Transcript Calcium Signaling - Georgia Institute of Technology

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
OverloadHypertrophy
Fiber Area
• Very rapid mass increase
• Very rapid fiber size increase
500
400
300
200
Capillaries
Plantaris mass (mg)
600
Control
100
Overload
0
0
5
Time (weeks)
Tsika, Herrick & Baldwin 1987
10
Plyley & al 1998
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
Normal muscle
Interstitial nuclei
appear within 4-8 hr
Armstrong & al., 1979
Inflammatory contribution to hypertrophy
• Damage removal?
• SC activation?
NSAID blocks MAC accumulation
and muscle growth
Novak & al., 2009
Satellite cells are required for hypertrophy
• Irradiation treatment
3x mass
after 90 days
– DNA damage
– Blocks mitosis
• Prior irradiation blocks
hypertrophy
• Cellular signaling is
preserved
Adams et al., 2002
Unless
irradiated
Synergist ablation
• Process
– Edema/inflammation
– Growth factor signaling
– Satellite cell activation
– Protein accumulation
• Stimulus
– Exaggerated activation of unaccustomed fibers
– Damage
– Stretch (digitigradeplantargrade)
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
Long
Short
Immobilization in adults
• Fiber length adjusts to immobilization length
• Range of motion is not important
• Muscle fiber vs
tendon length
change
Force
Shortened
Control
Muscle length
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 much
more powerful
than atrophy
Williams, 1990
Adult growth at ends
• Protein accumulates at ends
(radiotracer incorporation)
• Muscle mRNA & proteins
• Contrast with juvenile growth
Yu & al., 2003
Vinculin accumulates at fiber ends
Dix & Eisenberg, 1990
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
Normal muscle fibers
Lengthened at 3%/day
Simpson & al 1995
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) over
20 days
7 days
(+13 days at long position)
Simpson & al 1995
Muscle and tendon competition
• Young muscle adapts to ROM
– Immobilized tendon grows to
reduce 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 in
greater 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