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

Pura Muñoz-Cánoves, Camilla Scheele, Bente K Pedersen, Antonio L Serrano, Pura Muñoz-Cánoves, Camilla Scheele, Bente K Pedersen, Antonio L Serrano

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.

Keywords: IL-6; growth/atrophy; inflammation; metabolism; myogenesis; myokine; regeneration; satellite cell; signaling pathway; skeletal muscle.

© 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4163639/bin/febs-280-4131-g1.jpg

References

    1. Pedersen BK & Febbraio MA (2008) Muscle as an endocrine organ: focus on muscle‐derived interleukin‐6. Physiol Rev 88, 1379–1406
    1. Broholm C & Pedersen BK (2010) Leukaemia inhibitory factor – an exercise‐induced myokine. Exerc Immunol Rev 16, 77–85
    1. Broholm C, Laye MJ, Brandt C, Vadalasetty R, Pilegaard H, Pedersen BK & Scheele C (2011) LIF is a contraction‐induced myokine stimulating human myocyte proliferation. J Appl Physiol 111, 251–259
    1. Pedersen BK & Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8, 457–465
    1. Hirano T (1998) Interleukin‐6 and its receptor: ten years later. Int Rev Immunol 16, 249–284
    1. Rose‐John S, Scheller J, Elson G & Jones SA (2006) Interleukin‐6 biology is coordinated by membrane‐bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 80, 227–236
    1. Scheller J & Rose‐John S (2006) Interleukin‐6 and its receptor: from bench to bedside. Med Microbiol Immunol 195, 173–183
    1. Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, Zinkernagel R, Bluethmann H & Kohler G (1994) Impaired immune and acute‐phase responses in interleukin‐6‐deficient mice. Nature 368, 339–342
    1. Blatteis CM & Sehic E (1998) Cytokines and fever. Ann N Y Acad Sci 840, 608–618
    1. Lepper C, Conway SJ & Fan CM (2009) Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements. Nature 460, 627–631
    1. Yin H, Price F & Rudnicki MA (2013) Satellite cells and the muscle stem cell niche. Physiol Rev 93, 23–67
    1. Rocheteau P, Gayraud‐Morel B, Siegl‐Cachedenier I, Blasco MA & Tajbakhsh S (2012) A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125
    1. Puri PL & Sartorelli V (2000) Regulation of muscle regulatory factors by DNA‐binding, interacting proteins, and post‐transcriptional modifications. J Cell Physiol 185, 155–173
    1. Sartorelli V & Caretti G (2005) Mechanisms underlying the transcriptional regulation of skeletal myogenesis. Curr Opin Genet Dev 15, 528–535
    1. Tapscott SJ (2005) The circuitry of a master switch: myod and the regulation of skeletal muscle gene transcription. Development 132, 2685–2695
    1. Lluis F, Perdiguero E, Nebreda AR & Munoz‐Canoves P (2006) Regulation of skeletal muscle gene expression by p38 MAP kinases. Trends Cell Biol 16, 36–44
    1. Perdiguero E, Sousa‐Victor P, Ballestar E & Munoz‐Canoves P (2009) Epigenetic regulation of myogenesis. Epigenetics 4, 541–550
    1. Guasconi V & Puri PL (2009) Chromatin: the interface between extrinsic cues and the epigenetic regulation of muscle regeneration. Trends Cell Biol 19, 286–294
    1. Dilworth FJ & Blais A (2011) Epigenetic regulation of satellite cell activation during muscle regeneration. Stem Cell Res Ther 2, 18.
