Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle

Abstract We previously reported that growth promoter-induced skeletal muscle hypertrophy co-ordinately upregulated expression of genes associated with an integrated stress response (ISR), as well as potential ISR regulators. We therefore used Adeno-Associated Virus (AAV)-mediated overexpression of t...

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Autores principales:	Madelaine C. Brearley-Sholto, David M. Loczenski-Brown, Sarah Jones, Zoe C. T. R. Daniel, Francis J. P. Ebling, Tim Parr, John M. Brameld
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/eba2dd6150b34a2499ec3b93f21df763
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spelling	oai:doaj.org-article:eba2dd6150b34a2499ec3b93f21df7632021-12-02T19:16:18ZEffect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle10.1038/s41598-021-99432-42045-2322https://doaj.org/article/eba2dd6150b34a2499ec3b93f21df7632021-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-99432-4https://doaj.org/toc/2045-2322Abstract We previously reported that growth promoter-induced skeletal muscle hypertrophy co-ordinately upregulated expression of genes associated with an integrated stress response (ISR), as well as potential ISR regulators. We therefore used Adeno-Associated Virus (AAV)-mediated overexpression of these genes, individually or in combination, in mouse skeletal muscle to test whether they induced muscle hypertrophy. AAV of each target gene was injected into mouse Tibialis anterior (TA) and effects on skeletal muscle growth determined 28 days later. Individually, AAV constructs for Arginase-2 (Arg2) and Activating transcription factor-5 (Atf5) reduced hindlimb muscle weights and upregulated expression of genes associated with an ISR. AAV-Atf5 also decreased Myosin heavy chain (MyHC)-IIB mRNA, but increased MyHC-IIA and isocitrate dehydrogenase-2 (Idh2) mRNA, suggesting ATF5 is a novel transcriptional regulator of Idh2. AAV-Atf5 reduced the size of both TA oxidative and glycolytic fibres, without affecting fibre-type proportions, whereas Atf5 combined with Cebpg (CCAAT enhancer binding protein-gamma) only reduced the size of glycolytic fibres and tended to increase the proportion of oxidative fibres. It is likely that persistent Atf5 overexpression maintains activation of the ISR, thereby reducing protein synthesis and/or increasing protein degradation and possibly apoptosis, resulting in inhibition of muscle growth, with overexpression of Arg2 having a similar effect.Madelaine C. Brearley-SholtoDavid M. Loczenski-BrownSarah JonesZoe C. T. R. DanielFrancis J. P. EblingTim ParrJohn M. BrameldNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Madelaine C. Brearley-Sholto David M. Loczenski-Brown Sarah Jones Zoe C. T. R. Daniel Francis J. P. Ebling Tim Parr John M. Brameld Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle
description	Abstract We previously reported that growth promoter-induced skeletal muscle hypertrophy co-ordinately upregulated expression of genes associated with an integrated stress response (ISR), as well as potential ISR regulators. We therefore used Adeno-Associated Virus (AAV)-mediated overexpression of these genes, individually or in combination, in mouse skeletal muscle to test whether they induced muscle hypertrophy. AAV of each target gene was injected into mouse Tibialis anterior (TA) and effects on skeletal muscle growth determined 28 days later. Individually, AAV constructs for Arginase-2 (Arg2) and Activating transcription factor-5 (Atf5) reduced hindlimb muscle weights and upregulated expression of genes associated with an ISR. AAV-Atf5 also decreased Myosin heavy chain (MyHC)-IIB mRNA, but increased MyHC-IIA and isocitrate dehydrogenase-2 (Idh2) mRNA, suggesting ATF5 is a novel transcriptional regulator of Idh2. AAV-Atf5 reduced the size of both TA oxidative and glycolytic fibres, without affecting fibre-type proportions, whereas Atf5 combined with Cebpg (CCAAT enhancer binding protein-gamma) only reduced the size of glycolytic fibres and tended to increase the proportion of oxidative fibres. It is likely that persistent Atf5 overexpression maintains activation of the ISR, thereby reducing protein synthesis and/or increasing protein degradation and possibly apoptosis, resulting in inhibition of muscle growth, with overexpression of Arg2 having a similar effect.
format	article
author	Madelaine C. Brearley-Sholto David M. Loczenski-Brown Sarah Jones Zoe C. T. R. Daniel Francis J. P. Ebling Tim Parr John M. Brameld
author_facet	Madelaine C. Brearley-Sholto David M. Loczenski-Brown Sarah Jones Zoe C. T. R. Daniel Francis J. P. Ebling Tim Parr John M. Brameld
author_sort	Madelaine C. Brearley-Sholto
title	Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle
title_short	Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle
title_full	Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle
title_fullStr	Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle
title_full_unstemmed	Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle
title_sort	effect of aav-mediated overexpression of atf5 and downstream targets of an integrated stress response in murine skeletal muscle
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/eba2dd6150b34a2499ec3b93f21df763
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Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle

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