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Effect of sodium 4-phenylbutyrate on clenbuterol-mediated muscle growth

Brown, David M.; Jones, Sarah; Daniel, Zoe C.T.R.; Brearley, Madelaine C.; Lewis, Jo E.; Ebling, Francis J.P.; Parr, Tim; Brameld, John M.

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Authors

David M. Brown

Sarah Jones

Zoe C.T.R. Daniel

Madelaine C. Brearley

Jo E. Lewis

Francis J.P. Ebling

TIM PARR TIM.PARR@NOTTINGHAM.AC.UK
Professor of Nutritional Biochemistry

Profile image of JOHN BRAMELD

JOHN BRAMELD JOHN.BRAMELD@NOTTINGHAM.AC.UK
Professor of Nutritional Biochemistry



Abstract

Previously, we highlighted induction of an integrated stress response (ISR) gene program in skeletal muscle of pigs treated with a beta-adrenergic agonist. Hence we tested the hypothesis that the ER-stress inhibitor, sodium 4-phenylbutyrate (PBA), would inhibit Clenbuterol-mediated muscle growth and reduce expression of genes that are known indicators of an ISR in mice. Clenbuterol (1mg/kg/day) administered to C57BL6/J mice for 21 days increased body weight (p<0.001), muscle weights (p<0.01), and muscle fibre diameters (p<0.05). Co-administration of PBA (100mg/kg/day) did not alter the Clenbuterol-mediated phenotype, nor did PBA alone have any effects compared to that of the vehicle treated mice. Clenbuterol increased skeletal muscle mRNA expression of phosphoserine amino transferase 1 (PSAT1, p<0.001) and cyclophillin A (p<0.01) at day 3, but not day 7. Clenbuterol decreased mRNA expression of activating transcription factor (ATF) 4 and ATF5 at day 3 (p<0.05) and day 7 (p<0.01), X-box binding protein 1 (XBP1) variant 2 mRNA at day 3 only (p<0.01) and DNA damage inducible transcript 3 (DDIT3/CHOP) mRNA at day 7 only (p<0.05). Co-administration of PBA had no effect on Clenbuterol-induced changes in skeletal muscle gene expression. In contrast, treatment of C2C12 myotubes with 5mM PBA (8hr) attenuated the thapsigargin-induced ISR gene program. Prolonged (24-48hr) treatment with PBA caused atrophy (p<0.01), reduced neoprotein synthesis (p<0.0001) and decreased expression of myogenin and fast myosin heavy chain genes (p<0.01), indicating an inhibition of myogenic differentiation. In summary, Clenbuterol did not induce an ISR gene program in mouse muscle. On the contrary, it reduced expression of a number of ISR genes, but it increased expression of PSAT1 mRNA. Co-administration of PBA had no effect on Clenbuterol-mediated muscle growth or gene expression in mice, whereas PBA did inhibit thapsigargin-induced ISR gene expression in cultured C2C12 cells and appeared to inhibit myogenic differentiation, independent of altering ISR gene expression.

Citation

Brown, D. M., Jones, S., Daniel, Z. C., Brearley, M. C., Lewis, J. E., Ebling, F. J., Parr, T., & Brameld, J. M. (2018). Effect of sodium 4-phenylbutyrate on clenbuterol-mediated muscle growth. PLoS ONE, 13(7), Article e0201481. https://doi.org/10.1371/journal.pone.0201481

Journal Article Type Article
Acceptance Date Jul 19, 2018
Publication Date Jul 27, 2018
Deposit Date Jul 25, 2018
Publicly Available Date Jul 27, 2018
Journal PLoS ONE
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 13
Issue 7
Article Number e0201481
DOI https://doi.org/10.1371/journal.pone.0201481
Keywords Integrated stress response, beta-adrenergic agonist, ER-stress, hypertrophy, atrophy, activating transcription factor
Public URL https://nottingham-repository.worktribe.com/output/947941
Publisher URL http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201481
Contract Date Jul 25, 2018

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