For humans, frailty constitutes of one of the most prominent and consistent features of aging andrepresents the summation of the effects of muscle atrophy and weakness. For the elderly, physical frailtycontributes to impaired mobility, a high risk of falling, an increased incidence of muscle injury, and adecreased quality of life. Despite considerable effort over the past decade, little progress has been madein lessening the magnitude of the problem. During our first five years of support, research on a dozen ormore varieties of knockout and transgenic mice, this Program Project identified the Sodl^' mouse as ahighly promising model to test the working hypothesis of Project 1 that age-related skeletal muscleatrophy results from a decrease in the total number of motor units caused by increasedsuperoxide-mediated oxidative stress in neurons and muscles, such that: (i) oxidative stress inneurons initiates a loss of motor neurons, impairs axonal sprouting from surviving motorneurons, and inhibits nerve regeneration; and (ii) oxidative stress in muscles fibers inhibits reinnervationand contributes to decreased contractility of innervated muscle fibers. The workinghypothesis will be tested through experiments on SodfA and Sod1+/+ mice, transgenic Socf7v' mice withSod1 expression rescued only in nerves (Soc/fA(N+) mice) or muscles (Soc(7~/~(M+) mice), and tissue-specificknockout mice that lack CuZnSOD activity only in nerves (Sod1A3,4N)N) or muscles (Sod 1 A3,4^). Thesemodels allow us to test hypotheses regarding the contribution of systemic oxidative stress, as well astissue-specific oxidative stress on the structure and function of motor nerves, muscles, motor units andmuscle fibers. Genetically modified mice will be studied at 6-8 months and 18-20 months, whereasSod1+/+ mice will be studied at 6-8, 18-20, and 28-30 months. Unique aspects of the proposed studies arethe determination of motor unit properties and contractility of permeabilized single fibers from Soc/f/'mice,,null mice with tissue-specific rescue, and tissue-specific Sodl knockout mice. Furthermore, studies of therelative timing of changes in nerves and muscles that have not been undertaken previously in the sameanimals will be particularly illuminating for establishing cause-effect relationships of age-related changesin the neuromuscular system. Along with Projects 2 and 3, studies utilizing the very powerful mousemodels listed above will determine the mechanistic role of superoxide-induced oxidative stress in musclesand nerves in age-related skeletal muscle atrophy. The Public Health significance is the necessity tounderstand the mechanisms underlying age-associated skeletal muscle atrophy and weakness to providethe basis for health professionals to design and implement scientifically based strategies to ensure'successful aging' by reducing and perhaps even eliminating physical frailty in the elderly population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG020591-06A1
Application #
7436692
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (J4))
Project Start
2008-05-01
Project End
2013-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
6
Fiscal Year
2008
Total Cost
$311,560
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Zhang, Yiqiang; Unnikrishnan, Archana; Deepa, Sathyaseelan S et al. (2017) A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1-/- mice is correlated to increased cellular senescence. Redox Biol 11:30-37
Deepa, Sathyaseelan S; Bhaskaran, Shylesh; Espinoza, Sara et al. (2017) A new mouse model of frailty: the Cu/Zn superoxide dismutase knockout mouse. Geroscience 39:187-198
Pollock, Natalie; Staunton, Caroline A; Vasilaki, Aphrodite et al. (2017) Denervated muscle fibers induce mitochondrial peroxide generation in neighboring innervated fibers: Role in muscle aging. Free Radic Biol Med 112:84-92
Vasilaki, Aphrodite; Pollock, Natalie; Giakoumaki, Ifigeneia et al. (2016) The effect of lengthening contractions on neuromuscular junction structure in adult and old mice. Age (Dordr) 38:259-272
Sloboda, Darcée D; Brooks, Susan V (2016) Treatment with selectin blocking antibodies after lengthening contractions of mouse muscle blunts neutrophil accumulation but does not reduce damage. Physiol Rep 4:
Zhang, Yiqiang; Liu, Yuhong; Walsh, Michael et al. (2016) Liver specific expression of Cu/ZnSOD extends the lifespan of Sod1 null mice. Mech Ageing Dev 154:1-8
Sakellariou, Giorgos K; Pearson, Timothy; Lightfoot, Adam P et al. (2016) Mitochondrial ROS regulate oxidative damage and mitophagy but not age-related muscle fiber atrophy. Sci Rep 6:33944
Sakellariou, Giorgos K; Pearson, Timothy; Lightfoot, Adam P et al. (2016) Long-term administration of the mitochondria-targeted antioxidant mitoquinone mesylate fails to attenuate age-related oxidative damage or rescue the loss of muscle mass and function associated with aging of skeletal muscle. FASEB J 30:3771-3785
Jackson, Malcolm J (2016) Reactive oxygen species in sarcopenia: Should we focus on excess oxidative damage or defective redox signalling? Mol Aspects Med 50:33-40

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