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      The role of oxidative stress in skeletal muscle injury and regeneration: focus on antioxidant enzymes

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          Abstract

          Reactive oxygen species (ROS) are generated in skeletal muscle both during the rest and contractile activity. Myogenic cells are equipped with antioxidant enzymes, like superoxide dismutase, catalase, glutathione peroxidase, γ-glutamylcysteine synthetase and heme oxygenase-1. These enzymes not only neutralise excessive ROS, but also affect myogenic regeneration at several stages: influence post-injury inflammatory reaction, enhance viability and proliferation of muscle satellite cells and myoblasts and affect their differentiation. Finally, antioxidant enzymes regulate also processes accompanying muscle regeneration—induce angiogenesis and reduce fibrosis. Elevated ROS production was also observed in Duchenne muscular dystrophy (DMD), a disease characterised by degeneration of muscle tissue and therefore—increased rate of myogenic regeneration. Antioxidant enzymes are consequently considered as target for therapies counteracting dystrophic symptoms. In this review we present current knowledge regarding the role of oxidative stress and systems of enzymatic antioxidant defence in muscular regeneration after both acute injury and persistent muscular degeneration.

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          Most cited references151

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          TLR signaling augments macrophage bactericidal activity through mitochondrial ROS

          Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria, and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase (Phox) machinery 1 . However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to macrophage bactericidal activity, although the mechanisms linking innate immune signaling to mitochondria for mROS generation remain unclear 2-4 . Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of the TLR signaling adapter tumor necrosis factor receptor-associated factor 6 (TRAF6) to mitochondria where it engages evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a protein implicated in mitochondrial respiratory chain assembly 5 . Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT and TRAF6 depleted macrophages exhibit decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results therefore reveal a novel pathway linking innate immune signaling to mitochondria, implicate mROS as important components of antibacterial responses, and further establish mitochondria as hubs for innate immune signaling.
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            Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage.

            Following their discovery in 1961, it was speculated that satellite cells were dormant myoblasts, held in reserve until required for skeletal muscle repair. Evidence for this accumulated over the years, until the link between satellite cells and the myoblasts that appear during muscle regeneration was finally established. Subsequently, it was demonstrated that, when grafted, satellite cells could also self-renew, conferring on them the coveted status of 'stem cell'. The emergence of other cell types with myogenic potential, however, questioned the precise role of satellite cells. Here, we review recent recombination-based studies that have furthered our understanding of satellite cell biology. The clear consensus is that skeletal muscle does not regenerate without satellite cells, confirming their pivotal and non-redundant role.
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              Physiological functions of thioredoxin and thioredoxin reductase.

              Thioredoxin, thioredoxin reductase and NADPH, the thioredoxin system, is ubiquitous from Archea to man. Thioredoxins, with a dithiol/disulfide active site (CGPC) are the major cellular protein disulfide reductases; they therefore also serve as electron donors for enzymes such as ribonucleotide reductases, thioredoxin peroxidases (peroxiredoxins) and methionine sulfoxide reductases. Glutaredoxins catalyze glutathione-disulfide oxidoreductions overlapping the functions of thioredoxins and using electrons from NADPH via glutathione reductase. Thioredoxin isoforms are present in most organisms and mitochondria have a separate thioredoxin system. Plants have chloroplast thioredoxins, which via ferredoxin-thioredoxin reductase regulates photosynthetic enzymes by light. Thioredoxins are critical for redox regulation of protein function and signaling via thiol redox control. A growing number of transcription factors including NF-kappaB or the Ref-1-dependent AP1 require thioredoxin reduction for DNA binding. The cytosolic mammalian thioredoxin, lack of which is embryonically lethal, has numerous functions in defense against oxidative stress, control of growth and apoptosis, but is also secreted and has co-cytokine and chemokine activities. Thioredoxin reductase is a specific dimeric 70-kDa flavoprotein in bacteria, fungi and plants with a redox active site disulfide/dithiol. In contrast, thioredoxin reductases of higher eukaryotes are larger (112-130 kDa), selenium-dependent dimeric flavoproteins with a broad substrate specificity that also reduce nondisulfide substrates such as hydroperoxides, vitamin C or selenite. All mammalian thioredoxin reductase isozymes are homologous to glutathione reductase and contain a conserved C-terminal elongation with a cysteine-selenocysteine sequence forming a redox-active selenenylsulfide/selenolthiol active site and are inhibited by goldthioglucose (aurothioglucose) and other clinically used drugs.
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                Author and article information

                Contributors
                m.kozakowska@uj.edu.pl
                katarzyna.pietraszek@uj.edu.pl
                alicja.jozkowicz@uj.edu.pl
                48 12 664 6411 , jozef.dulak@uj.edu.pl
                Journal
                J Muscle Res Cell Motil
                J. Muscle Res. Cell. Motil
                Journal of Muscle Research and Cell Motility
                Springer International Publishing (Cham )
                0142-4319
                1573-2657
                4 January 2016
                4 January 2016
                2015
                : 36
                : 377-393
                Affiliations
                [ ]Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
                [ ]Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland
                Article
                9438
                10.1007/s10974-015-9438-9
                4762917
                26728750
                12b66bcc-16e1-4d13-b280-ba1c348cd24b
                © The Author(s) 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 14 July 2015
                : 7 December 2015
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004569, Ministerstwo Nauki i Szkolnictwa Wyższego (PL);
                Award ID: IP2012 025572
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004281, Narodowe Centrum Nauki (PL);
                Award ID: MAESTRO - 2012/06/A/NZ1/00004
                Award ID: OPUS - 2012/07/B/NZ1/02881
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © Springer International Publishing Switzerland 2015

                Molecular biology
                reactive oxygen spices,muscle regeneration,superoxide dismutase,catalase,glutathione peroxidase,heme oxygenase-1

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