title: Skeletal myosin light chain kinase regulates skeletal myogenesis by phosphorylation of MEF2C.
abstract: The MEF2 factors regulate transcription during cardiac and skeletal myogenesis. MEF2 factors establish skeletal muscle commitment by amplifying and synergizing with MyoD. While phosphorylation is known to regulate MEF2 function, lineage-specific regulation is unknown. Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis. A phosphorylation-deficient MEF2C mutant (MEFT80A) enhanced cardiac, but not skeletal myogenesis in P19 stem cells. Further, MEFT80A was deficient in recruitment of p300 to skeletal but not cardiac muscle promoters. In gain-of-function studies, skMLCK upregulated myogenic regulatory factor (MRF) expression, leading to enhanced skeletal myogenesis in P19 cells and more efficient myogenic conversion. In loss-of-function studies, MLCK was essential for efficient MRF expression and subsequent myogenesis in embryonic stem (ES) and P19 cells as well as for proper activation of quiescent satellite cells. Thus, skMLCK regulates MRF expression by controlling the MEF2C-dependent recruitment of histone acetyltransferases to skeletal muscle promoters. This work identifies the first kinase that regulates MyoD and Myf5 expression in ES or satellite cells.
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Ashraf Said
authors.initials: AS
authors.lastname: Al Madhoun
authors.forename: Virja
authors.initials: V
authors.lastname: Mehta
authors.forename: Grace
authors.initials: G
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Figeys
authors.forename: Nadine
authors.initials: N
authors.lastname: Wiper-Bergeron
authors.forename: Ilona S
authors.initials: IS
authors.lastname: Skerjanc
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018236:Carcinoma, Embryonal / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D026161:MADS Domain Proteins / Q000378:metabolism* / Q000502:physiology; D064326:MEF2 Transcription Factors; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000201:enzymology*; D018006:Myogenic Regulatory Factors / Q000378:metabolism* / Q000502:physiology; D009219:Myosin-Light-Chain Kinase / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D009928:Organ Specificity; D010766:Phosphorylation; D013912:Threonine / Q000378:metabolism
chemical_list: D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; D013912:Threonine; D009219:Myosin-Light-Chain Kinase