title: Increased IGF-IEc expression and mechano-growth factor production in intestinal muscle of fibrostenotic Crohn's disease and smooth muscle hypertrophy.
abstract: The igf1 gene is alternatively spliced as IGF-IEa and IGF-IEc variants in humans. In fibrostenotic Crohn's disease, the fibrogenic cytokine TGF-β1 induces IGF-IEa expression and IGF-I production in intestinal smooth muscle and results in muscle hyperplasia and collagen I production that contribute to stricture formation. Mechano-growth factor (MGF) derived from IGF-IEc induces skeletal and cardiac muscle hypertrophy following stress. We hypothesized that increased IGF-IEc expression and MGF production mediated smooth muscle hypertrophy also characteristic of fibrostenotic Crohn's disease. IGF-IEc transcripts and MGF protein were increased in muscle cells isolated from fibrostenotic intestine under regulation by endogenous TGF-β1. Erk5 and MEF2C were phosphorylated in vivo in fibrostenotic muscle; both were phosphorylated and colocalized to nucleus in response to synthetic MGF in vitro. Smooth muscle-specific protein expression of α-smooth muscle actin, γ-smooth muscle actin, and smoothelin was increased in affected intestine. Erk5 inhibition or MEF2C siRNA blocked smooth muscle-specific gene expression and hypertrophy induced by synthetic MGF. Conditioned media of cultured fibrostenotic muscle induced muscle hypertrophy that was inhibited by immunoneutralization of endogenous MGF or pro-IGF-IEc. The results indicate that TGF-β1-dependent IGF-IEc expression and MGF production in patients with fibrostenotic Crohn's disease regulates smooth muscle cell hypertrophy a critical factor that contributes to intestinal stricture formation.
authors.affiliation: Department of Medicine, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia; and.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Medicine, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia; and.
authors.forename: Kent
authors.initials: K
authors.lastname: Vu
authors.affiliation: Department of Medicine, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia; and.
authors.forename: Krystina
authors.initials: K
authors.lastname: Hazelgrove
authors.affiliation: Department of Medicine, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia; and Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia john.kuemmerle@vcuhealth.org.
authors.forename: John F
authors.identifier: http://orcid.org/0000-0003-0678-7038
authors.initials: JF
authors.lastname: Kuemmerle
mesh_terms: D021581:Active Transport, Cell Nucleus; D000328:Adult; D017398:Alternative Splicing; D019898:Autocrine Communication; D016022:Case-Control Studies; D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006801:Humans; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007415:Intestinal Obstruction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D008875:Middle Aged; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C583557:IGF1 protein, human; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C523997:mechano-growth factor E, human; D007334:Insulin-Like Growth Factor I; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7
keywords: extracellular-signal-regulated kinase (ERK); fibrosis; insulin-like growth factor (IGF); mechano growth factor; muscle hypertrophy