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

Brearley-Sholto, Madelaine C.; Loczenski-Brown, David M.; Jones, Sarah; Daniel, Zoe C.T.R.; Ebling, Francis J.P.; Parr, Tim; Brameld, John M.

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.

Citation

Brearley-Sholto, M. C., Loczenski-Brown, D. M., Jones, S., Daniel, Z. C., Ebling, F. J., Parr, T., & Brameld, J. M. (2021). Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle. Scientific Reports, 11(1), 1-13. https://doi.org/10.1038/s41598-021-99432-4

• Journal Article Type: Article
• Acceptance Date: Sep 24, 2021
• Online Publication Date: Oct 5, 2021
• Publication Date: 2021-12
• Deposit Date: Sep 26, 2021
• Publicly Available Date: Oct 12, 2021
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 1
• Article Number: 19796
• Pages: 1-13
• DOI: https://doi.org/10.1038/s41598-021-99432-4
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/6342879
• Publisher URL: https://www.nature.com/articles/s41598-021-99432-4
• Additional Information: Received: 27 January 2021; Accepted: 24 September 2021; First Online: 5 October 2021; : The authors declare no competing interests.