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      Neuron‐specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice

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          Abstract

          Age‐associated loss of muscle mass and function (sarcopenia) has a profound effect on the quality of life in the elderly. Our previous studies show that CuZnSOD deletion in mice ( Sod1 −/− mice) recapitulates sarcopenia phenotypes, including elevated oxidative stress and accelerated muscle atrophy, weakness, and disruption of neuromuscular junctions (NMJs). To determine whether deletion of Sod1 initiated in neurons in adult mice is sufficient to induce muscle atrophy, we treated young (2‐ to 4‐month‐old) Sod1flox/SlickHCre mice with tamoxifen to generate i‐mn‐Sod1KO mice. CuZnSOD protein was 40‐50% lower in neuronal tissue in i‐mn‐Sod1KO mice. Motor neuron number in ventral spinal cord was reduced 28% at 10 months and more than 50% in 18‐ to 22‐month‐old i‐mn‐Sod1KO mice. By 24 months, 22% of NMJs in i‐mn‐Sod1KO mice displayed a complete lack of innervation and deficits in specific force that are partially reversed by direct muscle stimulation, supporting the loss of NMJ structure and function. Muscle mass was significantly reduced by 16 months of age and further decreased at 24 months of age. Overall, our findings show that neuronal‐specific deletion of CuZnSOD is sufficient to cause motor neuron loss in young mice, but that NMJ disruption, muscle atrophy, and weakness are not evident until past middle age. These results suggest that loss of innervation is critical but may not be sufficient until the muscle reaches a threshold beyond which it cannot compensate for neuronal loss or rescue additional fibers past the maximum size of the motor unit.

          Abstract

          Using deletion of CuZnSOD in motor neurons to induce increased oxidative stress and mimic loss of motor neurons in spinal cord, we show that neuronal loss induces NMJ disruption that progresses over time to cause muscle atrophy and weakness in i‐mn‐Sod1KO mice. The delay between loss of motor neuron number and significant atrophy and weakness suggests there are compensatory mechanisms at play to mitigate the impact of reduced innervation (possibly including increased sprouting) that eventually fail over time.

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          Most cited references47

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          The Role of Oxidative Stress in Neurodegenerative Diseases

          Oxidative stress is induced by an imbalanced redox states, involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system. The brain is one of organs especially vulnerable to the effects of ROS because of its high oxygen demand and its abundance of peroxidation-susceptible lipid cells. Previous studies have demonstrated that oxidative stress plays a central role in a common pathophysiology of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Antioxidant therapy has been suggested for the prevention and treatment of neurodegenerative diseases, although the results with regard to their efficacy of treating neurodegenerative disease have been inconsistent. In this review, we will discuss the role of oxidative stress in the pathophysiology of neurodegenerative diseases and in vivo measurement of an index of damage by oxidative stress. Moreover, the present knowledge on antioxidant in the treatment of neurodegenerative diseases and future directions will be outlined.
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            Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.

            The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice revealed a variety of age-related structural alterations, including axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites, and fragmentation of the postsynaptic specialization. Alterations were significant by 18 mo of age and severe by 24 mo. A life-long calorie-restricted diet significantly decreased the incidence of pre- and postsynaptic abnormalities in 24-mo-old mice and attenuated age-related loss of motor neurons and turnover of muscle fibers. One month of exercise (wheel running) in 22-mo-old mice also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover. Time-lapse imaging in vivo revealed that exercise partially reversed synaptic alterations that had already occurred. These results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes.
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              Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier.

              Oxidative stress (OS) has been implicated in the pathophysiology of many neurological, particularly neurodegenerative diseases. OS can cause cellular damage and subsequent cell death because the reactive oxygen species (ROS) oxidize vital cellular components such as lipids, proteins, and DNA. Moreover, the brain is exposed throughout life to excitatory amino acids (such as glutamate), whose metabolism produces ROS, thereby promoting excitotoxicity. Antioxidant defense mechanisms include removal of O(2), scavenging of reactive oxygen/nitrogen species or their precursors, inhibition of ROS formation, binding of metal ions needed for the catalysis of ROS generation and up-regulation of endogenous antioxidant defenses. However, since our endogenous antioxidant defenses are not always completely effective, and since exposure to damaging environmental factors is increasing, it seems reasonable to propose that exogenous antioxidants could be very effective in diminishing the cumulative effects of oxidative damage. Antioxidants of widely varying chemical structures have been investigated as potential therapeutic agents. However, the therapeutic use of most of these compounds is limited since they do not cross the blood brain barrier (BBB). Although a few of them have shown limited efficiency in animal models or in small clinical studies, none of the currently available antioxidants have proven efficacious in a large-scale controlled study. Therefore, any novel antioxidant molecules designed as potential neuroprotective treatment in acute or chronic neurological disorders should have the mandatory prerequisite that they can cross the BBB after systemic administration.
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                Author and article information

                Contributors
                svbrooks@umich.edu
                Holly-VanRemmen@omrf.org
                Journal
                Aging Cell
                Aging Cell
                10.1111/(ISSN)1474-9726
                ACEL
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                1474-9718
                1474-9726
                04 September 2020
                October 2020
                : 19
                : 10 ( doiID: 10.1111/acel.v19.10 )
                : e13225
                Affiliations
                [ 1 ] Aging & Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City OK USA
                [ 2 ] Department of Musculoskeletal Biology Institute of Ageing and Chronic Disease MRC‐Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA) University of Liverpool Liverpool UK
                [ 3 ] Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI USA
                [ 4 ] Oklahoma Center For Neuroscience University of Oklahoma Health Sciences Center Oklahoma City OK USA
                [ 5 ] Oklahoma City VA Medical Center Oklahoma City OK USA
                [ 6 ] Department of Biochemistry and Molecular Biology University of Oklahoma Health Sciences Center Oklahoma City OK USA
                Author notes
                [*] [* ] Correspondence

                Holly Van Remmen, Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.

                Email: Holly-VanRemmen@ 123456omrf.org

                Susan V. Brooks, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109‐2200, USA.

                Email: svbrooks@ 123456umich.edu

                Author information
                https://orcid.org/0000-0003-4710-9970
                https://orcid.org/0000-0003-0883-0642
                Article
                ACEL13225
                10.1111/acel.13225
                7576239
                32886862
                9496fb11-9467-492d-a7d5-fc1f73182bb1
                © 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 March 2020
                : 01 July 2020
                : 26 July 2020
                Page count
                Figures: 6, Tables: 1, Pages: 15, Words: 9842
                Funding
                Funded by: U.S. Department of Veterans Affairs , open-funder-registry 10.13039/100000738;
                Award ID: 1IK6BX005234
                Award ID: 1IK6BX005238
                Funded by: National Institute on Aging , open-funder-registry 10.13039/100000049;
                Award ID: AG050676
                Award ID: AG051442
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                October 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:21.10.2020

                Cell biology
                aging,cuznsod,denervation,motor neuron,sarcopenia
                Cell biology
                aging, cuznsod, denervation, motor neuron, sarcopenia

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