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      Age-dependent alteration in muscle regeneration: the critical role of tissue niche

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          Abstract

          Although adult skeletal muscle is composed of fully differentiated fibers, it retains the capacity to regenerate in response to injury and to modify its contractile and metabolic properties in response to changing demands. The major role in the growth, remodeling and regeneration is played by satellite cells, a quiescent population of myogenic precursor cells that reside between the basal lamina and plasmalemma and that are rapidly activated in response to appropriate stimuli. However, in pathologic conditions or during aging, the complete regenerative program can be precluded by fibrotic tissue formation and resulting in functional impairment of the skeletal muscle. Our study, along with other studies, demonstrated that although the regenerative program can also be impaired by the limited proliferative capacity of satellite cells, this limit is not reached during normal aging, and it is more likely that the restricted muscle repair program in aging is presumably due to missing signals that usually render the damaged muscle a permissive environment for regenerative activity.

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          Most cited references130

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          Regulatory interactions between muscle and the immune system during muscle regeneration.

          Recent discoveries reveal complex interactions between skeletal muscle and the immune system that regulate muscle regeneration. In this review, we evaluate evidence that indicates that the response of myeloid cells to muscle injury promotes muscle regeneration and growth. Acute perturbations of muscle activate a sequence of interactions between muscle and inflammatory cells. The initial inflammatory response is a characteristic Th1 inflammatory response, first dominated by neutrophils and subsequently by CD68(+) M1 macrophages. M1 macrophages can propagate the Th1 response by releasing proinflammatory cytokines and cause further tissue damage through the release of nitric oxide. Myeloid cells in the early Th1 response stimulate the proliferative phase of myogenesis through mechanisms mediated by TNF-alpha and IL-6; experimental prolongation of their presence is associated with delayed transition to the early differentiation stage of myogenesis. Subsequent invasion by CD163(+)/CD206(+) M2 macrophages attenuates M1 populations through the release of anti-inflammatory cytokines, including IL-10. M2 macrophages play a major role in promoting growth and regeneration; their absence greatly slows muscle growth following injury or modified use and inhibits muscle differentiation and regeneration. Chronic muscle injury leads to profiles of macrophage invasion and function that differ from acute injuries. For example, mdx muscular dystrophy yields invasion of muscle by M1 macrophages, but their early invasion is accompanied by a subpopulation of M2a macrophages. M2a macrophages are IL-4 receptor(+)/CD206(+) cells that reduce cytotoxicity of M1 macrophages. Subsequent invasion of dystrophic muscle by M2c macrophages is associated with progression of the regenerative phase in pathophysiology. Together, these findings show that transitions in macrophage phenotype are an essential component of muscle regeneration in vivo following acute or chronic muscle damage.
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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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              Myogenic satellite cells: physiology to molecular biology.

              Adult skeletal muscle has a remarkable ability to regenerate following myotrauma. Because adult myofibers are terminally differentiated, the regeneration of skeletal muscle is largely dependent on a small population of resident cells termed satellite cells. Although this population of cells was identified 40 years ago, little is known regarding the molecular phenotype or regulation of the satellite cell. The use of cell culture techniques and transgenic animal models has improved our understanding of this unique cell population; however, the capacity and potential of these cells remain ill-defined. This review will highlight the origin and unique markers of the satellite cell population, the regulation by growth factors, and the response to physiological and pathological stimuli. We conclude by highlighting the potential therapeutic uses of satellite cells and identifying future research goals for the study of satellite cell biology.
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                Author and article information

                Contributors
                +39 06 49766956 , +39 06 4462854 , antonio.musaro@uniroma1.it
                Journal
                Biogerontology
                Biogerontology
                Biogerontology
                Springer Netherlands (Dordrecht )
                1389-5729
                1573-6768
                12 May 2013
                12 May 2013
                June 2013
                : 14
                : 3
                : 273-292
                Affiliations
                [ ]Institute Pasteur Cenci-Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, IIM, Sapienza University of Rome, Rome, Italy
                [ ]Institute of Histology and Embryology, Catholic University School of Medicine, Rome, Italy
                [ ]Thérapie des Maladies du Muscle Strié, Institut de Myologie UMRS 974-UPMC University, Paris 6, U974-Inserm, UMR7215-CNRS, AIM, GH Pitié-Salpétrière, 47 bd de L’Hôpital, Paris cedex 13, 75651 Paris, France
                [ ]Research Institute for Sport and Exercise Sciences, School of Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street Campus, Liverpool, L3 3AF UK
                [ ]Institute for Biomedical Research into Human Movement and Health Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester, M1 5GD UK
                [ ]Department of Experimental Diagnostic and Specialty Medicine and Interdepartmental Centre “L. Galvani” (CIG), University of Bologna, via S. Giacomo 12, 40126 Bologna, Italy
                [ ]Division of Clinical Physiology, School of Graduate Entry to Medicine, Derby Royal Hospital, University of Nottingham, Uttoxeter Rd, Derby, DE22 3DT UK
                [ ]Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
                [ ]Sapienza University of Rome-Unit of Histology and Medical Embryology, Rome, Italy
                Article
                9429
                10.1007/s10522-013-9429-4
                3719007
                23666344
                21081b64-77e5-475f-a863-48768cb0df28
                © The Author(s) 2013

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 29 January 2013
                : 29 April 2013
                Categories
                Research Article
                Custom metadata
                © Springer Science+Business Media Dordrecht 2013

                Geriatric medicine
                sarcopenia,muscle regeneration,satellite cells,tissue niche,growth factors,stem cells

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