    1. Spangenburg EE & Booth FW (2006) Leukemia inhibitory factor restores the hypertrophic response to increased loading in the LIF(‐/‐) mouse. Cytokine 34, 125–130
    1. Serrano AL, Baeza‐Raja B, Perdiguero E, Jardi M & Munoz‐Canoves P (2008) Interleukin‐6 is an essential regulator of satellite cell‐mediated skeletal muscle hypertrophy. Cell Metab 7, 33–44
    1. Guerci A, Lahoute C, Hebrard S, Collard L, Graindorge D, Favier M, Cagnard N, Batonnet‐Pichon S, Precigout G, Garcia Let al (2012) Srf‐dependent paracrine signals produced by myofibers control satellite cell‐mediated skeletal muscle hypertrophy. Cell Metab 15, 25–37
    1. Horsley V, Jansen KM, Mills ST & Pavlath GK (2003) IL‐4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113, 483–494
    1. Prokopchuk O, Liu Y, Wang L, Wirth K, Schmidtbleicher D & Steinacker JM (2007) Skeletal muscle IL‐4, IL‐4Ralpha, IL‐13 and IL‐13Ralpha1 expression and response to strength training. Exerc Immunol Rev 13, 67–75
    1. Kurek JB, Bower JJ, Romanella M, Koentgen F, Murphy M & Austin L (1997) The role of leukemia inhibitory factor in skeletal muscle regeneration. Muscle Nerve 20, 815–822
    1. Barnard W, Bower J, Brown MA, Murphy M & Austin L (1994) Leukemia inhibitory factor (LIF) infusion stimulates skeletal muscle regeneration after injury: injured muscle expresses lif mRNA. J Neurol Sci 123, 108–113
    1. Kurek JB, Nouri S, Kannourakis G, Murphy M & Austin L (1996) Leukemia inhibitory factor and interleukin‐6 are produced by diseased and regenerating skeletal muscle. Muscle Nerve 19, 1291–1301
    1. Zhang C, Li Y, Wu Y, Wang L, Wang X & Du J (2013) Interleukin‐6/signal transducer and activator of transcription 3 (STAT3) pathway is essential for macrophage infiltration and myoblast proliferation during muscle regeneration. J Biol Chem 288, 1489–1499
    1. Joe AW, Yi L, Natarajan A, Le Grand F, So L, Wang J, Rudnicki MA & Rossi FM (2010) Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol 12, 153–163
    1. Kami K & Senba E (1998) Localization of leukemia inhibitory factor and interleukin‐6 messenger ribonucleic acids in regenerating rat skeletal muscle. Muscle Nerve 21, 819–822
    1. Kami K & Senba E (2002) In vivo activation of STAT3 signaling in satellite cells and myofibers in regenerating rat skeletal muscles. J Histochem Cytochem 50, 1579–1589
    1. Gallucci S, Provenzano C, Mazzarelli P, Scuderi F & Bartoccioni E (1998) Myoblasts produce IL‐6 in response to inflammatory stimuli. Int Immunol 10, 267–273
    1. Baeza‐Raja B & Munoz‐Canoves P (2004) p38 MAPK‐induced nuclear factor‐kappaB activity is required for skeletal muscle differentiation: role of interleukin‐6. Mol Biol Cell 15, 2013–2026
    1. Hoene M, Runge H, Haring HU, Schleicher ED & Weigert C (2013) Interleukin‐6 promotes myogenic differentiation of mouse skeletal muscle cells: role of the STAT3 pathway. Am J Physiol Cell Physiol 304, C128–C136
    1. Yang Y, Xu Y, Li W, Wang G, Song Y, Yang G, Han X, Du Z, Sun L & Ma K (2009) STAT3 induces muscle stem cell differentiation by interaction with myoD. Cytokine 46, 137–141
    1. Spangenburg EE (2005) SOCS‐3 induces myoblast differentiation. J Biol Chem 280, 10749–10758
    1. Delling U, Tureckova J, Lim HW, De Windt LJ, Rotwein P & Molkentin JD (2000) A calcineurin–NFATc3‐dependent pathway regulates skeletal muscle differentiation and slow myosin heavy‐chain expression. Mol Cell Biol 20, 6600–6611
    1. Lu J, McKinsey TA, Zhang CL & Olson EN (2000) Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol Cell 6, 233–244
    1. Serra C, Palacios D, Mozzetta C, Forcales SV, Morantte I, Ripani M, Jones DR, Du K, Jhala US, Simone Cet al (2007) Functional interdependence at the chromatin level between the MKK6/p38 and IGF1/PI3K/AKT pathways during muscle differentiation. Mol Cell 28, 200–213
