Effect of sodium 4-phenylbutyrate on Clenbuterol-mediated muscle growth.

Autor: Brown DM; School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom., Jones S; School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom., Daniel ZCTR; School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom., Brearley MC; School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom., Lewis JE; School of Life Sciences, University of Nottingham, Medical School, Nottingham, United Kingdom., Ebling FJP; School of Life Sciences, University of Nottingham, Medical School, Nottingham, United Kingdom., Parr T; School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom., Brameld JM; School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2018 Jul 27; Vol. 13 (7), pp. e0201481. Date of Electronic Publication: 2018 Jul 27 (Print Publication: 2018).
DOI: 10.1371/journal.pone.0201481
Abstrakt: 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.
Competing Interests: This research was funded by the BBSRC and Zoetis (formally Pfizer Animal Health). The funders were not involved in the study design, collection, analysis or interpretation of the data, nor in the writing of the paper. Zoetis approved the decision to submit for publication. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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