
Takahashi & al., 2010
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Simulated exercise• Wong & Booth (1988)
– 7x6 stimulations 3x week, 16 weeks– ± external load– +20% muscle size, loaded– +0% muscle size, unloaded
• Greater loads result ingreater hypertrophy
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Training mode• Isometric / concentric / eccentric
– ie: do the higher forces of eccentric activation give greater hypertrophy?
Adams & al., 2004
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Stimulation pattern matters• Kernell, Donselaar & al., 1987• 8 wks training with “fast” or “slow” pattern• Blocks of 90 minutes or continuous• High force blocks increase force capacity
Continuous
Block
Block
Block
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Electrical stimulation on humans• Lieber & Kelly, 1993
– Efficacy of electrically evoked force– Tissue conductivity: contact, adipose, placement– Highly variable, and low (25% MVC)
Quadriceps area activated by EMS (Adams & al 1993)
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Summary• Muscle hypertrophies in response to overload
– Strength changes before muscle protein– Muscle mass changes before muscle protein
• Growth depends on conditions– Growth in length vs growth in girth– Activation frequency; duty cycle
• Multiple cell types are important– Myofiber– Inflammatory cells (macrophages)– Satellite cells