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      Age-associated NF-κB signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function

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          Abstract

          Skeletal muscle is a highly regenerative tissue, but muscle repair potential is increasingly compromised with advancing age. In this study, we demonstrate that increased NF-κB activity in aged muscle fibers contributes to diminished myogenic potential of their associated satellite cells. We further examine the impact of genetic modulation of NF-κB signaling in muscle satellite cells or myofibers on recovery after damage. These studies reveal that NF-κB activity in differentiated myofibers is sufficient to drive dysfunction of muscle regenerative cells via cell-non-autonomous mechanisms. Inhibition of NF-κB, or its downstream target Phospholipase A2, in myofibers rescued muscle regenerative potential in aged muscle. Moreover, systemic administration of sodium salicylate, an FDA-approved NF-κB inhibitor, decreased inflammatory gene expression and improved repair in aged muscle. Together, these studies identify a unique NF-κB regulated, non-cell autonomous mechanism by which stem cell function is linked to lipid signaling and homeostasis, and provide important new targets to stimulate muscle repair in aged individuals.

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          Most cited references34

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          IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.

          Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.
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            Stem cell aging: mechanisms, regulators and therapeutic opportunities.

            Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic 'memory' that is indelibly written or one that can be reset.
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              Notch-mediated restoration of regenerative potential to aged muscle.

              A hallmark of aging is diminished regenerative potential of tissues, but the mechanism of this decline is unknown. Analysis of injured muscle revealed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient up-regulation of the Notch ligand Delta and, thus, diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Notch signaling is a key determinant of muscle regenerative potential that declines with age.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                Aging
                ImpactJ
                Aging (Albany NY)
                Impact Journals LLC
                1945-4589
                November 2016
                14 November 2016
                : 8
                : 11
                : 2871-2884
                Affiliations
                1 Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Cambridge, MA 02138
                2 Joslin Diabetes Center, Boston, MA 02215, USA
                3 Division of Plastic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA
                4 Department of Biostatistics, Harvard School of Public Health, MA 02115, USA
                5 Department of Biomedical Engineering, Boston University, Boston 02215, USA
                6 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
                7 Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA
                Author notes
                Correspondence to: Amy J. Wagers; amy_wagers@ 123456harvard.edu
                Article
                101098
                10.18632/aging.101098
                5191876
                27852976
                141130ba-80db-4632-bdf6-573f4415a1f1
                Copyright: © 2016 Oh et al.
                History
                : 24 May 2016
                : 25 October 2016
                Categories
                Research Paper

                Cell biology
                satellite cell,skeletal muscle,aging,regeneration
                Cell biology
                satellite cell, skeletal muscle, aging, regeneration

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