Notch Pathway Activation Contributes to Inhibition of C2C12 Myoblast Differentiation by Ethanol |
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| Authors: | Michelle A. Arya Albert K. Tai Eric C. Wooten Christopher D. Parkin Elena Kudryavtseva Gordon S. Huggins |
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| Affiliation: | 1. Molecular Cardiology Research Institute Center for Translational Genomics, Tufts Medical Center, Boston, Massachusetts, United States of America.; 2. Genetics Program, Tufts University Sackler School of Biomedical Science, Boston, Massachusetts, United States of America.; 3. Study Center on the Immunogenetics of Infectious Disease, Tufts University, Boston, Massachusetts, United States of America.; University of Minnesota Medical School, United States of America, |
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| 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. |
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