Novel TAZ modulators enhance myogenic differentiation and muscle regeneration

Gun Hwa Park, Hana Jeong, Mi Gyeong Jeong, Eun Jung Jang, Myung Ae Bae, Ye Lim Lee, Nak Jung Kim, Jeong-Ho Hong, Eun Sook Hwang

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4051-4061
Number of pages11
JournalBritish Journal of Pharmacology
Volume171
Issue number17
DOIs
Publication statusPublished - 2014 Jan 1

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Regeneration
Muscles
Wounds and Injuries
MyoD Protein
Cell Transdifferentiation
Myoblasts
Mesenchymal Stromal Cells
Muscle Cells
Cell Differentiation
Skeletal Muscle
Transcription Factors
Fibroblasts
Phosphorylation
Gene Expression
In Vitro Techniques

ASJC Scopus subject areas

  • Pharmacology

Cite this

Park, G. H., Jeong, H., Jeong, M. G., Jang, E. J., Bae, M. A., Lee, Y. L., ... Hwang, E. S. (2014). Novel TAZ modulators enhance myogenic differentiation and muscle regeneration. British Journal of Pharmacology, 171(17), 4051-4061. https://doi.org/10.1111/bph.12755

Novel TAZ modulators enhance myogenic differentiation and muscle regeneration. / Park, Gun Hwa; Jeong, Hana; Jeong, Mi Gyeong; Jang, Eun Jung; Bae, Myung Ae; Lee, Ye Lim; Kim, Nak Jung; Hong, Jeong-Ho; Hwang, Eun Sook.

In: British Journal of Pharmacology, Vol. 171, No. 17, 01.01.2014, p. 4051-4061.

Research output: Contribution to journalArticle

Park, GH, Jeong, H, Jeong, MG, Jang, EJ, Bae, MA, Lee, YL, Kim, NJ, Hong, J-H & Hwang, ES 2014, 'Novel TAZ modulators enhance myogenic differentiation and muscle regeneration', British Journal of Pharmacology, vol. 171, no. 17, pp. 4051-4061. https://doi.org/10.1111/bph.12755
Park, Gun Hwa ; Jeong, Hana ; Jeong, Mi Gyeong ; Jang, Eun Jung ; Bae, Myung Ae ; Lee, Ye Lim ; Kim, Nak Jung ; Hong, Jeong-Ho ; Hwang, Eun Sook. / Novel TAZ modulators enhance myogenic differentiation and muscle regeneration. In: British Journal of Pharmacology. 2014 ; Vol. 171, No. 17. pp. 4051-4061.
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AB - 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.

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KW - muscle regeneration

KW - MyoD

KW - myogenic differentiation

KW - TAZ modulators

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