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Sarcopenia Age-associated decline in muscle function – Mass – Strength – Fast-to-slow transformation Causes – Motor neuron death – Changes in hormonal.

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Presentation on theme: "Sarcopenia Age-associated decline in muscle function – Mass – Strength – Fast-to-slow transformation Causes – Motor neuron death – Changes in hormonal."— Presentation transcript:

1 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

2 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 Pearson & al., 2002 Elite weightlifters Untrained

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

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

10 Response to overload Synergist ablation – Attenuated signaling – Low, but consistent hypertrophy Aged animals also much less AMP stress SA may be ‘weak’ stimulus Young Old mTOR 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 ATP Synthesis µM/min/mg Mt protein Oxidative modification 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 – Rescued by global SOD1 transgene – Rescued by motorneuron-specific SOD1 tg – MN SOD1 increases lifespan in WT SOD2 -/- neonatal lethal Wt SOD1 -/- Reveillaud & al., 1994Parks & al., 1998 SOD1 -/- SOD1 -/- +1tg SOD1 -/- + 2tg

14 Mouse SOD2 -/- neonatal lethal SOD1-/- mouse have reduced lifespan – Motorneuron deficiency – NMJ failure Elchuri & al., 2005Flood & 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) Holloszy & al., 1985 Sedentary Runners Pair-fed sedentary Pair-weight sedentary

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 Vaanholt & al., 2010 Control strain, with wheel Runners, with wheel Runners, no wheel Control strain Runners

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 –  -, but not  -MN decrease w/age Similar timing as muscle atrophy MN pools not preserved by FO  -MN o  -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

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