title: MAPK signaling pathways and HDAC3 activity are disrupted during differentiation of emerin-null myogenic progenitor cells.
abstract: Mutations in the gene encoding emerin cause Emery-Dreifuss muscular dystrophy (EDMD). Emerin is an integral inner nuclear membrane protein and a component of the nuclear lamina. EDMD is characterized by skeletal muscle wasting, cardiac conduction defects and tendon contractures. The failure to regenerate skeletal muscle is predicted to contribute to the skeletal muscle pathology of EDMD. We hypothesize that muscle regeneration defects are caused by impaired muscle stem cell differentiation. Myogenic progenitors derived from emerin-null mice were used to confirm their impaired differentiation and analyze selected myogenic molecular pathways. Emerin-null progenitors were delayed in their cell cycle exit, had decreased myosin heavy chain (MyHC) expression and formed fewer myotubes. Emerin binds to and activates histone deacetylase 3 (HDAC3). Here, we show that theophylline, an HDAC3-specific activator, improved myotube formation in emerin-null cells. Addition of the HDAC3-specific inhibitor RGFP966 blocked myotube formation and MyHC expression in wild-type and emerin-null myogenic progenitors, but did not affect cell cycle exit. Downregulation of emerin was previously shown to affect the p38 MAPK and ERK/MAPK pathways in C2C12 myoblast differentiation. Using a pure population of myogenic progenitors completely lacking emerin expression, we show that these pathways are also disrupted. ERK inhibition improved MyHC expression in emerin-null cells, but failed to rescue myotube formation or cell cycle exit. Inhibition of p38 MAPK prevented differentiation in both wild-type and emerin-null progenitors. These results show that each of these molecular pathways specifically regulates a particular stage of myogenic differentiation in an emerin-dependent manner. Thus, pharmacological targeting of multiple pathways acting at specific differentiation stages may be a better therapeutic approach in the future to rescue muscle regenerationin vivo.
authors.affiliation: University of the Sciences, Department of Pharmaceutical Sciences, 600 S. 43rd St, Philadelphia, PA 19104, USA.
authors.forename: Carol M
authors.initials: CM
authors.lastname: Collins
authors.affiliation: University of the Sciences, Department of Pharmaceutical Sciences, 600 S. 43rd St, Philadelphia, PA 19104, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ellis
authors.affiliation: University of the Sciences, Department of Pharmaceutical Sciences, 600 S. 43rd St, Philadelphia, PA 19104, USA j.holaska@usciences.edu.
authors.forename: James M
authors.identifier: 0000-0003-0273-9995
authors.initials: JM
authors.lastname: Holaska
mesh_terms: D000107:Acetylation; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D024510:Muscle Development / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology; D000099186:Histone Deacetylase 3
chemical_list: D002070:Butadienes; D005419:Flavonoids; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D007093:Imidazoles; D008565:Membrane Proteins; D018995:Myosin Heavy Chains; D009570:Nitriles; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013806:Theophylline; D000099186:Histone Deacetylase 3; C113580:U 0126; C092710:emerin; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Cell signaling; Emerin; Emery-Dreifuss muscular dystrophy; Lamin; Myogenic differentiation