    1. Perdiguero E, Ruiz‐Bonilla V, Gresh L, Hui L, Ballestar E, Sousa‐Victor P, Baeza‐Raja B, Jardi M, Bosch‐Comas A, Esteller Met al (2007) Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation. EMBO J 26, 1245–1256
    1. Bennett AM & Tonks NK (1997) Regulation of distinct stages of skeletal muscle differentiation by mitogen‐activated protein kinases. Science 278, 1288–1291
    1. Coolican SA, Samuel DS, Ewton DZ, McWade FJ & Florini JR (1997) The mitogenic and myogenic actions of insulin‐like growth factors utilize distinct signaling pathways. J Biol Chem 272, 6653–6662
    1. Wu Z, Woodring PJ, Bhakta KS, Tamura K, Wen F, Feramisco JR, Karin M, Wang JY & Puri PL (2000) p38 and extracellular signal‐regulated kinases regulate the myogenic program at multiple steps. Mol Cell Biol 20, 3951–3964
    1. Guttridge DC, Albanese C, Reuther JY, Pestell RG & Baldwin AS Jr (1999) NF‐kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 19, 5785–5799
    1. Megeney LA, Perry RL, LeCouter JE & Rudnicki MA (1996) bFGF and LIF signaling activates STAT3 in proliferating myoblasts. Dev Genet 19, 139–145
    1. Spangenburg EE & Booth FW (2002) Multiple signaling pathways mediate LIF‐induced skeletal muscle satellite cell proliferation. Am J Physiol Cell Physiol 283, C204–C211
    1. Kataoka Y, Matsumura I, Ezoe S, Nakata S, Takigawa E, Sato Y, Kawasaki A, Yokota T, Nakajima K, Felsani Aet al (2003) Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts. J Biol Chem 278, 44178–44187
    1. Sun L, Ma K, Wang H, Xiao F, Gao Y, Zhang W, Wang K, Gao X, Ip N & Wu Z (2007) JAK1–STAT1–STAT3, a key pathway promoting proliferation and preventing premature differentiation of myoblasts. J Cell Biol 179, 129–138
    1. Wang K, Wang C, Xiao F, Wang H & Wu Z (2008) JAK2/STAT2/STAT3 are required for myogenic differentiation. J Biol Chem 283, 34029–34036
    1. Diao Y, Wang X & Wu Z (2009) SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by inhibiting the leukemia inhibitory factor‐induced JAK1/STAT1/STAT3 pathway. Mol Cell Biol 29, 5084–5093
    1. Xiao F, Wang H, Fu X, Li Y, Ma K, Sun L, Gao X & Wu Z (2011) Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration. Cell Res 21, 350–364
    1. Hunt LC, Upadhyay A, Jazayeri JA, Tudor EM & White JD (2011) Caspase‐3, myogenic transcription factors and cell cycle inhibitors are regulated by leukemia inhibitory factor to mediate inhibition of myogenic differentiation. Skeletal Muscle 1, 17.
    1. Fernando P, Kelly JF, Balazsi K, Slack RS & Megeney LA (2002) Caspase 3 activity is required for skeletal muscle differentiation. Proc Natl Acad Sci USA 99, 11025–11030
    1. Glass DJ (2010) PI3 kinase regulation of skeletal muscle hypertrophy and atrophy. Curr Top Microbiol Immunol 346, 267–278
    1. Kaliman P, Canicio J, Shepherd PR, Beeton CA, Testar X, Palacin M & Zorzano A (1998) Insulin‐like growth factors require phosphatidylinositol 3‐kinase to signal myogenesis: dominant negative p85 expression blocks differentiation of L6E9 muscle cells. Mol Endocrinol 12, 66–77
    1. Wormald S & Hilton DJ (2004) Inhibitors of cytokine signal transduction. J Biol Chem 279, 821–824
    1. Leger B, Derave W, De Bock K, Hespel P & Russell AP (2008) Human sarcopenia reveals an increase in SOCS‐3 and myostatin and a reduced efficiency of Akt phosphorylation. Rejuvenation Res 11, 163–175B
    1. Trenerry MK, Carey KA, Ward AC, Farnfield MM & Cameron‐Smith D (2008) Exercise‐induced activation of STAT3 signaling is increased with age. Rejuvenation Res 11, 717–724
    1. Hsu YH, Sarker KP, Pot I, Chan A, Netherton SJ & Bonni S (2006) Sumoylated SnoN represses transcription in a promoter‐specific manner. J Biol Chem 281, 33008–33018
    1. Lee H, Quinn JC, Prasanth KV, Swiss VA, Economides KD, Camacho MM, Spector DL & Abate‐Shen C (2006) PIAS1 confers DNA‐binding specificity on the Msx1 homeoprotein. Genes Dev 20, 784–794
    1. Wrighton KH, Liang M, Bryan B, Luo K, Liu M, Feng XH & Lin X (2007) Transforming growth factor‐beta‐independent regulation of myogenesis by SnoN sumoylation. J Biol Chem 282, 6517–6524
