title: TNF-α and IGF1 modify the microRNA signature in skeletal muscle cell differentiation.
abstract: BACKGROUND
  Elevated levels of the inflammatory cytokine TNF-α are common in chronic diseases or inherited or degenerative muscle disorders and can lead to muscle wasting. By contrast, IGF1 has a growth promoting effect on skeletal muscle. The molecular mechanisms mediating the effect of TNF-α and IGF1 on muscle cell differentiation are not completely understood. Muscle cell proliferation and differentiation are regulated by microRNAs (miRNAs) which play a dominant role in this process. This study aims at elucidating how TNF-α or IGF1 regulate microRNA expression to affect myoblast differentiation and myotube formation.
  
  
  RESULTS
  In this study, we analyzed the impact of TNF-α or IGF1 treatment on miRNA expression in myogenic cells. Results reveal that i) TNF-α and IGF1 regulate miRNA expression during skeletal muscle cell differentiation in vitro, ii) microRNA targets can mediate the negative effect of TNF-α on fusion capacity of skeletal myoblasts by targeting genes associated with axon guidance, MAPK signalling, focal adhesion, and neurotrophin signalling pathway, iii) inhibition of miR-155 in combination with overexpression of miR-503 partially abrogates the inhibitory effect of TNF-α on myotube formation, and iv) MAPK/ERK inhibition might participate in modulating the effect of TNF-α and IGF1 on miRNA abundance.
  
  
  CONCLUSIONS
  The inhibitory effects of TNF-α or the growth promoting effects of IGF1 on skeletal muscle differentiation include the deregulation of known muscle-regulatory miRNAs as well as miRNAs which have not yet been associated with skeletal muscle differentiation or response to TNF-α or IGF1. This study indicates that miRNAs are mediators of the inhibitory effect of TNF-α on myoblast differentiation. We show that intervention at the miRNA level can ameliorate the negative effect of TNF-α by promoting myoblast differentiation. Moreover, we cautiously suggest that TNF-α or IGF1 modulate the miRNA biogenesis of some miRNAs via MAPK/ERK signalling. Finally, this study identifies indicative biomarkers of myoblast differentiation and cytokine influence and points to novel RNA targets.
authors: Physiology Weihenstephan, ZIEL Research Center for Nutrition and Food Sciences, Technische Universität München, Weihenstephaner Berg 3, D-85354, Freising, Germany. meyers@wzw.tum.de.
authors: Swanhild U
authors: SU
authors: Meyer
authors: SIRION Biotech GmbH, Am Klopferspitz 19, 82152, Martinsried, Germany. thirion@sirion-biotech.de.
authors: Christian
authors: C
authors: Thirion
authors: CNRS FRE 3377, Univ. Paris-Sud, CEA Saclay, iBiTec-S/ SBIGeM, F-91191, Gif-sur-Yvette, France. anna.polesskaya@cea.fr.
authors: Anna
authors: A
authors: Polesskaya
authors: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany. stefan.bauersachs@usys.ethz.ch.|Current address: ETH Zurich, Institute of Agricultural Sciences, Animal Physiology, Universitätstrasse 2 / LFW B 58.1, 8092, Zurich, Switzerland. stefan.bauersachs@usys.ethz.ch.
authors: Stefan
authors: S
authors: Bauersachs
authors: Department of Statistics, Ludwig-Maximilians-Universität München, Ludwigstr. 33, 80539, Munich, Germany. sebastian.kaiser@stat.uni-muenchen.de.
authors: Sebastian
authors: S
authors: Kaiser
authors: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-Universität München, Marchioninistr. 17, 81377, Munich, Germany. sabine.krause@med.uni-muenchen.de.
authors: Sabine
authors: S
authors: Krause
authors: Physiology Weihenstephan, ZIEL Research Center for Nutrition and Food Sciences, Technische Universität München, Weihenstephaner Berg 3, D-85354, Freising, Germany. michael.pfaffl@wzw.tum.de.
authors: Michael W
authors: MW
authors: Pfaffl
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C583557:IGF1 protein, human; C524942:MIRN155 microRNA, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I
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