title: MIBG, an inhibitor of arginine-dependent mono(ADP-ribosyl)ation, prevents differentiation of L6 skeletal myoblasts by inhibiting expression of myogenin and p21(cip1).
abstract: The development of skeletal muscle is controlled by a highly synchronized series of cellular events, and various signals from both inside and outside the cell play a role in the switch from multipotential mesodermal stem cells to muscle fibers. Meta-iodobenzylguanidine (MIBG), an inhibitor of mono(ADP-ribosyl)ation, has been shown to prevent terminal differentiation of skeletal myoblasts; however, its mechanism of action has not been established. We recently reported that MIBG is capable of preventing phenotypic modulation of smooth muscle cells by interfering with specific trans-acting factors [L. Yau, B. Litchie, S. Thomas, B. Storie, N. Yurkova, P. Zahradka, Endogenous mono-ADP-ribosylation mediates smooth muscle cell proliferation and migration via protein kinase N-dependent induction of c-fos expression. Eur. J. Biochem. 270 (2003) 101-110.]. We therefore examined the effect of MIBG on select myogenic regulatory factors known to control terminal differentiation. It was confirmed that MIBG, but not inhibitors of poly-ADP-ribose polymerase (3-aminobenzamide, PD128763), inhibits fusion of L6 skeletal myoblasts in a concentration-dependent manner. Moreover, inhibition by MIBG correlated with a failure to induce expression of myogenin and p21(cip1), while levels of MyoD and MEF2 were unaffected. Time-of-addition studies revealed that MIBG also affected a late event possibly linked to cell fusion. Finally, arginine-dependent mono(ADP-ribosyl)transferase activity increased over the first 24 h of the differentiation period. These data support a role for arginine-dependent mono(ADP-ribosyl)transferase as an essential positive regulator of differentiation in skeletal muscle cells that operates by modulating the expression of specific myogenic factors.
authors.affiliation: Department of Physiology, University of Manitoba, Canada R3E 3J7.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Yau
authors.forename: Brenda
authors.initials: B
authors.lastname: Litchie
authors.forename: Peter
authors.initials: P
authors.lastname: Zahradka
mesh_terms: D019797:3-Iodobenzylguanidine / Q000494:pharmacology*; D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002459:Cell Fusion; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051379:Mice; D024510:Muscle Development / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology; D032446:Myoblasts / Q000166:cytology*; D018008:Myogenin / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C503801:Myog protein, mouse; D018008:Myogenin; D019797:3-Iodobenzylguanidine; D036002:ADP Ribose Transferases