    1. Kontaridis MI, Eminaga S, Fornaro M, Zito CI, Sordella R, Settleman J & Bennett AM (2004) SHP‐2 positively regulates myogenesis by coupling to the Rho GTPase signaling pathway. Mol Cell Biol 24, 5340–5352
    1. Miyake T, Alli NS, Aziz A, Knudson J, Fernando P, Megeney LA & McDermott JC (2009) Cardiotrophin‐1 maintains the undifferentiated state in skeletal myoblasts. J Biol Chem 284, 19679–19693
    1. Pedersen BK (2011) Exercise‐induced myokines and their role in chronic diseases. Brain Behav Immun 25, 811–816
    1. Pedersen BK (2009) The diseasome of physical inactivity – and the role of myokines in muscle – fat cross talk. J Physiol 587, 5559–5568
    1. Fischer CP (2006) Interleukin‐6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev 12, 6–33
    1. Nieman DC, Nehlsen‐Cannarella SL, Fagoaga OR, Henson DA, Utter A, Davis JM, Williams F & Butterworth DE (1998) Influence of mode and carbohydrate on the cytokine response to heavy exertion. Med Sci Sports Exerc 30, 671–678
    1. Nehlsen‐Cannarella SL, Fagoaga OR, Nieman DC, Henson DA, Butterworth DE, Schmitt RL, Bailey EM, Warren BJ, Utter A & Davis JM (1997) Carbohydrate and the cytokine response to 2.5 h of running. J Appl Physiol 82, 1662–1667
    1. Ullum H, Haahr PM, Diamant M, Palmo J, Halkjaer‐Kristensen J & Pedersen BK (1994) Bicycle exercise enhances plasma IL‐6 but does not change IL‐1 alpha, IL‐1 beta, IL‐6, or TNF‐alpha pre‐mRNA in BMNC. J Appl Physiol 77, 93–97
    1. Starkie RL, Angus DJ, Rolland J, Hargreaves M & Febbraio MA (2000) Effect of prolonged, submaximal exercise and carbohydrate ingestion on monocyte intracellular cytokine production in humans. J Physiol 528, 647–655
    1. Starkie RL, Rolland J, Angus DJ, Anderson MJ & Febbraio MA (2001) Circulating monocytes are not the source of elevations in plasma IL‐6 and TNF‐alpha levels after prolonged running. Am J Physiol Cell Physiol 280, C769–C774
    1. Febbraio MA, Ott P, Nielsen HB, Steensberg A, Keller C, Krustrup P, Secher NH & Pedersen BK (2003) Hepatosplanchnic clearance of interleukin‐6 in humans during exercise. Am J Physiol Endocrinol Metab 285, E397–E402
    1. Keller C, Steensberg A, Pilegaard H, Osada T, Saltin B, Pedersen BK & Neufer PD (2001) Transcriptional activation of the IL‐6 gene in human contracting skeletal muscle: influence of muscle glycogen content. FASEB J 15, 2748–2750
    1. Steensberg A, Keller C, Starkie RL, Osada T, Febbraio MA & Pedersen BK (2002) IL‐6 and TNF‐alpha expression in, and release from, contracting human skeletal muscle. Am J Physiol Endocrinol Metab 283, E1272–E1278
    1. Hiscock N, Chan MH, Bisucci T, Darby IA & Febbraio MA (2004) Skeletal myocytes are a source of interleukin‐6 mRNA expression and protein release during contraction: evidence of fiber type specificity. FASEB J 18, 992–994
    1. Rosendal L, Sogaard K, Kjaer M, Sjogaard G, Langberg H & Kristiansen J (2005) Increase in interstitial interleukin‐6 of human skeletal muscle with repetitive low‐force exercise. J Appl Physiol 98, 477–481
    1. Steensberg A, Van Hall G, Osada T, Sacchetti M, Saltin B & Pedersen KB (2000) Production of interleukin‐6 in contracting human skeletal muscles can account for the exercise‐induced increase in plasma interleukin‐6. J Physiol 529, 237–242
    1. De Rossi M, Bernasconi P, Baggi F, de Waal Malefyt R & Mantegazza R (2000) Cytokines and chemokines are both expressed by human myoblasts: possible relevance for the immune pathogenesis of muscle inflammation. Int Immunol 12, 1329–1335
    1. Bartoccioni E, Michaelis D & Hohlfeld R (1994) Constitutive and cytokine‐induced production of interleukin‐6 by human myoblasts. Immunol Lett 42, 135–138
    1. Keller C, Hellsten Y, Steensberg A & Pedersen BK (2006) Differential regulation of IL‐6 and TNF‐alpha via calcineurin in human skeletal muscle cells. Cytokine 36, 141–147
