Transcriptomic analysis identifies a role of PI3K-Akt signalling in the responses of skeletal muscle to acute hypoxia in vivo.

Autor: Gan Z; School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA., Powell FL; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Zambon AC; Department of Biopharmaceutical Sciences, Keck Graduate Institute, Claremont, CA, 91711, USA., Buchholz KS; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA., Fu Z; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Ocorr K; Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Bodmer R; Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Moya EA; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Stowe JC; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA., Haddad GG; Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA.; Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA.; Rady Children's Hospital San Diego, 3020 Children's Way, San Diego, CA, 92123, USA., McCulloch AD; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA.; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2017 Sep 01; Vol. 595 (17), pp. 5797-5813. Date of Electronic Publication: 2017 Jul 27.
DOI: 10.1113/JP274556
Abstrakt: Key Points: Changes in gene expression that occur within hours of exposure to hypoxia in in vivo skeletal muscles remain unexplored. Two hours of hypoxia caused significant down-regulation of extracellular matrix genes followed by a shift at 6 h to altered expression of genes associated with the nuclear lumen while respiratory and blood gases were stabilized. Enrichment analysis of mRNAs classified by stability rates suggests an attenuation of post-transcriptional regulation within hours of hypoxic exposure, where PI3K-Akt signalling was suggested to have a nodal role by pathway analysis. Experimental measurements and bioinformatic analyses suggested that the dephosphorylation of Akt after 2 h of hypoxic exposure might deactivate RNA-binding protein BRF1, hence resulting in the selective degradation of mRNAs.
Abstract: The effects of acute hypoxia have been widely studied, but there are few studies of transcriptional responses to hours of hypoxia in vivo, especially in hypoxia-tolerant tissues like skeletal muscles. We used RNA-seq to analyse gene expression in plantaris muscles while monitoring respiration, arterial blood gases, and blood glucose in mice exposed to 8% O 2 for 2 or 6 h. Rapid decreases in blood gases and a slower reduction in blood glucose suggest stress, which was accompanied by widespread changes in gene expression. Early down-regulation of genes associated with the extracellular matrix was followed by a shift to genes associated with the nuclear lumen. Most of the early down-regulated genes had mRNA half-lives longer than 2 h, suggesting a role for post-transcriptional regulation. These transcriptional changes were enriched in signalling pathways in which the PI3K-Akt signalling pathway was identified as a hub. Our analyses indicated that gene targets of PI3K-Akt but not HIF were enriched in early transcriptional responses to hypoxia. Among the PI3K-Akt targets, 75% could be explained by a deactivation of adenylate-uridylate-rich element (ARE)-binding protein BRF1, a target of PI3K-Akt. Consistent decreases in the phosphorylation of Akt and BRF1 were experimentally confirmed following 2 h of hypoxia. These results suggest that the PI3K-Akt signalling pathway might play a role in responses induced by acute hypoxia in skeletal muscles, partially through the dephosphorylation of ARE-binding protein BRF1.
(© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)
Databáze: MEDLINE
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