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

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 Fastslow MHC 0.5% annual loss of aerobic capacity Lexell & al., 1988 Elite weightlifters Untrained Pearson & al., 2002

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 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

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

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 similar Haddad & Adams, 2006

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

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)

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)

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

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 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

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) Sedentary Runners Pair-fed sedentary Pair-weight sedentary Holloszy & al., 1985

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

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 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)

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