    1. Haugen F, Norheim F, Lian H, Wensaas AJ, Dueland S, Berg O, Funderud A, Skalhegg BS, Raastad T & Drevon CA (2010) IL‐7 is expressed and secreted by human skeletal muscle cells. Am J Physiol Cell Physiol 298, C807–C816
    1. Green CJ, Pedersen M, Pedersen BK & Scheele C (2011) Elevated NF‐kappaB activation is conserved in human myocytes cultured from obese type 2 diabetic patients and attenuated by AMP‐activated protein kinase. Diabetes 60, 2810–2819
    1. Whitham M, Chan MH, Pal M, Matthews VB, Prelovsek O, Lunke S, El‐Osta A, Broenneke H, Alber J, Bruning JCet al (2012) Contraction‐induced interleukin‐6 gene transcription in skeletal muscle is regulated by c‐Jun terminal kinase/activator protein‐1. J Biol Chem 287, 10771–10779
    1. Lambernd S, Taube A, Schober A, Platzbecker B, Gorgens SW, Schlich R, Jeruschke K, Weiss J, Eckardt K & Eckel J (2012) Contractile activity of human skeletal muscle cells prevents insulin resistance by inhibiting pro‐inflammatory signalling pathways. Diabetologia 55, 1128–1139
    1. Pedersen BK (2012) Muscular interleukin‐6 and its role as an energy sensor. Med Sci Sports Exerc 44, 392–396
    1. Ruderman NB, Keller C, Richard AM, Saha AK, Luo Z, Xiang X, Giralt M, Ritov VB, Menshikova EV, Kelley DEet al (2006) Interleukin‐6 regulation of AMP‐activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome. Diabetes 55(Suppl 2), S48–S54
    1. Fischer CP, Plomgaard P, Hansen AK, Pilegaard H, Saltin B & Pedersen BK (2004) Endurance training reduces the contraction‐induced interleukin‐6 mRNA expression in human skeletal muscle. Am J Physiol Endocrinol Metab 287, E1189–E1194
    1. Wolsk E, Mygind H, Grondahl TS, Pedersen BK & Van Hall G (2010) IL‐6 selectively stimulates fat metabolism in human skeletal muscle. Am J Physiol Endocrinol Metab 299, E832–E840
    1. Van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MAet al (2003) Interleukin‐6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88, 3005–3010
    1. Steensberg A, Fischer CP, Sacchetti M, Keller C, Osada T, Schjerling P, Van Hall G, Febbraio MA & Pedersen BK (2003) Acute interleukin‐6 administration does not impair muscle glucose uptake or whole‐body glucose disposal in healthy humans. J Physiol 548, 631–638
    1. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen‐Behrens C, Watt MJ, James DEet al (2006) Interleukin‐6 increases insulin‐stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP‐activated protein kinase. Diabetes 55, 2688–2697
    1. Febbraio MA, Hiscock N, Sacchetti M, Fischer CP & Pedersen BK (2004) Interleukin‐6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 53, 1643–1648
    1. Al‐Khalili L, Bouzakri K, Glund S, Lonnqvist F, Koistinen HA & Krook A (2006) Signaling specificity of interleukin‐6 action on glucose and lipid metabolism in skeletal muscle. Mol Endocrinol 20, 3364–3375
    1. Kelly M, Gauthier MS, Saha AK & Ruderman NB (2009) Activation of AMP‐activated protein kinase by interleukin‐6 in rat skeletal muscle: association with changes in cAMP, energy state, and endogenous fuel mobilization. Diabetes 58, 1953–1960
    1. Sadagurski M, Norquay L, Farhang J, D'Aquino K, Copps K & White MF (2010) Human IL6 enhances leptin action in mice. Diabetologia 53, 525–535
    1. Wunderlich FT, Strohle P, Konner AC, Gruber S, Tovar S, Bronneke HS, Juntti‐Berggren L, Li LS, Van Rooijen N, Libert Cet al (2010) Interleukin‐6 signaling in liver‐parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab 12, 237–249
    1. Bouzakri K, Plomgaard P, Berney T, Donath MY, Pedersen BK & Halban PA (2011) Bimodal effect on pancreatic beta‐cells of secretory products from normal or insulin‐resistant human skeletal muscle. Diabetes 60, 1111–1121
    1. Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, Eppler E, Bouzakri K, Wueest S, Muller YDet al (2011) Interleukin‐6 enhances insulin secretion by increasing glucagon‐like peptide‐1 secretion from L cells and alpha cells. Nat Med 17, 1481–1489
