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
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
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
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
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
Inflammatory response• Neutrophils, Macrophages• Produce growth & repair factors• Satellite cell synergy
Armstrong & al., 1979
Interstitial nuclei appear within 4-8 hrNormal muscle
Inflammatory contribution to hypertrophy
• Damage removal?• SC activation?
Novak & al., 2009
NSAID blocks MAC accumulation and muscle growth
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
Synergist ablation• Process
– Edema/inflammation– Growth factor signaling– Satellite cell activation– Protein accumulation
• Stimulus– Exaggerated activation of unaccustomed fibers– Damage– Stretch (digitigradeplantargrade)
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
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
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
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
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
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
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
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
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
Limb Lengthening
Ilizarov device on a dog at implant At 1 week (Fitch & al., 1996)
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
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
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
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
Training mode• Isometric / concentric / eccentric
– ie: do the higher forces of eccentric activation give greater hypertrophy?
Adams & al., 2004
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
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)
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