1. 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

2. Functional overload Fiber area is an important determinant of P 0 and power – What drives fiber hypertrophy? – What can go wrong? Animal models – Synergist ablation – Weighting – Electrical stimulation

3. 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

4. Overload  Hypertrophy Very rapid mass increase Very rapid fiber size increase Tsika, Herrick & Baldwin 1987 Time (weeks) Plantaris mass (mg) Plyley & al 1998 Fiber Area Capillaries

5. 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

6. Inflammatory response Neutrophils, Macrophages Produce growth & repair factors Satellite cell synergy Armstrong & al., 1979 Interstitial nuclei appear within 4-8 hr Normal muscle

7. Inflammatory contribution to hypertrophy Damage removal? SC activation? Novak & al., 2009 NSAID blocks MAC accumulation and muscle growth

8. 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

9. Synergist ablation Process – Edema/inflammation – Growth factor signaling – Satellite cell activation – Protein accumulation Stimulus – Exaggerated activation of unaccustomed fibers – Damage – Stretch (digitigrade  plantargrade)

10. Chronic Stretch Fiber length is an important determinant of V max, L 0, 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

11. 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

12. 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

13. Immobilization in adults Fiber length adjusts to immobilization length Range of motion is not important Muscle fiber vs tendon length change Muscle length Force Shortened Control

14. 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

15. 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

16. Adult growth at ends Protein accumulates at ends (radiotracer incorporation) Muscle mRNA & proteins Contrast with juvenile growth Vinculin accumulates at fiber ends Dix & Eisenberg, 1990 Yu & al., 2003

17. 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

18. 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

19. Limb Lengthening Ilizarov device on a dog at implant At 1 week (Fitch & al., 1996)

20. 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 fibersLengthened at 3%/day

21. 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 days7 days (+13 days at long position) Simpson & al 1995

22. Muscle and tendon competition Young muscle adapts to ROM – Immobilized tendon grows to reduce fiber growth Adult muscle adapts to L 0 – Less sensitive to ROM? – Tendon less plastic? – Immobilization model minimizes ROM Tendon and perimysial hypertrophy under tension Takahashi & al., 2010

23. 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

24. Training mode Isometric / concentric / eccentric – ie: do the higher forces of eccentric activation give greater hypertrophy? Adams & al., 2004

25. 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

26. 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)

27. 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