    1. Tisdale MJ (2009) Mechanisms of cancer cachexia. Physiol Rev 89, 381–410
    1. Carson JA & Baltgalvis KA (2010) Interleukin‐6 as a key regulator of muscle mass during cachexia. Exerc Sport Sci Rev 38, 168–176
    1. Tsoli M & Robertson G (2013) Cancer cachexia: malignant inflammation, tumorkines, and metabolic mayhem. Trends Endocrinol Metab 24, 174–183
    1. Fearon KC, Glass DJ & Guttridge DC (2012) Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab 16, 153–166
    1. Strassmann G, Fong M, Kenney JS & Jacob CO (1992) Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89, 1681–1684
    1. Oldenburg HS, Rogy MA, Lazarus DD, Van Zee KJ, Keeler BP, Chizzonite RA, Lowry SF & Moldawer LL (1993) Cachexia and the acute‐phase protein response in inflammation are regulated by interleukin‐6. Eur J Immunol 23, 1889–1894
    1. Garcia‐Martinez C, Lopez‐Soriano FJ & Argiles JM (1994) Interleukin‐6 does not activate protein breakdown in rat skeletal muscle. Cancer Lett 76, 1–4
    1. Goodman MN (1994) Interleukin‐6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 205, 182–185
    1. Williams A, Wang JJ, Wang L, Sun X, Fischer JE & Hasselgren PO (1998) Sepsis in mice stimulates muscle proteolysis in the absence of IL‐6. Am J Physiol 275, R1983–R1991
    1. Ebisui C, Tsujinaka T, Morimoto T, Kan K, Iijima S, Yano M, Kominami E, Tanaka K & Monden M (1995) Interleukin‐6 induces proteolysis by activating intracellular proteases (cathepsins B and L, proteasome) in C2C12 myotubes. Clin Sci (Lond) 89, 431–439
    1. Espat NJ, Auffenberg T, Rosenberg JJ, Rogy M, Martin D, Fang CH, Hasselgren PO, Copeland EM & Moldawer LL (1996) Ciliary neurotrophic factor is catabolic and shares with IL‐6 the capacity to induce an acute phase response. Am J Physiol 271, R185–R190
    1. Llovera M, Carbo N, Lopez‐Soriano J, Garcia‐Martinez C, Busquets S, Alvarez B, Agell N, Costelli P, Lopez‐Soriano FJ, Celada Aet al (1998) Different cytokines modulate ubiquitin gene expression in rat skeletal muscle. Cancer Lett 133, 83–87
    1. Tsujinaka T, Ebisui C, Fujita J, Kishibuchi M, Morimoto T, Ogawa A, Katsume A, Ohsugi Y, Kominami E & Monden M (1995) Muscle undergoes atrophy in association with increase of lysosomal cathepsin activity in interleukin‐6 transgenic mouse. Biochem Biophys Res Commun 207, 168–174
    1. Tsujinaka T, Fujita J, Ebisui C, Yano M, Kominami E, Suzuki K, Tanaka K, Katsume A, Ohsugi Y, Shiozaki Het al (1996) Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice. J Clin Invest 97, 244–249
    1. Fujita J, Tsujinaka T, Yano M, Ebisui C, Saito H, Katsume A, Akamatsu K, Ohsugi Y, Shiozaki H & Monden M (1996) Anti‐interleukin‐6 receptor antibody prevents muscle atrophy in colon‐26 adenocarcinoma‐bearing mice with modulation of lysosomal and ATP‐ubiquitin‐dependent proteolytic pathways. Int J Cancer 68, 637–643
    1. Soda K, Kawakami M, Kashii A & Miyata M (1994) Characterization of mice bearing subclones of colon 26 adenocarcinoma disqualifies interleukin‐6 as the sole inducer of cachexia. Jpn J Cancer Res 85, 1124–1130
    1. Soda K, Kawakami M, Kashii A & Miyata M (1995) Manifestations of cancer cachexia induced by colon 26 adenocarcinoma are not fully ascribable to interleukin‐6. Int J Cancer 62, 332–336
    1. Haddad F, Zaldivar F, Cooper DM & Adams GR (2005) IL‐6‐induced skeletal muscle atrophy. J Appl Physiol 98, 911–917
    1. Janssen SP, Gayan‐Ramirez G, Van den Bergh A, Herijgers P, Maes K, Verbeken E & Decramer M (2005) Interleukin‐6 causes myocardial failure and skeletal muscle atrophy in rats. Circulation 111, 996–1005
    1. Bodell PW, Kodesh E, Haddad F, Zaldivar FP, Cooper DM & Adams GR (2009) Skeletal muscle growth in young rats is inhibited by chronic exposure to IL‐6 but preserved by concurrent voluntary endurance exercise. J Appl Physiol 106, 443–453
