title: Notch pathway activation contributes to inhibition of C2C12 myoblast differentiation by ethanol.
abstract: The loss of muscle mass in alcoholic myopathy may reflect alcohol inhibition of myogenic cell differentiation into myotubes. Here, using a high content imaging system we show that ethanol inhibits C2C12 myoblast differentiation by reducing myogenic fusion, creating smaller and less complex myotubes compared with controls. Ethanol administration during C2C12 differentiation reduced MyoD and myogenin expression, and microarray analysis identified ethanol activation of the Notch signaling pathway target genes Hes1 and Hey1. A reporter plasmid regulated by the Hes1 proximal promoter was activated by alcohol treatment in C2C12 cells. Treatment of differentiating C2C12 cells with a gamma secretase inhibitor (GSI) abrogated induction of Hes1. On a morphological level GSI treatment completely rescued myogenic fusion defects and partially restored other myotube parameters in response to alcohol. We conclude that alcohol inhibits C2C12 myoblast differentiation and the inhibition of myogenic fusion is mediated by Notch pathway activation.
authors: Molecular Cardiology Research Institute Center for Translational Genomics, Tufts Medical Center, Boston, Massachusetts, United States of America ; Genetics Program, Tufts University Sackler School of Biomedical Science, Boston, Massachusetts, United States of America.
authors: Michelle A
authors: MA
authors: Arya
authors: Albert K
authors: AK
authors: Tai
authors: Eric C
authors: EC
authors: Wooten
authors: Christopher D
authors: CD
authors: Parkin
authors: Elena
authors: E
authors: Kudryavtseva
authors: Gordon S
authors: GS
authors: Huggins
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002459:Cell Fusion; D048430:Cell Shape / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D020869:Gene Expression Profiling; D057166:High-Throughput Screening Assays; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000431:Ethanol; D018398:Homeodomain Proteins; D017570:MyoD Protein; D018008:Myogenin; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse
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