Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle

Raichur, S., Fitzsimmons, R. L., Myers, S. A., Pearen, M. A., Lau, P., Eriksson, N., Wang, S. M. and Muscat, G. E. O. (2010) Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle. Nucleic Acids Research., 38 13: 4296-4312. doi:10.1093/nar/gkq180


Author Raichur, S.
Fitzsimmons, R. L.
Myers, S. A.
Pearen, M. A.
Lau, P.
Eriksson, N.
Wang, S. M.
Muscat, G. E. O.
Title Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle
Journal name Nucleic Acids Research.   Check publisher's open access policy
ISSN 0305-1048
1362-4962
Publication date 2010-07
Sub-type Article (original research)
DOI 10.1093/nar/gkq180
Open Access Status DOI
Volume 38
Issue 13
Start page 4296
End page 4312
Total pages 7
Place of publication Oxford, U.K.
Publisher Oxford University Press
Collection year 2011
Language eng
Formatted abstract
The retinoic acid receptor-related orphan receptor (ROR) alpha has been demonstrated to regulate lipid metabolism. We were interested in the RORα1 dependent physiological functions in skeletal muscle. This major mass organ accounts for ~40% of the total body mass and significant levels of lipid catabolism, glucose disposal and energy expenditure. We utilized the strategy of targeted muscle-specific expression of a truncated (dominant negative) RORα1ΔDE in transgenic mice to investigate RORα1 signaling in this tissue. Expression profiling and pathway analysis indicated that RORα influenced genes involved in: (i) lipid and carbohydrate metabolism, cardiovascular and metabolic disease; (ii) LXR nuclear receptor signaling and (iii) Akt and AMPK signaling. This analysis was validated by quantitative PCR analysis using TaqMan low-density arrays, coupled to statistical analysis (with Empirical Bayes and Benjamini- Hochberg). Moreover, westerns and metabolic profiling were utilized to validate the genes, proteins and pathways (lipogenic, Akt, AMPK and fatty acid oxidation) involved in the regulation of metabolism by RORα1. The identified genes and pathways were in concordance with the demonstration of hyperglycemia, glucose intolerance, attenuated insulin-stimulated phosphorylation of Akt and impaired glucose uptake in the transgenic heterozygous Tg-RORα1ΔDE animals. In conclusion, we propose that RORα1 is involved in regulating the Akt2-AMPK signaling pathways in the context of lipid homeostasis in skeletal muscle.
© The Author(s) 2010. Published by Oxford University Press.
Keyword Activated Protein-kinase
Amino terminal domains
Gene expression
Insulin resistance
Transcriptional resistance
Glucose transport
Transgenic mice
Target gene
Actin gene
Ampk
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Sun, 22 Aug 2010, 00:04:41 EST