    1. Steensberg A, Febbraio MA, Osada T, Schjerling P, Van Hall G, Saltin B & Pedersen BK (2001) Interleukin‐6 production in contracting human skeletal muscle is influenced by pre‐exercise muscle glycogen content. J Physiol 537, 633–639
    1. Van Hall G, Steensberg A, Fischer C, Keller C, Moller K, Moseley P & Pedersen BK (2008) Interleukin‐6 markedly decreases skeletal muscle protein turnover and increases nonmuscle amino acid utilization in healthy individuals. J Clin Endocrinol Metab 93, 2851–2858
    1. Raj DS, Moseley P, Dominic EA, Onime A, Tzamaloukas AH, Boyd A, Shah VO, Glew R, Wolfe R & Ferrando A (2008) Interleukin‐6 modulates hepatic and muscle protein synthesis during hemodialysis. Kidney Int 73, 1054–1061
    1. De Benedetti F, Alonzi T, Moretta A, Lazzaro D, Costa P, Poli V, Martini A, Ciliberto G & Fattori E (1997) Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin‐like growth factor‐I. A model for stunted growth in children with chronic inflammation. J Clin Invest 99, 643–650
    1. Nemet D, Eliakim A, Zaldivar F & Cooper DM (2006) Effect of rhIL‐6 infusion on GH→IGF‐I axis mediators in humans. Am J Physiol Regul Integr Comp Physiol 291, R1663–R1668
    1. De Benedetti F, Pignatti P, Vivarelli M, Meazza C, Ciliberto G, Savino R & Martini A (2001) In vivo neutralization of human IL‐6 (hIL‐6) achieved by immunization of hIL‐6‐transgenic mice with a hIL‐6 receptor antagonist. J Immunol 166, 4334–4340
    1. Firth SM & Baxter RC (2002) Cellular actions of the insulin‐like growth factor binding proteins. Endocrinol Rev 23, 824–854
    1. De Benedetti F, Meazza C, Oliveri M, Pignatti P, Vivarelli M, Alonzi T, Fattori E, Garrone S, Barreca A & Martini A (2001) Effect of IL‐6 on IGF binding protein‐3: a study in IL‐6 transgenic mice and in patients with systemic juvenile idiopathic arthritis. Endocrinology 142, 4818–4826
    1. Dall R, Lange KH, Kjaer M, Jorgensen JO, Christiansen JS, Orskov H & Flyvbjerg A (2001) No evidence of insulin‐like growth factor‐binding protein 3 proteolysis during a maximal exercise test in elite athletes. J Clin Endocrinol Metab 86, 669–674
    1. Pihl S, Carlsson‐Skwirut C, Berg U, Ekstrom K & Bang P (2006) Acute interleukin‐6 infusion increases IGFBP‐1 but has no short‐term effect on IGFBP‐3 proteolysis in healthy men. Horm Res 65, 177–184
    1. Nystrom G, Pruznak A, Huber D, Frost RA & Lang CH (2009) Local insulin‐like growth factor I prevents sepsis‐induced muscle atrophy. Metabolism 58, 787–797
    1. Braun TP, Zhu X, Szumowski M, Scott GD, Grossberg AJ, Levasseur PR, Graham K, Khan S, Damaraju S, Colmers WFet al (2011) Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic‐pituitary‐adrenal axis. J Exp Med 208, 2449–2463
    1. Lieskovska J, Guo D & Derman E (2003) Growth impairment in IL‐6‐overexpressing transgenic mice is associated with induction of SOCS3 mRNA. Growth Horm IGF Res 13, 26–35
    1. Franckhauser S, Elias I, Rotter Sopasakis V, Ferre T, Nagaev I, Andersson CX, Agudo J, Ruberte J, Bosch F & Smith U (2008) Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia 51, 1306–1316
    1. Haddad F & Adams GR (2006) Aging‐sensitive cellular and molecular mechanisms associated with skeletal muscle hypertrophy. J Appl Physiol 100, 1188–1203
    1. Morris RT, Spangenburg EE & Booth FW (2004) Responsiveness of cell signaling pathways during the failed 15‐day regrowth of aged skeletal muscle. J Appl Physiol 96, 398–404
    1. Mieulet V, Roceri M, Espeillac C, Sotiropoulos A, Ohanna M, Oorschot V, Klumperman J, Sandri M & Pende M (2007) S6 kinase inactivation impairs growth and translational target phosphorylation in muscle cells maintaining proper regulation of protein turnover. Am J Physiol Cell Physiol 293, C712–C722
    1. Li YP, Chen Y, John J, Moylan J, Jin B, Mann DL & Reid MB (2005) TNF‐alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB J 19, 362–370
    1. Zhang G & Li YP (2012) p38beta MAPK upregulates atrogin1/MAFbx by specific phosphorylation of C/EBPbeta. Skeletal Muscle 2, 20.
