For humans, frailty constitutes of one of the most prominent and consistent features of aging and represents the summation of the effects of muscle atrophy and weakness. For the elderly, physical frailty contributes to impaired mobility, a high risk of falling, an increased incidence of muscle injury, and a decreased quality of life. Despite considerable effort over the past decade, little progress has been made in lessening the magnitude of the problem. During our first five years of support, research on a dozen or more varieties of knockout and transgenic mice, this Program Project identified the Sodl^'mouse as a highly promising model to test the working hypothesis of Project 1 that age-related skeletal muscle atrophy results from a decrease in the total number of motor units caused by increased superoxide-mediated oxidative stress in neurons and muscles, such that: (i) oxidative stress in neurons initiates a loss of motor neurons, impairs axonal sprouting from surviving motor neurons, and inhibits nerve regeneration;and (ii) oxidative stress in muscles fibers inhibits reinnervation and contributes to decreased contractility of innervated muscle fibers. The working hypothesis will be tested through experiments on SodfA and Sod1+/+ mice, transgenic Socf7v"""""""" mice with Sod1 expression rescued only in nerves (Soc/fA(N+) mice) or muscles (Soc(7~/~(M+) mice), and tissue-specific knockout mice that lack CuZnSOD activity only in nerves (Sod1A3,4N)N) or muscles (Sod 1 A3,4^). These models allow us to test hypotheses regarding the contribution of systemic oxidative stress, as well as tissue-specific oxidative stress on the structure and function of motor nerves, muscles, motor units and muscle fibers. Genetically modified mice will be studied at 6-8 months and 18-20 months, whereas Sod1+/+ mice will be studied at 6-8, 18-20, and 28-30 months. Unique aspects of the proposed studies are the 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 the relative timing of changes in nerves and muscles that have not been undertaken previously in the same animals will be particularly illuminating for establishing cause-effect relationships of age-related changes in the neuromuscular system. Along with Projects 2 and 3, studies utilizing the very powerful mouse models listed above will determine the mechanistic role of superoxide-induced oxidative stress in muscles and nerves in age-related skeletal muscle atrophy. The Public Health significance is the necessity to understand the mechanisms underlying age-associated skeletal muscle atrophy and weakness to provide the 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.

Public Health Relevance

It is known that human exposure to air pollution particulates is associated with increased hospitalization due to lung infections. However, the potential effects of inhaled ENPs on innate immune function has received surprisingly little attention. This research will determine the doses and physicochemical types of ENPs that affect innate immune function in macrophages, with a focus on developing dose-response data needed for risk analysis..

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-5)
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University of Michigan Ann Arbor
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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
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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:
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
Ivannikov, Maxim V; Van Remmen, Holly (2015) Sod1 gene ablation in adult mice leads to physiological changes at the neuromuscular junction similar to changes that occur in old wild-type mice. Free Radic Biol Med 84:254-262

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