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      Interleukin‐6 myokine signaling in skeletal muscle: a double‐edged sword?

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          Abstract

          Interleukin ( IL)‐6 is a cytokine with pleiotropic functions in different tissues and organs. Skeletal muscle produces and releases significant levels of IL‐6 after prolonged exercise and is therefore considered as a myokine. Muscle is also an important target of the cytokine. IL‐6 signaling has been associated with stimulation of hypertrophic muscle growth and myogenesis through regulation of the proliferative capacity of muscle stem cells. Additional beneficial effects of IL‐6 include regulation of energy metabolism, which is related to the capacity of actively contracting muscle to synthesize and release IL‐6. Paradoxically, deleterious actions for IL‐6 have also been proposed, such as promotion of atrophy and muscle wasting. We review the current evidence for these apparently contradictory effects, the mechanisms involved and discuss their possible biological implications.

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          Most cited references 127

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          Muscles, exercise and obesity: skeletal muscle as a secretory organ.

          During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.
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            Cancer cachexia: mediators, signaling, and metabolic pathways.

            Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase.

              Although interleukin-6 (IL-6) has been associated with insulin resistance, little is known regarding the effects of IL-6 on insulin sensitivity in humans in vivo. Here, we show that IL-6 infusion increases glucose disposal without affecting the complete suppression of endogenous glucose production during a hyperinsulinemic-euglycemic clamp in healthy humans. Because skeletal muscle accounts for most of the insulin-stimulated glucose disposal in vivo, we examined the mechanism(s) by which IL-6 may affect muscle metabolism using L6 myotubes. IL-6 treatment increased fatty acid oxidation, basal and insulin-stimulated glucose uptake, and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increased AMP-activated protein kinase (AMPK). To determine whether the activation of AMPK mediated cellular metabolic events, we conducted experiments using L6 myotubes infected with dominant-negative AMPK alpha-subunit. The effects described above were abrogated in AMPK dominant-negative-infected cells. Our results demonstrate that acute IL-6 treatment enhances insulin-stimulated glucose disposal in humans in vivo, while the effects of IL-6 on glucose and fatty acid metabolism in vitro appear to be mediated by AMPK.
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                Author and article information

                Journal
                FEBS J
                FEBS J
                10.1111/(ISSN)1742-4658
                FEBS
                The Febs Journal
                Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies
                1742-464X
                1742-4658
                18 June 2013
                20 August 2013
                : 280
                : 17 , Myogenesis ( doiID: 10.1111/febs.2013.280.issue-17 )
                : 4131-4148
                Affiliations
                [ 1 ] Cell Biology Group Department of Experimental and Health SciencesPompeu Fabra University (UPF), Institució Catalana de Recerca i Estudis Avançats (ICREA), CIBER on Neurodegenerative diseases (CIBERNED) BarcelonaSpain
                [ 2 ] The Centre of Inflammation and Metabolism Department of Infectious Diseases and CMRC RigshospitaletUniversity of Copenhagen Denmark
                Author notes
                [* ] Correspondence

                P. Muñoz‐Cánoves and A. L. Serrano, Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), 08003, Barcelona, Spain

                Fax: +34 93 316 0901

                Tel: +34 93 316 0891

                E‐mails: pura.munoz@ 123456upf.edu ; antonio.serrano@ 123456upf.edu

                Note Pura Muñoz‐Cánoves and Antonio L. Serrano contributed equally to this work

                Article
                FEBS12338
                10.1111/febs.12338
                4163639
                23663276
                © 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Pages: 18
                Product
                Funding
                Funded by: EU‐FP7
                Funded by: MICINN
                Award ID: SAF2009‐09782
                Award ID: FIS‐PS09/01267
                Award ID: SAF2012‐38547
                Award ID: PLE2009‐0124
                Funded by: CIBERNED
                Funded by: Danish National Research Foundation
                Award ID: DNRF55
                Categories
                Review Article
                Muscle Fibrosis and Inflammation
                Custom metadata
                2.0
                febs12338
                September 2013
                Converter:WILEY_ML3GV2_TO_NLM version:4.1.3 mode:remove_FC converted:15.09.2014

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