Nuclear receptor signaling plays an important role in energy metabolism. In this study we demonstrate that the nuclear receptor corepressor RIP140 is a key regulator of metabolism in skeletal muscle. RIP140 is expressed in a fiber type-specific manner, and manipulation of its levels in null, heterozygous, and transgenic mice demonstrate that low levels promote while increased expression suppresses the formation of oxidative fibers. Expression profiling reveals global changes in the expression of genes implicated in both myofiber phenotype and metabolic functions. Genes involved in fatty-acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis are upregulated in the absence of RIP140. Analysis of cultured myofibers demonstrates that the changes in expression are intrinsic to muscle cells and that nuclear receptor-regulated genes are direct targets for repression by RIP140. Therefore RIP140 is an important signaling factor in the regulation of skeletal muscle function and physiology.
Bibliographical noteFunding Information:
The authors wish to thank Jenny Morgan and Charlotte Collins for their help with the generation of the muscle cell lines, Caroline Small for assistance with the metabolic cage studies, Sameirah Macchiarulo for vector construction, and Nina Messner for DNA microinjection and transgenic mouse generation. We also wish to thank Tim Willson and William Zuercher (GSK) for providing nuclear receptor ligands and Joseph Hoh for the gift of the IIX-specific antibody. We also acknowledge the Clinical Sciences Centre/Imperial College Microarray Centre for technical assistance with the microarray data. This work was supported by grants from the Wellcome Trust (061930 to A.S., J.H.S., R.W., and M.P.) and the BBSRC (02/B1/S/08214 to D.N.) and by a Wellcome Trust Functional Genomics Initiative, the Biological Atlas of Insulin Resistance (BAIR).
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology