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Nucleic Acids Research Advance Access originally published online on December 15, 2007
Nucleic Acids Research 2008 36(3):826-838; doi:10.1093/nar/gkm1107
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Nucleic Acids Research, 2008, Vol. 36, No. 3 826-838
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Modulation of utrophin A mRNA stability in fast versus slow muscles via an AU-rich element and calcineurin signaling

Joe V. Chakkalakal1, Pedro Miura1, Guy Bélanger1, Robin N. Michel2 and Bernard J. Jasmin1,3,*

1Department of Cellular and Molecular Medicine and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5, 2Department of Chemistry and Biochemistry, Department of Exercise Science and Centre for Structural and Functional Genomics, Concordia University, The Richard J. Renaud Science Complex, Montreal, QC, Canada H4B 1R6 and 3Ottawa Health Research Institute, Molecular Medicine Program, Ottawa Hospital, General Campus, Ottawa, ON, Canada K1H 8L6

*To whom correspondence should be addressed. Tel: (613) 562 5800 ext: 8383. Fax: (613) 562 5636. Email: jasmin{at}uottawa.ca

Received October 29, 2007. Revised November 19, 2007. Accepted November 26, 2007.

We examined the role of post-transcriptional mechanisms in controlling utrophin A mRNA expression in slow versus fast skeletal muscles. First, we determined that the half-life of utrophin A mRNA is significantly shorter in the presence of proteins isolated from fast muscles. Direct plasmid injection experiments using reporter constructs containing the full-length or truncated variants of the utrophin 3'UTR into slow soleus and fast extensor digitorum longus muscles revealed that a region of 265 nucleotides is sufficient to confer lower levels of reporter mRNA in fast muscles. Further analysis of this region uncovered a conserved AU-rich element (ARE) that suppresses expression of reporter mRNAs in cultured muscle cells. Moreover, stability of reporter mRNAs fused to the utrophin full-length 3'UTR was lower in the presence of fast muscle protein extracts. This destabilization effect seen in vivo was lost upon deletion of the conserved ARE. Finally, we observed that calcineurin signaling affects utrophin A mRNA stability through the conserved ARE. These results indicate that ARE-mediated mRNA decay is a key mechanism that regulates expression of utrophin A mRNA in slow muscle fibers. This is the first demonstration of ARE-mediated mRNA decay regulating the expression of a gene associated with the slow myogenic program.

Present address: Joe V. Chakkalakal, Harvard University, Dept Molecular and Cellular Biology, Fairchild Bldg. Rm. 149, 7 Divinity Ave., Cambridge, MA 02138, USA


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