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