title: Novel TAZ modulators enhance myogenic differentiation and muscle regeneration.
abstract: OBJECTIVE
  The transcriptional co-activator with PDZ-binding motif (TAZ) is a key controller of mesenchymal stem cell differentiation through its nuclear localization and subsequent interaction with master transcription factors. In particular, TAZ directly associates with myoblast determining protein D (MyoD) and activates MyoD-induced myogenic gene expression, thereby enhancing myogenic differentiation. Here, we have synthesized and characterized low MW compounds modulating myogenic differentiation via induction of TAZ nuclear localization.
  
  
  METHODS
  COS7 cells stably transfected with GFP-TAZ were used in a high content imaging screen for compounds specifically enhancing nuclear localization of TAZ. We then studied the effects of such TAZ modulators on myocyte differentiation of C2C12 cells and myogenic transdifferentiation of mouse embryonic fibroblast cells in vitro and muscle regeneration in vivo.
  
  
  RESULTS
  We identified two TAZ modulators, TM-53, and its structural isomer, TM-54. Each compound strongly enhanced nuclear localization of TAZ by reducing S89-phosphorylation and dose-dependently augmented myogenic differentiation and MyoD-mediated myogenic transdifferentiation through an activation of MyoD-TAZ interaction. The myogenic stimulatory effects of TM-53 and TM-54 were impaired in the absence of TAZ, but retrieved by the restoration of TAZ. In addition, administration of TM-53 and TM-54 enhanced injury-induced muscle regeneration in vivo and attenuated myofiber injury in vitro.
  
  
  CONCLUSIONS
  The novel TAZ modulators TM-53 and TM-54 accelerated myogenic differentiation and improved muscle regeneration and function after injury, demonstrating that low MW compounds targeting the nuclear localization of TAZ have beneficial effects in skeletal muscle regeneration and in recovery from muscle degenerative diseases.
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top5 Research Program, Ewha Womans University, Seoul, Korea.
authors.forename: Gun Hwa
authors.initials: GH
authors.lastname: Park
authors.forename: Hana
authors.initials: H
authors.lastname: Jeong
authors.forename: Mi-Gyeong
authors.initials: MG
authors.lastname: Jeong
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Jang
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
authors.forename: Ye-Lim
authors.initials: YL
authors.lastname: Lee
authors.forename: Nak Jung
authors.initials: NJ
authors.lastname: Kim
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Hong
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Hwang
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000597213:2-butyl-5-styryl-1-(2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl)-1H-benzoimidazole-6-carboxylic acid methyl ester; C000597212:2-butyl-6-styryl-1-(2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester; D001562:Benzimidazoles; D018008:Myogenin; D013777:Tetrazoles
keywords: MyoD; TAZ modulators; muscle injury; muscle regeneration; myogenic differentiation