    1. Zhang L, Du J, Hu Z, Han G, Delafontaine P, Garcia G & Mitch WE (2009) IL‐6 and serum amyloid A synergy mediates angiotensin II‐induced muscle wasting. J Am Soc Nephrol 20, 604–612
    1. Sun DF, Zheng Z, Tummala P, Oh J, Schaefer F & Rabkin R (2004) Chronic uremia attenuates growth hormone‐induced signal transduction in skeletal muscle. J Am Soc Nephrol 15, 2630–2636
    1. Spangenburg EE, Brown DA, Johnson MS & Moore RL (2006) Exercise increases SOCS‐3 expression in rat skeletal muscle: potential relationship to IL‐6 expression. J Physiol 572, 839–848
    1. Giger JM, Bodell PW, Zeng M, Baldwin KM & Haddad F (2009) Rapid muscle atrophy response to unloading: pretranslational processes involving MHC and actin. J Appl Physiol 107, 1204–1212
    1. Bonetto A, Aydogdu T, Kunzevitzky N, Guttridge DC, Khuri S, Koniaris LG & Zimmers TA (2011) STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia. PLoS ONE 6, e22538.
    1. Bonetto A, Aydogdu T, Jin X, Zhang Z, Zhan R, Puzis L, Koniaris LG & Zimmers TA (2012) JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL‐6 and in experimental cancer cachexia. Am J Physiol Endocrinol Metab 303, E410–E421
    1. Yamada E, Bastie CC, Koga H, Wang Y, Cuervo AM & Pessin JE (2012) Mouse skeletal muscle fiber‐type‐specific macroautophagy and muscle wasting are regulated by a Fyn/STAT3/Vps34 signaling pathway. Cell Rep 1, 557–569
    1. Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S & Sandri M (2009) Autophagy is required to maintain muscle mass. Cell Metab 10, 507–515
    1. Song YH, Li Y, Du J, Mitch WE, Rosenthal N & Delafontaine P (2005) Muscle‐specific expression of IGF‐1 blocks angiotensin II‐induced skeletal muscle wasting. J Clin Invest 115, 451–458
    1. Yoshida T, Semprun‐Prieto L, Sukhanov S & Delafontaine P (2010) IGF‐1 prevents ANG II‐induced skeletal muscle atrophy via Akt‐ and Foxo‐dependent inhibition of the ubiquitin ligase atrogin‐1 expression. Am J Physiol Heart Circ Physiol 298, H1565–H1570
    1. Rui L, Yuan M, Frantz D, Shoelson S & White MF (2002) SOCS‐1 and SOCS‐3 block insulin signaling by ubiquitin‐mediated degradation of IRS1 and IRS2. J Biol Chem 277, 42394–42398
    1. Keller P, Keller C, Carey AL, Jauffred S, Fischer CP, Steensberg A & Pedersen BK (2003) Interleukin‐6 production by contracting human skeletal muscle: autocrine regulation by IL‐6. Biochem Biophys Res Commun 310, 550–554
    1. Weigert C, Dufer M, Simon P, Debre E, Runge H, Brodbeck K, Haring HU & Schleicher ED (2007) Upregulation of IL‐6 mRNA by IL‐6 in skeletal muscle cells: role of IL‐6 mRNA stabilization and Ca2+‐dependent mechanisms. Am J Physiol Cell Physiol 293, C1139–C1147
    1. Ji LL, Gomez‐Cabrera MC, Steinhafel N & Vina J (2004) Acute exercise activates nuclear factor (NF)‐kappaB signaling pathway in rat skeletal muscle. FASEB J 18, 1499–1506
    1. Vella L, Caldow MK, Larsen AE, Tassoni D, Della Gatta PA, Gran P, Russell AP & Cameron‐Smith D (2012) Resistance exercise increases NF‐kappaB activity in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 302, R667–R673

Source: PubMed

3
Subskrybuj