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Novel TAZ modulators enhance myogenic differentiation and muscle regeneration

Title
Novel TAZ modulators enhance myogenic differentiation and muscle regeneration
Authors
Park G.H.Jeong H.Jeong M.-G.Jang E.J.Bae M.A.Lee Y.-L.Kim N.J.Hong J.-H.Hwang E.S.
Ewha Authors
황은숙
SCOPUS Author ID
황은숙scopus
Issue Date
2014
Journal Title
British Journal of Pharmacology
ISSN
0007-1188JCR Link
Citation
British Journal of Pharmacology vol. 171, no. 17, pp. 4051 - 4061
Keywords
muscle injurymuscle regenerationMyoDmyogenic differentiationTAZ modulators
Publisher
John Wiley and Sons Inc.
Indexed
SCI; SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
Background and Purpose 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. Experimental Approach 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. Key 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 and Implications 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. © 2014 The British Pharmacological Society.
DOI
10.1111/bph.12755
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약학대학 > 약학과 > Journal papers
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