1. Sarcopenia Age-associated decline in muscle function Causes
Mass
Strength
Fast-to-slow transformation
Causes
Motor neuron death
Changes in hormonal status
Changes in activity
Molecular mechanisms

2. Sarcopenia phenomenology
Atrophy associated with aging
1-2% annual loss of strength beginning age 40-50
% annual loss of specific tension
Slowing
Fastslow MHC
0.5% annual loss of aerobic capacity
Lexell & al., 1988
Elite weightlifters
Untrained
Pearson & al., 2002

3. Cachexia Muscle wasting secondary to pathology
Cancer
HIV/AIDS
Usually without change in fat mass
Distinct from starvation/anorexia
Strong predictor of mortality
Chronic inflammation
Insulin resistance

4. Sacopenia causes Hormonal Lifestyle Neural
Testosterone (HRT little change in strength or mass)
GH/IGF-1; estrogen
Lifestyle
Young people are hyperactive: mate seeking and reproduction
Old people are hypoactive: job and child maturation
Neural
Motor neuron population declines parallel muscle
Capacity for neural remodeling declines
Lamberts & al., 1997

5. Lifestyle hypothesis Social structure encourages disuse
Animal sarcopenia
Mice, rats, cats, dogs
Voluntary activity declines after mid-life
Muscle mass declines after mid-life
Rat voluntary run distance (Holloszy &al., 1985)
Rat muscle mass vs age Lushaj & al., 2008

6. Non-mammalian sarcopenia
Worms (C elegans)
Flies (Drosophila)
Note: No satellite cells
Mitochondrial swelling and dysfunction
Myofibrillar degeneration
C elegans muscle (g: 2 d young; h: 18 d old)
Herndon & al., 2002
Drosophila flight muscle 7 days (L) 86 days (R)
Takahashi & al., 1970

7. Insulin/IGF-1 signaling
Content increases
IGF-1 (mRNA)
IGF-1 receptor & activation
Downstream signaling declines
IRS1 content
Active IRS-1
Protein synthesis
20-30% lower at 70 y.o. vs 30
Resistance exercise similar
Haddad & Adams, 2006

8. Atrogene signaling Little change in MuRF/Mafbx Increase Akt
akt generally pro-growth so its elevation may reveal ineffective attempt to maintain mass
Reduced autophagy
Gaugler & al., 2011

9. Response to exercise 8X10 @ 70% 1RM Equivalence of loading?
Akt-mTOR similar peak, but condensed
ERK attenuated
Protein synth well predicted by signaling
Equivalence of loading?
Fry & al., 2011 (humans)

10. Response to overload Synergist ablation
mTOR
Synergist ablation
Attenuated signaling
Low, but consistent hypertrophy
Aged animals also much less AMP stress
SA may be ‘weak’ stimulus
Young
Old
p70S6k
4EBP-1
Thomson & Gordon, 2006 (rats)

11. Mitochondria Decline in mitochondrial DNA
Increase in DNA oxidative modification
Decline in Mt protein
Decline in Mt protein activity
Citrate Synthase
µM/min/mg Mt protein
Oxidative modification
ATP Synthesis
µM/min/mg Mt protein
Short & al., 2005

12. Oxidative stress hypothesis
Mitochondrial dysfunction increases oxidative damage, and degeneration/apoptosis
ROS protection
SOD1 (Cu-Zn, cytosolic)
SOD2 (Mn, mitochondrial)

13. Drosophila Global SOD1 k/o shortens lifespan SOD2-/- neonatal lethal
Rescued by global SOD1 transgene
Rescued by motorneuron-specific SOD1 tg
MN SOD1 increases lifespan in WT
SOD2-/- neonatal lethal Wt
SOD1-/-
SOD1-/-
SOD1-/- +1tg
SOD1-/- + 2tg
Reveillaud & al., 1994
Parks & al., 1998

14. Mouse SOD2-/- neonatal lethal SOD1-/- mouse have reduced lifespan
Motorneuron deficiency
NMJ failure
Elchuri & al., 2005
Flood & al., 1999

15. Muscle-specific knockouts
Conditional MnSOD-/- have normal sarcopenia (ie: not accelerated)
Conditional Cu-Zn SOD -/-
Exercise intolerance, atrophy
Lifespan?
Transgenic overexpression of SOD1 improves ischemia-reperfusion recovery

16. Chronic exercise
Exercise increases mitochondria, mitochondrial function, and oxidant scavenging
Ad lib wheel running
2-7 miles/day
Stop at 4-6 months 8% food restriction
Pair-fed sedentary
Pair-weight sedentary (25% CR)
Sedentary
Runners
Pair-fed sedentary
Pair-weight sedentary
Holloszy & al., 1985

17. Born runners Mice bred 30 generations for wheel running
No survival benefit of exercise
Missing group: C-
Running is good for you, only if you don’t like it
Control strain
Runners
Control strain, with wheel
Runners, with wheel
Runners, no wheel
Vaanholt & al., 2010

18. Motorneuron hypothesis
Neural degeneration results in denervation & atrophy
Motor unit number estimation (EMG)
Find single motor unit amplitude (CMAP)
Divide total EMG amplitude by CMAP
Motor unit number in Young, Old, and old Master Runners (Power & al 2012)
Motor unit number vs age in humans (Lexell, 1985)

19. MU decrease in animals Retrograde label Count cells
Size discriminates among MN classes
a-, but not g-MN decrease w/age
Similar timing as muscle atrophy
MN pools not preserved by FO
g-MN
o a-MN
MN pool in rat MG (Hashizume & al., 1988)

20. Muscle-motor neuron interaction
SOD1G93A mouse
Dysfunctional SOD1
ALS model
mIGF-1
Muscle specific transgene
Substantially improves survival
Maintains MN #
Dobrowolny & al., 2005

21. Motor neuron survival Neurons, esp MN, seem highly sensitive to ROS
Failure of ROS-protection may kill MN
Denervation-induced atrophy
Muscle-derived factors may sustain nerve
IGF-1
Neurotrophin
Exercise provides minimal MN protection

22. Summary Humans begin to fall apart sometime around 40 years
Activity hypothesis
Oxidative stress hypothesis
Neural degeneration hypothesis
Parallel declines in: strength, activity, muscle mass, MN population
Reduced protein synthesis
Sustained or reduced protein degradation
Hyperactive pro-growth signaling
Overload is a countermeasure not a cure
Reduced sensitivity to hypertrophic stimuli
Oxidative stress aggravates MN degeneration