Sarcopenia• Age-associated decline in muscle function

– Mass– Strength– Fast-to-slow transformation

• Causes– Motor neuron death– Changes in hormonal status– Changes in activity

• Molecular mechanisms

Sarcopenia phenomenology• Atrophy associated

with aging– 1-2% annual loss of

strength beginning age 40-50

– 0.5-1.5% annual loss of specific tension

• Slowing– Fastslow MHC– 0.5% annual loss of

aerobic capacity

Lexell & al., 1988

Pearson & al., 2002

Elite weightlifters

Untrained

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

Sacopenia causes• Hormonal

– 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 declinesLamberts & al., 1997

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 muscle mass vs age Lushaj & al., 2008Rat voluntary run distance (Holloszy &al., 1985)

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

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

similarHaddad & Adams, 2006

Atrogene signaling• Little change in MuRF/Mafbx• Increase Akt

– akt generally pro-growthso its elevation may revealineffective attempt to maintain mass

• Reduced autophagy

Gaugler & al., 2011

Response to exercise

Fry & al., 2011 (humans)

• 8X10 @ 70% 1RM– Akt-mTOR similar peak, but condensed– ERK attenuated– Protein synth well predicted

by signaling

• Equivalence of loading?

Response to overload• Synergist ablation

– Attenuated signaling– Low, but consistent hypertrophy

• Aged animals also much less AMPstress

• SA may be ‘weak’ stimulus

YoungOld

mTOR

p70S6k

4EBP-1

Thomson & Gordon, 2006 (rats)

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

pro

tein

ATP Synthesis

µM

/min

/mg

Mt

pro

tein

Oxidative modification

Short & al., 2005

Oxidative stress hypothesis• Mitochondrial dysfunction increases oxidative

damage, and degeneration/apoptosis• ROS protection

– SOD1 (Cu-Zn, cytosolic)– SOD2 (Mn, mitochondrial)

Drosophila• Global SOD1 k/o shortens lifespan

– Rescued by global SOD1 transgene– Rescued by motorneuron-specific SOD1 tg– MN SOD1 increases lifespan in WT

• SOD2-/- neonatal lethal

WtSOD1-/-

Reveillaud & al., 1994 Parks & al., 1998

SOD1-/-

SOD1-/- +1tgSOD1-/- + 2tg

Mouse• SOD2-/- neonatal lethal• SOD1-/- mouse have reduced lifespan

– Motorneuron deficiency– NMJ failure

Elchuri & al., 2005 Flood & al., 1999

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

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)

Holloszy & al., 1985

SedentaryRunners

Pair-fed sedentaryPair-weight sedentary

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

Vaanholt & al., 2010

Control strain, with wheelRunners, with wheel

Runners, no wheel

Control strainRunners

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)

MU decrease in animals• Retrograde label• Count cells

– Size discriminates among MN classes– -, but not -MN decrease w/age

• Similar timing as muscle atrophy• MN pools not preserved by FO

• -MNo -MN

MN pool in rat MG (Hashizume & al., 1988)

Muscle-motor neuron interaction• SOD1G93A mouse

– Dysfunctional SOD1– ALS model

• mIGF-1– Muscle specific transgene– Substantially improves

survival– Maintains MN #

Dobrowolny & al., 2005

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

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